EP2755986A1

EP2755986A1 - Engineered nucleic acids and methods of use thereof

Info

Publication number: EP2755986A1
Application number: EP12831509.0A
Authority: EP
Inventors: Stephane Bancel; Jason P. SCHRUM; Alexander Aristarkhov
Original assignee: Moderna Therapeutics Inc
Current assignee: Moderna Inc
Priority date: 2011-09-12
Filing date: 2012-09-11
Publication date: 2014-07-23
Also published as: WO2013039857A1; EP2755986A4

Abstract

Provided are compositions and methods for delivering biological moieties such as modified nucleic acids into cells to kill or reduce the growth of microorganisms. Such compositions and methods include the use of modified messenger RNAs, and are useful to treat or prevent microbial infection, or to improve a subject's heath or wellbeing.

Description

GINEERED NUCLEIC ACIDS AND METHODS OF USE THEREOF

REFERENCE TO THE SEQUENCE LISTING

[0001] The present application is being filed along with a Sequence Listing in electronic format. The Sequence Listing is provided as a file entitled M006SEQLST.txt created on

September 11, 2012 which is 1,385,538 bytes in size. The information in electronic format of the sequence listing is incorporated herein by reference in its entirety.

REFERENCE TO LENGTHY TABLE

f 00021 The specification includes a lengthy Table 1. Lengthy Table 1 has been submitted via EFS-Web in electronic format as follows: File name: M006TBL.pdf, Date created: September 11, 2012; File size: 693,875 Bytes and is incorporated herein by reference in its entirety. Please refer to the end of the specifi cation for access instructions,

CROSS REFERENCE TO RELATED APPLICATIONS

[0003] This applicatio claims priority to US Provisional Application No. 61/533,537, filed September 12, 2011, entitled Engineered Nucleic Acids and Methods of Use Thereof, the contents of which is incorporated by reference in its entirety.

BACKGROUND OF THE INVENTION

[0004] Naturally occurring NAs are synthesized from four basic ribonucleotides: ATP, CTP, UTP and GTP, but may contain post-transcriptionally modified nucleotides. Further, over one hundred natural nucleotide modifications have been identified in all RNA species (Rozensks, J, Grain, P, and McCloskey, J. (1999). The RNA Modification Database: 1999 update. Nucl Acids Res 27: 196-197). Nucleotides are modified in RNA to alter functional, structural, or catalytic roles of the parent RNA molecule. More recently, nucleotide modifications have been described to play a role in differentiating host cell RNA species from invading pathogenic RNA species. However, the precise mechanism by which nucleotide modifications alter the host immune response machinery and subsequently affect the translation efficiency of mRNA is unclear.

[0005] There is a need in the art for biological modalities to address the modulation of intracellul ar translation of nucleic acids.

[0ΘΘ6] Unless explained otherwise, all technical and scientific terms used herein have the same meaning as commonly un derstood to one of ordinary skill in the art to which this disclosure belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described herein. The materials, methods, and examples are illustrative only and not intended to be limiting, Other features of the disclosure are apparent from the following detailed description and the claims.

SUMMARY OF THE INVENTION

[0007] Provided herein are modified nucleic acids encoding anti-microbial polypeptides (AMPs) (e.g., anti-bacterial polypeptides), e.g., anti-microbial polypeptides described herein, precursors thereof, or partially or fully processed forms of these precursors. In certain embodiments, the anti-microbial polypeptide is an anti-bacterial polypeptide. In certain embodiments, the anti-microbial polypeptide is an anti -fungal polypeptide. In certain embodiments, the anti-microbial polypeptide is an anti-viral polypeptide. In certain

embodiments, the anti-microbial polypeptide is an anti-protozoa! polypeptide. In certain embodiments, the anti-microbial polypeptide is an anti-tumor/cancer polypeptide. In certain embodiment, the anti-microbial polypeptide is an anti-parasitic polypeptide. In certain embodiment, the anti-microbial polypeptide is an anti-prion polypeptide. In certain

embodiments, the anti-microbial polypeptide has one or more of anti-bacterial, anti-fungal, antiviral, anti-protozoal, anti -tumor/cancer, anti-parasitic, or anti-prion activity, In certain embodiments, the modified nucleic acid comprises mRNA. In particular embodiments, the modified mRNA (mmRNA) is derived from cDNA. In certain embodiments, the mmRNA comprises at least two nucleoside modifications. In certain embodiments, these nucleoside modifications are 5-methyicytosine and pseudouridine.

[0008] Provided herein are isolated nucleic acids (e.g., modified mRNAs encoding an antimicrobial polypeptide described herein) comprising a translatable region and at least two different nucleoside modifications, wherein the nucleic acid exhibits reduced degradation in a cell into which the nucleic acid is introduced, relative to a corresponding unmodified nucleic acid. For example, the degradation rate of the nucleic acid is reduced by at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or 90%, compared to the degradation rate of the

corresponding unmodified nucleic acid. In certain embodiments, the nucleic acid comprises RNA, DNA, TNA, GNA, or a hybrid thereof. In certain embodiments, the nucleic acid comprises messenger RNA (mRNA), In certain embodiments, the mRNA does not substantially induce an innate immune response of the cell, into which the mRNA. is introduced. In. certain embodiments, the mRNA comprises at least one nucleoside selected from the group consisting of pyridin-4-one ribonucleoside, 5-aza-uridme, 2-thio-5-aza-uridine, 2-thiouridine, 4-thio- pseudourid ie, 2-thio-pseudouridine, 5-hydroxyuridine, 3-meihyluridine, 5-carboxymethyl- uridine, l-carboxyniethyl-pseudouridiiie, 5-propynyl-uridine, l-propynyl-pseudouridine, 5- taurinomethyluridme, 1 -taurinomethyi-pseudouridine, 5-taurinomethyl-2-thio-uridine, 1- tauriiiomethyl-4-thio-uridine, 5-methyl-uridine, 1-niethyl-pseudouridine, 4-thio-l-methyl- pseudouridme, 2-thi.o- 1 -metbyl-pseudouridme, 1 -methyl - 1 -deaza-pseudouridine, 2-thio- 1 - methyl- 1-deaza-pseudouriditie, dihydrouridine, dihydropseiidouridine, 2-thio-dihydrouridine, 2- thio-dihydropseudouridine, 2-methoxyuridine, 2-methoxy-4-thio-uridine, 4-methoxy- pseudouridine, and 4-methoxy-2-thio-pseudouridine. In certain embodiments, the mRNA comprises at least one nucleoside selected from the group consisting of 5-aza-cytidine, pseudoisocytidine, 3-methyl-cytidine, N4-acetylcytidin.e, 5-formylcytidine, ^'N4-methylcytidine,

5- hydroxymethylcytidine, 1 -methyl-pseudoisocytidine, pyrrolo-cytidine, pyrrolo- pseudoisocytidine, 2-thio-cytidine, 2-thio-5-methyl-cytidine, 4-thio-pseudoisocyti.dine, 4-th.io-l- methyl-pseudoisocytidine, 4-thio- 1 -methyl- 1 -deaza-pse doisocytidine, 1 -methyl- 1 -deaza- pseudoisocytidine, zebularine, 5-aza-zebuiarine, 5-methyl-zebularine, 5-aza-2-thio-zebularine, 2- thio-zebularine, 2-niethoxy-cytidine, 2-methoxy-5-methyi-cytidine, 4-methoxy- pseudoisocytidine, and 4-methoxy-l -methyl-pseudoisocytidine. In other embodiments, the mRNA comprises at least one nucleoside selected from the group consisting of 2-aminopurine, 2,

6- diaminopurine, 7-deaza-adenine, 7-deaza-S-aza-ademiie, 7-deaza-2-amiiiopurine, 7-deaza-8- aza-2-aminopurine, 7-deaza-2,6-diaminopurine, 7-deaza-8-aza-2, 6-diaminopurine, 1 - methyladenosine, N6-methyladenosine, N6-isopentenyladenosine, N6-(cis- hydroxyisopentenyl)adenosine, 2-melbylihio-N6-(cis-hydroxyisopentenyl) adenosine, N6- glycinylcarbamoyladenosine, N6-threonylcarbamoyladenosine, 2-methyIthio-N6-threonyl carbamoyladenosine, N6,N6-dimethyiadenosme, 7-methyl adenine, 2-methylthio-adenine, and 2- methoxy-adenine. In yet other embodiments, the mRN A comprises at least one nucleoside selected from the group consisting of inosine, 1-methyl-inosine, wyosine, wybutosine, 7-deaza- guanosine, 7-deaza-8-aza-guanosine, 6-thio-guanosine, 6~thio~7~deaza-guanosine, 6-thio-7- deaza-8-aza-guanosine. 7-methyl-guanosine, 6-thio-7-methyI-guanosine, 7-methyIinosine, 6- methoxy-guanosine, 1 -methylguanosine, N2-methylguanosine, N2,N2-dimethyiguanosine, 8- oxo-guanosine, 7-methyl-8-oxo-guanosine, l-methyl-6-thio-guanosme, N2~n:iethyl~6-thio- guanosine, and 2,N2-dimeihyl-6-thio-guanosine.

[0ΘΘ9] In some embodiments, the nucleic acids provided herein comprise a 5 ' untranslated region (UTR) and/or a 3'UTR, wherein each of the two different nucleoside modifications are independently present in the 5 'UTR and/or 3'UTR, In some embodiments, nucleic acids are provided herein, wherein at least one of the two different nucleoside modifications are present in the translatable region. In some embodiments, nucleic acids provided herein are capable of binding to at least one polypeptide that prevents or reduces an innate immune response of a cell into which the nucleic acid is introduced.

[0010] Further provided herein are isolated nucleic acids (e.g., modified mRNAs described herein) comprising (i) a translatable region encoding an anti-microbial polypeptide (e.g., an antibacterial polypeptide), e.g., an anti-microbial polypeptide described herein, (ii) at least one nucleoside modification, and (iii) at least one intronic nucleotide sequence capable of being excised from the nucleic acid.

[0011] Further provided herein are isolated nucleic acids (e.g., modified mRNAs described herein) comprising (i) a translatable region encoding an anti-microbial polypeptide (e.g., an antibacterial polypeptide), e.g., an anti-microbial polypeptide described herein, (ii) at least two different nucleoside modifications, and (iii) a degradation domain.

[0012] Further provided herein are isolated nucleic acids (e.g., modified mRNAs described herein) comprising (i) a translatable region encoding an anti-microbial polypeptide (e.g., an antibacterial polypeptide), e.g., an anti-microbial polypeptide described herein, and (ii) at least two different nucleoside modifications, wherein the translatable region encodes a polypeptide variant having an altered activity relative to a reference polypeptide. In certain embodiments, isolated mRNAs are provided, wherein the altered activity comprises an increased activity or wherein the altered activity comprises a decreased activity,

[0013] Further provided herein are non-enzyrnatically synthesized nucleic acids (e.g., modified mRNAs described herein) comprising at least one nucleoside modification, and comprising a translatable region encoding an anti-microbial polypeptide (e.g., an anti-bacterial polypeptide), e.g., an anti-microbial polypeptide described herein. In certain embodiments, the non-enzymaticaily synthesized mRNA comprises at least two different nucleoside modifications, [0014] Further provided herein are isolated nucleic acids (e.g., modified mRNAs described herein) comprising a noncoding region and at least one nucleoside modification that reduces an innate immune response of a ceil into which the nucleic acid is introduced, wherein the nucleic acid sequesters one or more translational machinery components, In certain embodiments, the isolated nucleic acids comprising a noncoding region and at least one nucleoside modification described herein are provided in an amount effective to reduce protein expression in the cell. In certain embodiments, the translational machinery component is a ribosomal protein or a transfer R A (tRNA). In certain embodiments, the nucleic acid comprises a small nucleolar RNA (sno- RNA), microRNA (miRNA), small interfering RNA (siRNA) or Piwi-interaciing RNA (piRNA), [0015] Further provided herein are isolated nucleic acids (e.g., modified mRNAs described herein) comprising (i) a first translatable region, (ii) at least one nucleoside modification, and (iii) an mternal ribosome entry site (HIES). In certain embodiments, the IRES is obtained from a picomavirus, a pest virus, a polio virus, an encephalomyocarditis virus, a foot-and-mouth disease virus, a hepatitis C vims, a classical swine fever virus, a murine leukemia virus, a simian immune deficiency virus or a cricket paralysis vims. In certain embodiments, the isolated nucleic acid further comprises a second translatable region, In certain embodiments, the isolated nucleic acid further comprises a Kozak sequence, in some embodiments, the first translatable region encodes an anti-microbial polypeptide (e.g., an anti-bacterial polypeptide), e.g., an antimicrobial polypeptide described herein, In some embodiments, the second translatable region encodes an anti-microbial polypeptide (e.g., an anti-bacterial polypeptide), e.g. , an anti-microbial polypeptide described herein. In some embodiments, the first and the second translatable regions encode anti-microbial polypeptides (e.g., an anti-bacterial polypeptides), e.g., anti-microbial polypeptides described herein.

[0016] Further, provided herein are compositions (e.g., pharmaceutical compositions) comprising the modified nucleic acids described herein. In certain embodiments, the

composition further comprises a pharmaceutically acceptable carrier, In certain embodiments, the composition is formulated for systemic or local administration, In certain embodiments, the composition is formulated for intravenous administration, in certain embodiments, the composition is formulated for oral administration. In certain embodiments, the composition is formulated for topical administration. In certain embodiments, the composition is formulated for administration via a dressing (e.g. , wound dressing), In certain embodiments, the composition is formulated for administration via a bandage (e.g., adhesive bandage). In certain embodiments, the composition is formulated for administration by inhalation, In certam embodiments, the composition is formulated for rectal administration. In certain embodiments, the composition is formulated for vaginal administra tion, in certain embodiments, the composition comprises naked modified nucleic acids. In other embodiments, the modified nucleic acid is complexed or encapsulated. In another embodiment, the administration of the composition described herein may be administered at least once.

[0017] Provided herein are pharmaceutical compositions comprising: (i) an effective amount of a synthetic messenger ribonucleic acid (mRN A) encoding an anti-microbial polypeptide (e.g. , an anti-bacterial polypeptide), e.g., an anti-microbial polypeptide described herein; and (ii) a pharmaceutically acceptable carrier, wherein i) the mRNA comprises pseudouridine, 5 'methyl- cytidine, or a combination thereof or ii) the mRNA does not comprise a substantial amount of a nucleotide or nucleotides selected from the group consisting of uridine, cytidine, and a combination of uridine and cytidine, and wherein the composition is suitable for repeated administration (e.g., intravenous administration) to a mammalian subject in need thereof, in some embodiments, the anti-microbial polypeptide (e.g., anti-bacterial polypeptide) is under !OkDa, e.g., under 8kDa, 6kDa, 4kDa, 2kDa, or lkDa. In some embodiments, the anti-microbial polypeptide (e.g., anti-bacterial polypeptide) comprises or consists of from about 6 to about 100 amino acids, e.g., from about 6 to about 75 amino acids, about 6 to about 50 amino acids, about 6 to about 25 amino acids, about 25 to about 100 amino acids, about 50 to about 100 amino acids, or about 75 to about 300 amino acids. In certain embodiments, the anti-microbial polypeptide (e.g., anti-bacterial polypeptide) comprises or consists of from about 15 to about 45 amino acids. In some embodiments, the anti-microbial polypeptide (e.g., anti-bacterial polypeptide) is substantially cationic. In some embodiments, the anti-microbial polypeptide (e.g., anti-bacterial polypeptide) is substantially amphipathic. In certain embodiments, the anti-microbial polypeptide (e.g., anti-bacterial polypeptide) is substantially cationic and amphipathic. In some embodiments, the anti-microbial polypeptide (e.g., anti-bacterial polypeptide) is cytostatic to a Gram-positive bacterium. In some embodiments, the anti-microbial polypeptide (e.g., antibacterial polypeptide) is cytotoxic to a Gram-positive bacterium. In some embodiments, the anti-microbial polypeptide (e.g., anti -bacterial polypeptide) is cytostatic and cytotoxic to a Gram- positive bacterium. In some embodiments, the anti-microbial polypeptide (e.g. , anti-bacterial polypeptide) is cytostatic to a Gram-negative bacterium, in some embodiments, the antimicrobial polypeptide (e.g., anti-bacteria] polypeptide) is cytotoxic to a Gram-negative bacterium. In some embodiments, the anti-microbial polypeptide (e.g., anti-bacterial polypeptide) is cytostatic and cytotoxic to a Gram-negative bacterium. In some embodiments, the anti-microbial polypeptide is cytostatic to a virus, fungus, protozoan, parasite, prion, or a combination thereof. In some embodiments, the anti-microbial polypeptide is cytotoxic to a virus, fungus, protozoan, parasite, prion, or a combination thereof. In certain embodiments, the anti-microbial polypeptide is cytostatic and cytotoxic to a virus, fungus, protozoan, parasite, prion, or a combination thereof. In some embodiments, the anti-microbial polypeptide is cytotoxic to a tumor or cancer cell (e.g., human tumor or cancer cell). In some embodiments, the anti-microbial polypeptide is cytostatic to a tumor or cancer cell (e.g., human tumor or cancer cell). In certain embodiments, the anti-microbial polypeptide is cytotoxic and cytostatic to a tumor or cancer cell (e.g., human tumor or cancer cell). In some embodiments, the antimicrobial polypeptide (e.g., anti-bacterial polypeptide) is a secreted polypeptide. In certain embodiments, the anti-microbial polypeptide (e.g., anti-bacterial polypeptide) is selected from the group consisting of anti-microbial polypeptides (e.g., anti-bacterial polypeptides) and/or SEQ ID NOs: 1-2915. In certain embodiments, the anti-microbial polypeptide (e.g., anti-bacterial polypeptide) comprises or consists of hBD-2 (SEQ ID NO: 191 or 192), ί I -37 (SEQ ID NO: 6), or RNase-7 (SEQ ID NO: 262), In some embodiments, the composition (e.g., pharmaceutical composition) provided herein further comprises a lipid-based transfection reagent. In some embodiments, the synthetic messenger ribonucleic acid (mRNA) encoding an anti-microbial polypeptide (e.g., an anti-bacterial polypeptide), e.g., an anti-microbial polypeptide described herein, lacks at least one destabilizing element.

[0018] Further provided herein are pharmaceutical compositions comprising and/or consisting essentially of: (i) an effective amount of a synthetic messenger ribonucleic acid (mRNA) encoding an anti-microbial polypeptide (e.g., an anti-bacterial polypeptide), e.g., an anti-microbial polypeptide described herein; (ii) a cell penetration agent; and (in) a

pharmaceutically acceptable carrier, wherein i) the mRNA comprises pseudouridine, 5 'methyl- cytidine or a combination thereof, or ii) the mRNA does not comprise a substantial amount of a. nucleotide or nucleotides selected from the group consisting of uridine, cytidine, and a combination of uridine and cytidine, and wherein the composition is suitable for repeated administration (e.g., intravenous administration) to an animal (e.g., mammalian) subject in need thereof,

f 0019 [ Provided herein are methods of treating a subject hav ing and/or being suspected of having a microbial infection (e.g., a acterial infection) and/or a disease, disorder, or condition, e.g., a disease, disorder, or condition associated with a microbial infection (e.g., a bacterial infection), the methods comprising administering to a subject in need of such treatment a composition described herein in an amount sufficient to treat the microbial infection arid/or the disease, disorder, or condition. In specific embodiments, the disease, disorder, or condition is associated with one or more cellular and/or molecular changes affecting, for example, the level, activity, and/or localization of an anti-microbiai polypeptide (e.g., an anti-bacterial polypeptide), e.g., an anti-microbiai polypeptide described herein, precursors thereof, or a partially or fully processed form of these precursors. In certain embodiments, the method of treating a subject having or being suspected of having a microbial infection (e.g., a bacterial infection) and/or a disease, disorder, or condition, e.g., a disease, disorder, or condition associated with a microbial infection (e.g., a bacterial infection), comprises administering to the subject in need of such treatment a composition comprising a modified nucleic acid described herein in an amount sufficient to kill or reduce the growth of microorganisms (e.g., bacteria, fungi, viruses,

protozoan, parasites, prions, or a combination thereof), to kill or reduce the growth of tumor/cancer ceils, and'or to modulate one or more activities associated with, therefore to treat the microbial infection and/or the disease, disorder, or condition in the subject.

10020 | Further provided herein are methods of treating and/or preventing a microbial infection (e.g., a bacterial infection) of a target animal ceil (e.g., mammalian cell), comprising the step of contacting the target animal cell (e.g., mammalian cell) with a composition comprising a synthetic messenger ribonucleic acid (mRNA) encoding an anti-microbiai polypeptide (e.g., an anti-bacterial polypeptide) in an amount effective to be cytostatic and/or cytotoxic to one or more microorganisms (e.g., bacteria) infecting the target animal ceil (e.g., mammalian cell), In some embodiments, the composition is effective to be cytostatic and/or cytotoxic to one or more microorganisms (e.g., bacteria) adjacent to the target animal cell (e.g., mammalian cell). In some embodiments, the target animal cell (e.g., mammalian cell) is present in an animal subject (e.g., a mammalian subject). In certain embodiments, the subject is a human. In certain embodiments, the subject is a livestock animal. In some embodiments, the composition is administered to the subject by an intravenous route, in certain embodiments, the composition is administered to the subject orally. In certain embodiments, the composition is administered to the subject topically. In certain embodiments, the composition is administered to the subject by inhalation, In certain embodiments, the composition is administered to the subject rectally. In certain embodiments, the composition is administered to the subject vaginally. In certain embodiments, the method further comprises the step of administering an effective amount of an anti-microbial agent (e.g., an anti-bacterial agent), e.g., an anti-microbial agent described herein, to the subject at the same time or at a different time from the administering the composition, e.g., before or after the administering the composition. In some embodiments, the anti-microbial agent is an anti-microbial polypeptide, e.g., a microbial polypeptide described herein, In some embodiments, the anti-microbial agent is a small molecule anti-microbial agent, e.g., a small molecule anti-microbial agent described herein. In another embodiment, the administration of the composi tion described herein may be administered at least once.

[0021] Further provided herein are methods for treating and/or preventing a microbial infection (e.g., a bacterial infection) and/or a disease, disorder, or condition associated with a microbial infection (e.g., a bacterial infection), and/or a symptom thereof, in a animal (e.g., a mammalian) subject, comprising contacting a cell of the subject with a nucleic acid described herein, wherein the translatable region of the nucleic acid encodes an anti-microbial polypeptide (e.g., an anti-bacterial polypeptide), under conditions such that an effective amount of the antimicrobial polypeptide (e.g., an anti-bacterial polypeptide) is present in the cell, thereby treating or preventing a microbial infection (e.g., bacterial infection) and/or a disease, disorder, or condition associated with the microbial infection (e.g. , bacterial infection), and/or a symptom thereof, in the subject. In certam embodiments, the cell is an epithelial cell, an endothelial cell, or a mesotheliai cell. In certain embodiments, the nucleic acid comprises an RNA molecule formulated for administration by an intravenous route. In certain embodiments, the nucleic acid comprises an RNA molecule formulated for oral administration. In certain embodiments, the nucleic acid comprises an RNA molecule formulated for topical administration. In certain embodiments, the nucleic acid comprises an RNA molecule formulated for administration by inhalation. In certain embodiments, the nucleic acid comprises an RNA molecule formulated for rectal administration. In certain embodiments, the nucleic acid comprises an RNA molecule formulated for vaginal administration. [0022] Further provided herein are methods for inducing in vivo translation of a recombinant polypeptide (e.g., an anti-mierobial polypeptide (e.g., an anti-bacterial polypeptide), e.g., an antimicrobial polypeptide described herein) in an animal (e.g., a mammalian) subject in need thereof, comprising the step of administering to the subject an effective amount of a composition comprising a nucleic acid comprising: (i) a translatable region encoding the recombinant polypeptide; and (ii) at least one nucleoside modification, under conditions such that the nucleic acid is localized into a cell of the subject and the recombinant polypeptide is capable of being translated in the cell from the nucleic acid. In certain embodiments, the composition comprises mRNA. In certain embodiments, methods are provided, wherein the recombinant polypeptide comprises a functional activity substantially absent in the ceil in which the recombinant polypeptide is translated. In certain embodiments, the recombinant polypeptide comprises a polypeptide substantially absent in the cell in the absence of the composition. In certain embodiments, the recombinant polypeptide comprises a polypeptide that antagonizes the activity of an endogenous protein present in, on the surface of, or secreted from the cell , In certain embodiments, the recombinant polypeptide comprises a polypeptide that antagonizes the activity of a biological moiety present in, on the surface of, or secreted from the cell. In certain embodiments, the biological moiety comprises a lipid, a lipoprotein, a nucleic acid, a

carbohydrate, or a small molecule toxin, In certain embodiments, the recombinant polypeptide is capable of being secreted from the cell. In certain embodiments, the recombinant polypeptide is capable of being transloca ted to the plasma membrane of the ceil. In certain embodiments, methods are pro vided, wherein the composition is formulated for administration intramuscularly , transarterially, intraperitoneally, intravenously, intranasally, subcutaneously, endoscopically, transdermally, or intrathecally. In certain embodiments, methods are provided, wherein the composition is formulated for extended release.

[ΘΘ23] Further pro vided herein are methods for inducing translation of a recombinant polypeptide (e.g., an anti-microbial polypeptide (e.g., an anti-bacterial polypeptide), e.g., an antimicrobial polypeptide described herein) in a cell population, comprising the step of contacting the cell population with an effective amount of a composition comprising a nucleic acid comprising: (i) a. translatable region encoding the recombinant polypeptide; and (ii) at least one nucleoside modification, under conditions such that the nucleic acid is localized into one or more ceils of the ceil population and the recombinant polypeptide is translated in the cell from the nucleic acid. In certain embodiments, methods are provided, wherein the composition comprises rnRNA. In certain embodiments, the composition comprises a cell penetrating compound. In certain embodiments, methods are provided, wherein the step of contacting the cell with the composition is repeated one or more times, In certain embodiments, the step of contacting the cell with the composition is repeated a sufficient number of times such that a predetermined efficiency of protein translation in the cell population.

[0024] Further pro vided herein are meth ods of reducing the innate imm une response of a cell to an exogenous nucleic acid (e.g., a modified rnRNA described herein), comprising the steps of: (a) contacting the cell with a first composition comprising a first dose of a first exogenous nucleic acid comprising a translatable region (e.g., encoding an anti-microbial polypeptide (e.g., an anti-bacterial polypeptide), e.g., an anti-microbial polypeptide described herein) and at least one nucleoside modification; (b) determining the level of the innate immune response of the cell to the first exogenous nucleic acid; (c) contacting the cell with a second composition comprising either: (i) a second dose of the first exogenous nucleic acid, wherein the second dose contains a lesser amount of the first exogenous nucleic acid as compared to the first dose; or (ii) a first dose of a second exogenous nucleic acid, thereby reducing the innate immune response of the cell. In certain embodiments, methods are provided, wherein the step of contacting the cell with the first composition and/or the second composition is repeated one or more times, In certain

embodiments, a predetermined efficiency of protein transl ation in the cel l is achieved.

[0025] Provided herein are methods of providing a composition (e.g., a composition described herein) to a target tissue of a subject (e.g., a mammalian subject) in need thereof comprising the step of contacting the target tissue comprising one or more target ceils with the composition under conditions such that the composition is substantially retained in the target tissue, and wherein the composition comprises: (a) an effective amount of a ribonucleic acid, wherein the ribonucleic acid is engineered to a void an innate immune response of a cell into which the ribonucleic acid enters, and wherein the ribonucleic acid comprises a nucleotide sequence encoding a polypeptide of interest (e.g., a anti-microbial polypeptide described herein), wherein the protein of interest has an anti-microbial activity; (b) optionally, a cell penetration agent: and (c) a. pharmaceutically acceptable carrier, under conditions such that the polypeptide of interest is produced in at least one target cell

[0026] Further provided herein are isolated polypeptides (e.g. , anti-microbial polypeptides (e.g., anti-bacterial polypeptides), e.g., anti-mi crobial polypeptides described herein) produced by translation of the mR As described herein.

f 0027 [ Further provided herein are isolated complexes comprising a conj ugate of a protein and a nucleic acid (e.g. , a nucleic acid described herein), comprising (i) an mRNA comprising a translatable region encoding an anti-microbial polypeptide (e.g., an anti-bacterial polypeptide), e.g., an anti-microbial polypeptide described herein, and at least two different nucleoside modifications; and (ii) one or more polypeptides bound to the mRNA in an amount effective to prevent or reduce an innate immune response of a cell into which the complex is introduced.

[0028] Further provided herein are libraries comprising a plurality of polynucleotides, wherein the polynucleotides individually comprise: (i) a nucleic acid sequence encoding a polypeptide (e.g. , an anti-microbial polypeptide (e.g., an anti-bacterial polypeptide), e.g., an antimicrobial polypeptide described herein); and (ii) at least one nucleoside modification. In certain embodiments, libraries are provided, wherein the polypeptide comprises an antibody or functional, portion thereof. I certain embodiments, libraries are provided, wherein the polynucleotides comprise mRNA, In certain embodiments, libraries are provided, wherein the at least one nucleoside modification is selected from the group consisting of pyridin-4-one ribonucleoside, 5-aza-uridine, 2-thio-5-aza-uridine, 2-thiouridine, 4-thio-pseudouridine, 2-thio- pseudouridine, 5-hydrox uridine, 3-methyluridme, 5-carboxymethyl-uridme, 1 -carboxymethyl- pseudouridine, 5-propynyl-uridine, 1-propynyl-pseudouridine, 5-taurinomethyluridine, I- taurmomethyl-pseudouridine, 5-tauriiiomethyl-2-thio-uridine, l-taurinometiiyl-4-thio-uridine, 5- methyl-uridine, 1 -methyl-pseudouridine, 4-thio-l-methyl-pseudouridine, 2-thio- 1 -methyl- pseudouridine, 1 -methyl- 1 -deaza-pseudouridine, 2-thio- 1 -methyl- 1 -deaza-pseudouridme, dihydrouridine, dihydropseudouridine, 2-thio-dihydrouridine, 2-thio-dihydropseudouridine, 2- methoxyuridine, 2-methoxy-4-thio-uridine, 4-methoxy-pseudouridine, 4-niethoxy-2-thio- pseudouridine, 5-aza-cytidme, pseudoisocytidine, 3-meihyl-cytidine, N4-acetylcytidine, 5- formyleytidine, N4-methylcytidine, 5-hydroxymethylcytidme, 1 -methyl-pseudoisocytidine, pyrrol o-cytidine, pyrrolo-pseudoisocytidine, 2-thio-cytidine, 2~thio-5 -methyl -cytidine, 4-thio- pseudoisoc^idine, 4-thio- 1 -methyl-pseudoisocytidine, 4-thio- 1 -methyl- 1 -deaza- pseudoisocytidine, 1 -methyl- 1 -deaza-pseudoisocytidine, zebularine, 5-aza-zebularine, 5-methyl- zebularine, 5-aza-2-thio-zebularine, 2-thio-zebuiarine, 2-methoxy-cytidine, 2-methoxy-5-methyl- cytidine, 4-methoxy-pseudoisocytidine, 4-methoxy- 1 -methyl-pseudoisocytidine, 2-aminopurine, 2, 6-diaminopurine, 7-deaza-adenine, 7-deaza-8-aza-adenine, 7-deaza-2-aniinopurine, 7-deaza-8- aza-2-amm op urine, 7~deaza-2,6-diammopmine, 7~deaza-8-aza~2,6-diarmnopurme, 1- methyladetiosine, N6-metbyladenosine, N6-isopentenyladenosme, N6-(cis- hydroxyisopentenyljadenosine, 2-melhylthio-N6-(cis-hydroxyisopentenyl) adenosine, N6- glycinylcarbamoyladenosine, N6-threonylcarbamoyladenosirie, 2-methylthio-N6-threonyl carbanioyladenosine, 6,N6-dimethyladenosine, 7-methyladenine, 2-methylthio-adenine, 2- methoxy-adenine, inosine, 1-methyl-mosine, yosine, wybutosine, 7-deaza-guanosine, 7-deaza- 8-aza-guanosine, 6-thio-guanosine, 6-thio-7-deaza-guanosine, 6-thio-7-deaza-8-aza-guanosme,

7- methyl-guanosine, 6-thio-7-methyl-guanosine, 7-methylinosine, 6-methoxy-guanosine, 1 - methylguanosine, N2-methylguanosine, N2,N2-dimethylguanosme, 8-oxo-guanosin.e, 7-methyl-

8- oxo-guanosine, i~methyl-6 hio-guanosine, N2-methyl-6-thio-guanosine, and N2,N2-dimethyi- 6-thio-guanosine.

[0029] Further provided herein are methods for enhancing protein (e.g. , an anii-microbial polypeptide (e.g., an anti -bacterial polypeptide), e.g., an anti-microbial polypeptide described herein) product yield in a ceil culture process, comprising the steps of: (a) providing a ceil culture comprising a plurality of host cells; (b) contacting the cell culture with a composition comprising a nucleic acid comprising a translatable region encoding an anti-microbial polypeptide (e.g., an anti-bacterial polypeptide), e.g., an anti-microbial polypeptide described herein), and at least one nucleoside modification, wherein the nucleic acid exhibits increased protein production eiiiciency in a cell culture into which the nucleic acid is introduced, relative to a corresponding unmodified nucleic acid, in certain embodiments, methods are provided, wherein the increased protein production efficiency comprises increased cell transiection. In certain embodiments, the increased protein production efficiency comprises increased protein translation from the nucleic acid. In certain embodiments, the increased protein production efficiency comprises decreased nucleic acid degradation. In certain embodiments, the increased protein production efficiency comprises reduced innate immune response of the host cell. In certain embodiments, methods are provided, wherein the cell culture comprises a fed-batch mammalian cell culture process.

[0030] Further pro vided herein are methods for optimizing expression of an engineered protein (e.g., an anti-microbial polypeptide (e.g., an anti-bacterial polypeptide), e.g., an antimicrobial polypeptide described herein) in a target ceil, comprising the steps of; (a) providing a plurality of target cell types; (b) independently contacting with each of the plurality of target ceil types an isolated nucleic acid comprising a translatable region encoding an engineered polypeptide and at least one nucleoside modification; and (c) detecting the presence and/or level of the engineered polypeptide in the plurality of target cell types, thereby optimizing expression of an engineered polypeptide in a target ceil. In certain embodiments, the engineered polypeptide comprises a post-transiationai modification, in certain embodiments, the engineered polypeptide comprises a tertiary structure. In certain embodiments, methods are provided, wherein the target cell comprises a mammalian cell line.

[0031] Further provided herein are methods of antagonizing a biological pathway in a cell, e.g., a biological pathway associated with a microbial infection (e.g., a bacterial infection), comprising the step of contacting the cell with an effective amount of a composition comprising a nucleic acid comprising: (i) a translatable region encoding a recombinant polypeptide (e.g., an anti-microbial polypeptide (e.g., an anti-bacterial polypeptide), e.g., an anti-niicrobial polypeptide described herein); and (ii) at least one nucleoside modification, under conditions such that the nucleic acid is localized into the cell and the recombinant polypeptide is capable of being translated in the cell from the nucleic acid, wherei the recombinant polypeptide inhibits the activity of a polypeptide functional in the biological pathway. In certain embodiments, methods are provided, wherein the biological pathway is defective in a cell having a microbial infection (e.g. , a bacterial infection) and/or in a disease, disorder or condition (e.g. , a disease, disorder, or condition described herein) associated with a microbial infection (e.g., a bacterial infection).

[0032] Further provided herein are methods of agonizing a biological pathway in a cell, e.g. a biological pathway associated with a microbial infection (e.g., a bacterial infection), comprising the step of contacting the cell with an effective amount of a composition comprising a nucleic acid comprising: (i) a translatable region encoding a recombinant polypeptide (e.g., an anti-microbial polypeptide (e.g., an anti-bacterial polypeptide), e.g., an anti-microbial polypeptide described herein); and (ii) at least one nucleoside modification, under conditions such that the nucleic acid is localized into the cell and the recombinant polypeptide is capable of being translated in the cell from the nucleic acid, wherein the recombinant polypeptide induces the activity of a polypeptide functional in the biological pathway. In certain embodiments, the agonized biological pathway modulates an anti-microbial (e.g., anti-bacterial) activity. In certain embodiments, the biological pathway is reversibly agonized.

[0033] Further provided herein are methods for enhancing nucleic acid deliver)' into a ceil population, comprising the steps of: (a) providing a cell culture comprising a plurality of host cells; (b) contacting the cell population with a composition comprising an enhanced nucleic acid comprising a translatable region encoding a polypeptide (e.g., an anti-microbial polypeptide (e.g., an anti-bacterial polypeptide), e.g., an anti-microbial polypeptide described herein) and at least one nucleoside modiiication, wherem the enhanced nucleic acid exhibits enhanced retention in the cell population, relative to a corresponding unmodified nucleic acid. In certain

embodiments, methods are provided, wherein the retention of the enhanced nucleic acid is at least about 50% greater than the retention of the unmodified nucleic acid, in some embodiments, the retention of the enhanced nucleic acid is at least about 100% greater than the retention of the unmodified nucleic acid, in other embodiments, the retention of the enhanced nucleic acid is at least about 200% greater than the retention of the unmodified nucleic acid. In certain

embodiments, methods are provided, wherein the step of contacting the cell with the composition is repeated one or more times.

[0034] Further pro vided herein are methods of nucleic acid co-delivery into a cell population, comprising the steps of: (a) providing a cell culture comprising a plurality of host cells; (b) contacting the cell population with a composition comprising: (i) a first enhanced nucleic acid comprising a translatable region encoding a polypeptide (e.g., an anti-microbial polypeptide (e.g. , an anti-bacterial polypeptide), e.g., an anti-microbial polypeptide described herein) and at least one nucleoside modification; and (ii) a first unmodified nucleic acid, wherem the composition does not substantially induce an innate immune response of the cell population.

[0035] Further provided herein are methods of nucleic acid deli ver into a cell population, comprising the steps of: (a) providing a cell culture comprising a plurality of host cells: (b) contacting the cell population with a first composition comprising: (i) a first enhanced nucleic acid comprising a translatable region encoding a recombinant polypeptide (e.g., an anti-microbial polypeptide (e.g., an anti-bacterial polypeptide), e.g., an anti-microbial polypeptide described herein) and at least one nucleoside modification; and (ii) a first unmodified nucleic acid, wherein the composition does not subs tantially induce an innate immune response of the cell population: and (c) contacting the cell population with a second composition comprising a first unmodified nucleic acid. [0036] Further provided herein are kits comprising a composition (e.g., a pharmaceutical composition) comprising a modified mRNA encoding an anti-microbiai polypeptide (e.g., an anti-bacterial polypeptide), e.g., an anti-microbial polypeptide described herein, in one or more containers, and instructions for use thereof.

[0037] Further provided here are kits for polypeptide production in a subject (e.g., a mammalian subject) suffering from or at risk of developing a microbial infection, comprising a first isolated nucleic acid comprising a translatable region and a nucleic acid modification, wherein the nucleic acid is capable of evading an innate immune response of a ceil of the subject into which the first isolated nucleic acid is introduced, wherein the translatable region encodes a therapeutic polypeptide, e.g., a therapeutic polypeptide comprising an anti-microbial activity (e.g., a anti-microbial polypeptide described herein), and packaging and instructions therefore. In some embodiments, the instructions comprise instructions for the repeated administration of the first isolated nucleic acid to a cell or a population of ceils. In some embodiments, the therapeutic polypeptide is useful in the treatment of an infection in the mammalian subject by a microbial pathogen. In some embodiments, the kit further comprises a second isolated nucleic acid comprising a translatable region. In some embodiments, the translatable region in the second isolated nucleic acid encodes an anti-microbial polypeptide (e.g., an anti- bacterial polypeptide), e.g., an anti-microbial polypeptide described herein. In some embodiments, the translatable region of the second isolated nucleic acid encodes the same anti-microbial polypeptide as the first isolated nucleic acid. In some embodiments, the translatable region of the second isolated nucleic acid encodes a different anti-microbial polypeptide than the first isolated nucleic acid. In some embodiments, the second nucleic acid comprises a nucleic acid modification. In some embodiments, the second nucleic acid does not comprise a nucleic acid modification.

[0038] Further pro vided herein are dressings (e.g. , wound dressings) or bandages (e.g. , adhesive bandages) comprising a pharmaceutical composition comprising a modified mRNA encoding an anti-microbial polypeptide (e.g., an anti-bacterial polypeptide), e.g., an antimicrobial polypeptide described herein. DETAILED DESCRIPTION OF THE INVENTION

[0039] In general, exogenous nucleic acids, particularly viral nucleic acids, introduced into cells induce an innate immune response, resulting in interferon (IFN) production and celi death. However, it is of great interest for therapeutics, diagnostics, reagents and for biological assays to deliver a nucleic acid, e.g., a ribonucleic acid (RNA) inside a cell, either in vivo or ex vivo, such as to cause intracellular translation of the nucleic acid and production of the encoded protein. Of particular importance is the delivery and function of a noii-integrative nucleic acid, as nucleic acids characterized by integration into a target cell are generally imprecise in their expression levels, deleteriously transferable to progeny and neighbor cells, and suffer from the substantial risk of mutation. Provided herein in pail are nucleic acids encoding useful polypeptides capable of killing or reducing the growth of microorganisms (e.g., bacteria), killing or reducing the growth of tumor or cancer cells, and/or modulating a cell's function and/or activity, and methods of making and using these nucleic acids and polypeptides. As described herein, these nucleic acids are capable of reducing the innate immune activity of a population of cells into which they are introduced, thus increasing the efficiency of protein production in that cell population.

Further, one or more additional advantageous activities and/or properties of the nucleic acids and proteins of the invention are described.

[0040] Provided herein are modified nucleic acids encoding an anti-microbial polypeptide (e.g., an anti-bacterial polypeptide), e.g., an anti-microbial polypeptide described herein, precursors thereof, or partially or fully processed forms of these precursors. In certain embodiments, the modified nucleic acid comprises mRNA. In particular embodiments, the modified mRNA (mmRNA) is derived from cDNA. In certain embodiments, the rnrnRNA comprises at least two nucleoside modifications. In certain embodiments, these nucleoside modifications comprise 5-niethylcytosme and pseudouridine. In some embodiments, around 25%. around 50%, around 75%, or up to and including 100% of cytosine and uridine nucleotides of the modified nucleic acid are modi fied nucl eotides. In certain embodiments, the mmRN A comprises a 5' cap structure and a 3' poly- tail. In specific embodiments, the 5' cap structure is a Cap 1 structure. In specific embodiments, the poly-A tail comprises at least 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, or 200 nucleotides.

10041 [ Further, provided herein are compositions comprising the modified nucleic acids described herein. In certain embodiments, the composition further comprises a pharmaceutically acceptable carrier. In certain embodiments, the carrier is formulated for systemic or local administration. In certain embodiments, the composition is formulated for intravenous administration. In certain embodiments, the composition is formulated for oral administration. In certain embodiments, the composition is formulated for topical administration. In certain embodiments, the composition is formulated for administration via a dressing (e.g., wound dressing). In certain embodiments, the composition is formulated for administration via a bandage (e.g., adhesive bandage). In certain embodiments, the composition is formulated for administration by inhalation. In certain embodiments, the composition is formulated for rectal administration. In certain embodiments, the composition is formulated for vaginal

administration. In certain embodiments, the composition comprises naked modified nucleic acids. In other embodiments, die modified nucleic acid is complexed or encapsulated. For example, the modified nucleic acid may be complexed in liposomal form or may be encapsulated in a nanopailicle. In certain embodiments, the modified nucleic acid, the complex, or the nanoparticle further comprises one or more targeting moieties. These moieties can be used to target delivery in vivo to certain organs, tissues, or cells.

[0042] Provided herein are methods of treating a subject having or being suspected of having a microbial infection (e.g., a bacterial infection) and/or a disease, disorder, or condition associated with a microbial infection (e.g., a bacterial infection), the methods comprising administering to a subject in need of such treatment a composition described herein in an amount sufficient to treat the microbial infection (e.g., bacterial infection) and/or the disease, disorder, or condition associated with the microbial infection (e.g., bacterial infection). In specific embodiments, the disease, disorder, or condition is associated with one or more cellular and/or molecular changes affecting, for example, the level, activity, and/or localization of an antimicrobial polypeptide (e.g., an anti-bacterial polypeptide), e.g., an anti-microbial polypeptide described herein, precursors thereof, or a partial ly or fully processed form of these precursors. Cellular and or molecular changes may affect transcription, translation, posttranslational modification, processing, folding, intra- and/or extracellular trafficking, intra- and/or

extracellular stability/turnover, and/or signaling of one or more molecules associated with an anti-microbial (e.g., anti-bacterial) activity, In certain embodiments, activities associated with an anti-microbial polypeptide (e.g., an anti-bacterial polypeptide), e.g., an anti-microbial polypeptide described herein, are compromised, e.g., 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 5% or less of wild-type activity, in certain embodiments, the method of treating a subject having or being suspected of having a microbial infection (e.g., a bacterial infection) and/or a disease, disorder, or condition associated with a microbial infection (e.g., a bacterial infection) comprises administering to the subject in need of such treatment a composition comprising a modified nucleic acid described herein in an amount sufficient to kill, reduce, or inhibit the growth of microorganisms (e.g. , bacteria) and/or to treat the disease, disorder, or condition,

[0043] A major drawback of many current treatments for diseases described herein is the necessity to produce anti -microbial agents (e.g., anti-bacterial agents) as polypeptides.

Polypeptides are ordinarily expressed in and isolated from mammalian or bacterial cultures. Bacterial cultures and many cancer-derived cell culture systems do not faithfully recapitulate post-translational modifications, e.g., glycosylation and amidation, and protein precursors may not be fully processed. In some instances, the lack of posttranslational modification and processing influences the activity of the final protein product, its localization and/or its target specificity. In other instances, precursors and final cleavage products can have different physiological effects. For production of recombinant protein s, the polypeptide product that is effective for a particular treatment must usually he predetermined because the proteins if administered do not undergo any additional processing. Any modification that is vital for activity must also be present on the recombinant protein because they will not be added by the host when the recombinant proteins are administered. Recombinant protein production and purification is expensive and labor intensive. Protein expression host systems may harbor pathogens (e.g. viruses) that ma contaminate the purified product. Proteins and particularly protein modifications are inherently unstable und require specific storage conditions and generally have a short shelf life. To be efficacious, recombinant proteins must be further modified, particularly by pegyiation to avoid rapid degradation in vivo. Still, site-specific pegyiation remains difficult because it can lead to l oss of activity, loss of target specificity and/or protein aggregation. Veronese et al. Bioconjugate Cbem. 18: 1 824-1830 (2007).

[0044] The modified mRNA molecules described herein do not share these problems. In comparison to recombinant proteins, they exhibit increased stability for shipping, handling and storage, are easy to mass produce, and when translated from the modified mRN A, the polypeptide can undergo an array of cell- and/or tissue-specific posttranslational processing, folding and modification.

Anti-microbial polypeptide

[0045] Anti-microbial polypep tides (AMPs) are small peptides of variable length, sequence and structure with broad spectrum acti vity against a wide range of microorganisms including bacteria, viruses, fungi, protozoa, parasites, prions, and tumor/cancer cells. See, e.g. , Zaiou, J ol Med, 2007; 85:317, It has been shown that AMPs have broad-spectrum of rapid onset of killing activities, with potentially low levels of induced resistance and concomitant broad antiinflammatory effects, In some embodiments, the anti-microbial polypeptide (e.g., an antibacterial polypeptide) is under !OkDa, e.g., under 8kDa, 6kDa, 4kDa, 2kDa, or lkDa. In some embodiments, the anti-microbial polypeptide (e.g., an anti-bacterial polypeptide) consists of from about 6 to about 100 amino acids, e.g., from about 6 to about 75 amino acids, about 6 to about 50 amino acids, about 6 to about 25 amino acids, abou 25 to about 100 amino acids, about 50 to about .100 amino acids, or about 75 to about 100 amino acids. In certain embodiments, the antimicrobial polypeptide (e.g., an anti-bacterial polypeptide) consists of from about 15 to about 45 amino acids. In some embodiments, the anti-microbial polypeptide (e.g., an anti-bacterial polypeptide) is substantially cationic. In some embodiments, the anti-microbial polypeptide (e.g., an anti-bacterial polypeptide) is substantially amphipathic. In certain embodiments, the anti-microbial polypeptide (e.g., an anti-bacterial polypeptide) is substantially cationic and amphipathic. In some embodiments, the anti-microbial polypeptide (e.g., an anti-bacterial polypeptide) is cytostatic to a Gram-positive bacterium. In some embodiments, the antimicrobial polypeptide (e.g., an anti-bacterial polypeptide) is cytotoxic to a Gram-positive bacterium. In some embodiments, the anti-microbial polypeptide (e.g., an anti-bacterial polypeptide) is cytostatic and cytotoxic to a Gram-positive bacterium. In some embodiments, the anti-microbial polypeptide (e.g., an anti-bacterial polypeptide) is cytostatic to a Gram- negative bacterium. In some embodiments, the anti-microbial polypeptide (e.g., an anti-bacterial polypeptide) is cytotoxic to a Gram-negative bacterium. In some embodiments, the antimicrobial polypeptide (e.g., an anti-bacterial polypeptide) is cytostatic and cytotoxic to a Gram- positive bacterium. In some embodiments, the anti-microbial polypeptide is cytostatic to a virus, fungus, protozoan, parasite, prion, or a combination thereof. In some embodiments, the antimicrobial polypeptide is cytotoxic to a vims, fungus, protozoan, parasite, prion, or a combination thereof, In certain embodiments, the anti-microbiai polypeptide is cytostatic and cytotoxic to a virus, fungus, protozoan, parasite, prion, or a combination thereof. In some embodiments, the anti-microbial polypeptide is cytotoxic to a tumor or cancer cell (e.g., a human tumor or cancer cell), In some embodiments, the anti-microbial polypeptide is cytostatic to a tumor or cancer cell (e.g., a human tumor or cancer ceil). In certain embodiments, the anti-microbial polypeptide is cytotoxic and cytostatic to a tumor or cancer cell (e.g., a human tumor or cancer cell), In some embodiments, the anti-microbial polypeptide (e.g., an anti-bacterial polypeptide) is a secreted polypeptide.

[0046] AM Ps have been isolated and described from a wide range of animals;

microorganisms, invertebrates, plants, amphibians, birds, fish, and mammals (Wang et a!..

Nucleic Acids Res. 2009; 37 (Database issue):D933-7). For example, anti-microbial

polypeptides are described in Antimicrobial Peptide Database

(http://aps.immc,edu/AP/main,php; Wang ei al, Nucleic Acids Res. 2009; 37 (Database issue):D933-7), CAMP: Collection of Anti -Microbial Peptides

(http://www.bicninh.res n/antimicrobial/; Thomas et al, Nucleic Acids Res. 2010; 38 (Database issue):D774-80), US 5221732, US 5447914, US 5519115, US 5607914, US 5714577, US 5734015, US 5798336, US 5821224, US 5849490, US 5856127, US 5905187, US 5994308, US 5998374, US 6107460, US 6191254, US 621 1148, US 6300489, US 6329504, US 6399370, US 6476189, US 6478825, US 6492328, US 6514701, US 6573361, US 6573361, US 6576755, US 6605698, US 6624140, US 6638531, US 6642203, US 6653280, US 6696238, US 6727066, US 6730659, US 6743598, US 6743769, US 6747007, US 6790833, US 6794490, US 6818407, US 6835536, US 6835713, US 6838435, US 6872705, US 6875907, US 6884776, US 6887847, US 6906035, US 691 1524, US 6936432, US 7001924, US 7071293, US 7078380, US 7091 185, US 7094759, US 7166769, US 7244710, US 7314858, and US 7582301 , the contents of which are incorporated by reference in their entirety.

[0047] In certain embodiments, the anti-microbial polypeptide (e.g., anti-bacterial polypeptide) is selected from the group consisting of anti-microbial polypeptides (e.g., antibacterial polypeptides) provided in Lengthy Table 1. Shown in Lengthy Table 1 , in addition to the name of the anti-microbiai polypeptide (e.g., anti-bacterial polypeptide) is the definition of the polypepti de and the sequence and SEQ ID NO of the polypepti de.

i [0048] Exemplary anti-microbial polypeptides also include, but not limited to hBD-2, LL-37, and RNase-7,

f 004 [ The human defensin hBD-2 is expressed throughout human epithelia. The sequence of the precursor peptide consists of 41 residues present in the mature peptide as well as a leader sequence of secreted peptide. Disruption of hBD-2 expression, as in cystic fibrosis, might be associated with recurrent infections of skin and other epithelia.

[0050] The anti-microbial peptide, LL-37 is processed from the cathelicidin precursor hCAPlS. The inhibition of LL-37 expression by Shigella likely causes about 160 million people develop intestinal infections yearly, resulting in over 1 million deaths. It is a multifunctional effector molecule capable of directly killing pathogens, modulating the immune response, stimulating proliferation, angiogenesis, and cellular migration, inhibiting apoptosis, and is associated with inflammation, it may play a part in epithelial cell proliferation as a part in wound closure and that its reduction in chronic wounds impairs re-epiihelialization and may contribute to their failure to heal,

[0051] R Ase-7 is a potent AMP that was identified in the skin, human kidney and urinary tract. The systemic delivery of this mRNAs will likely allow expression of natural for the body antibiotic polypeptides even in tissues which are not supposed to be under microbial attack at normal physiological stage but have that danger under disease conditions.

[0052] In some embodiments, the anti-microbial polypeptide comprises or consists of a defensin. Exemplary defensors include, but not limited to, a-defensins (e.g., neutrophil defensin 1 , defensin alpha 1 , neutrophil defensin 3, neutrophil defensin 4, defensin 5, defensin 6), β- defensins (e.g., beta-defensin 1, beta-defensin 2, beta-defensin 103, beta-defensin 107, beta- defensin 1 10, beta-defensin 136), and θ-defensins. In other embodiments, the anti-microbial polypeptide comprises or consists of a cathelicidin (e.g., hCAPI S).

[0053] The anti-microbial polypeptides described herein may block cell fusion and/or viral entry by one or more enveloped viruses (e.g., HIV, HCV), For example, the anti-microbial polypeptide can comprise or consist of a synthetic peptide corresponding to a region, e.g., a consecutive sequence of at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 amino acids of the transmembrane subunit of a viral envelope protein, e.g., HTV-1 g l20 or gp41. The amino acid and nucleotide sequences of HIV-1 gpl 20 or gp41 are described in, e.g., Kuiken et al, (2008). "HIV Sequence Compendium", Los Alamos National Laboratory. In some embodiments, the anti-microbial polypeptide has at least about 75%, 80%, 85%, 90%, 95%, 100% sequence homology to the corresponding viral protein sequence. In certain embodiments, the antimicrobial polypeptide comprises or consists of enfuvirtide (FUZEON®): Ac-Tyr-Thr-Ser-Leu- Ile-His-Ser-Leu- Ile-Glu-Glu-Ser-Gln-Asii-Gln-Gln-Glu-Lys-Asii-Glu-Gln-Glu-Leu-Leii-Glis- 1 ^η-Α8 -ίγ8-Ί -ΑΐΕ-86ί·-1.,6^η-Ί^'τ -Α8^η-^'Γ{ -]¾6- Η2.

[0054] The anti-microbial polypeptides described herein may block viral particle assembly and formation of one or more infective enveloped viruses (e.g., HIV, HCV). For example, the anti-microbial polypeptide can comprise or consist of a synthetic peptide corresponding to a region, e.g., a consecutive sequence of at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 amino acids of the capsid subunit of a viral capsid protein, e.g., the HIV capsid protein. The amino acid and nucleotide sequences of the HIV-1 capsid protein are described in, e.g., Ruiken et ai., (2008). "HIV Sequence Compendium", Los Alamos National Laboratory. In some embodiments, the anti-microbial polypeptide has at least about 75%, 80%), 85%, 90%, 95%, 100% sequence homology to the corresponding viral protein sequence. In other embodiments, the anti-microbial polypeptide comprises or consists of a synthetic peptide corresponding to a region, e.g., a consecutive sequence of at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 amino acids of the binding domain of a capsid binding protein. In some embodiments, the anti-microbial polypeptide has at least about 75%, 80%, 85%, 90%, 95%, 100% sequence homology to the corresponding sequence of the capsid binding protein.

[0055] The anti-microbial polypeptides described herein may block protease dinierization and inhibit cleavage of viral proproteins (e.g., HIV Gag-pol processing) into functional proteins thereby preventing release of one or more enveloped viruses (e.g., HIV, HCV). For example, the anti-microbial polypeptide can comprise or consist of a synthetic peptide corresponding to a region, e.g., a consecutive sequence of at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 amino acids of a viral protease, e.g., the HIV-1 protease. The amino acid and nucleotide sequences of the HIV- 1 protease are described in, e.g., Ruiken et al, (2008), "HIV Sequence Compendium ", Los Alamos National Laboratory. In some embodiments, the anti-microbial polypeptide has at least about 75%, 80%, 85%, 90%, 95%, 100% sequence homology to the corresponding viral protein sequence. In other embodiments, the anti-microbial polypeptide can comprise or consist of a synthetic peptide corresponding to a region, e.g., a consecutive sequence of at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, or 60 amino acids of the binding domain of a protease binding protein, in some embodiments, the anti-microbial polypeptide has at least about 75%, 80%, 85%, 90%. 95%, 100% sequence homology to the corresponding sequence of the protease binding protein.

[0056] The anti-microbial polypeptides described herein can include a polypeptide corresponding to the inhibitory region of the endogenous human protein TRIM5-a or cyclophilm A (peptidylproiyl isomerase A). The sequences of human TRIM5-a and cyclophilm A are described, e.g., in Stremlau et al, Nature, 2004; 427(6977):848-53 and Takahashi et al, Nature 1989; 337 (6206), 473-475, respectively.

[0057] The anti-microbial polypeptides described herein can include an in vitro-Qvoh/Qd polypeptide directed against a viral pathogen, e.g. , a polypeptide identified or selected by the method described in Example 7.

Modified nucleic acids.

[0058] This invention provides nucleic acids, including RNAs such as mRNAs that contain one or more modified nucleosides (termed "modified nucleic acids"), which have useful properties including the lack of a substantial induction of the innate immune response of a cel l into which the mRNA is introduced. Because these modified nucleic acids enhance the efficiency of protein production , intracellular retention of nucleic acids, and viability of contacted cells, as well as possess reduced immunogenicity, these nucleic acids having these properties are termed "enhanced nucleic acids" herein.

[0059] The term "nucleic acid," in its broadest sense, includes any compound and/or substance that is or can be incorporated into an oligonucleotide chain. Exemplary nucleic acids for use in accordance with the present invention include, but are not limited to, one or more of DMA, RNA, hybrids thereof, RNAi-inducing agents, RNAi agents, siR As, shRNAs, miRNAs, antisense RNAs, ribozymes, catalytic DMA, RNAs that induce triple helix formation, aptaniers, vectors, etc. , described in detail herein.

[0060] Provided are modified nucleic acids containing a translatable region encoding an antimicrobial polypeptide (e.g., an anti-bacterial polypeptide), e.g., an anti-microbial polypeptide described herein, and one, two, or more than two different nucleoside modifications. In some embodiments, the modified nucleic acid exhibits reduced degradation in a. cell into which the nucleic acid is introduced, relative to a corresponding unmodified nucleic acid. For example, the degradation rate of the nucleic acid is reduced by at least 10%, 20%, 30%, 40%, 50%), 60%, 70%, 80%, or 90%, compared to the degradation rate of the corresponding unmodified nucleic acid. Exemplary nucleic acids include ribonucleic acids (RNAs), deoxyribonucleic acids (D As), thxeose nucleic acids (T As), glycol nucleic acids (GNAs), peptide nucleic acids (P As), locked nucleic acids (LNAs) or a hybrid thereof, In preferred embodiments, the modified nucleic acid includes messenger RNAs (mRNAs). As described herein, the nucleic acids of the invention do not substantially induce an innate immune response of a cell into which the mR A is introduced.

[0061] in some embodiments, modified nucleosides include pyridin-4-one ribonucleoside, 5- aza-uridine, 2-thio-5-aza-uridine, 2-thiouridine, 4-thio-pseudouridine, 2-thio-pseudouridine, 5- hydroxyuridine, 3-methyluridine, 5-carboxymemyl-uridine, 1 -carboxymethyl-pseudouridine, 5- propynyl-uridine, 1 -propynyl-pseudouridine. 5-taurinomethyluridine, 1 -taurmomeihyl- pseudouridine, 5-taurinomethyl-2-thio-uridine, l-taurinomethyl-4 hio-uridine, 5-methyl-uridine, 1 -methyl-pseudouridine, 4-thio- 1 -meihyl-pseudouridme, 2-thio- 1 -methyl-pseudouridine, 1 - methyl- 1 -deaza-pseudouridine, 2-thio- .1 -methyl- 1 -deaza-pseudouridine, dihydrouridine, dihydropseudouridine, 2-thio-dihydroutidine, 2-thio-dihydropseudouridine, 2-methoxyuridine, 2- methoxy-4-thio-uri.dine, 4-rnethoxy-pseudouridine, and 4-metboxy-2-thio-pseudouri.dine,

[0062] in some embodiments, modified nucleosides include 5-aza-cytidine,

pseudoisocytidine, 3-methyl-cytidine, N4~acetylcytidine, 5-formylcytidine, N4-m.ethylcytidine, 5-hydroxymethylcytidine, 1 -methyl-pseudoisocytidine, pyrrolo-cytidine, pyrrolo- pseudoisocytidine, 2-thio-cyddine, 2-thio-5-methyl-cytidine_!, 4-thio-pseudoisocytidine, 4-thio-l- methyl-pseudoisocytidine, 4-thio- 1 -methyl- 1 -deaza-pseudoisocytidine, 1 -methyl- ϊ-deaza- pseudoisocytidine, zebularine, 5-aza-zebularine, 5-methyl-zebularine, 5-aza-2-thio-zebuiarine, 2- thio-zebularine, 2-methoxy-cytidine, 2-methoxy-5-methyi-cytidine, 4-methoxy- pseudoisocytidine, and 4-methoxy- 1 -niethyi-pseudoisocytidine.

[Θ063] In other embodiments, modified nucleosides include 2-aminopurine, 2, 6- diaminopurine, 7-deaza-adenine, 7-deaza-8-aza-adenine, 7-deaza-2-aniinopurine, 7-deaza-8-aza- 2-aminop rine, 7-deaza-2,6-diaminopurine, 7-deaza-8-aza~2,6~diaminopurine, 1- methyladenosine, 6-methyladenosine, N6-isopentenyladenosine, N6-(cis- hydroxyisopentenyl)adenosine, 2-melhylthio-N6-(cis-hydroxyisopentenyl) adenosine, N6- glycinylcarhamoyladenosine, 6~threonylcarbamoyladenosine, 2-methyithio-N6-threonyl carbamoyladenosine, N6,N6-diniethyladenosine, 7-methyladenine, 2-methylthio-adenine, and 2- methoxy-adenirie.

f 0064 [ In certain embodiments it is desirable to intracellularly degrade a modified nucleic acid introduced into the cell, for example if precise timing of protein production is desired, Thus, the invention provides a modified nucleic acid containing a degradation domain, which is capable of being acted on in a directed manner within a cell.

[0065] In other embodiments, modified nucleosides include inos ie, 1-methyl-inosine, wyosine, wybutosine, 7-deaza-guanosine, 7-deaza-8-aza-guanosine, 6-thio-guaiiosine, 6-thio-7- deaza-guanosine, 6~thio-7~deaza-8-aza~guanosine, 7-methyl-guanosine, 6-thio-7-methyl- guanosine, 7-metliyiinosine, 6-methoxy-guanosine, 1-methylguanosine, N2-methylguanosine, N2,N2-dimethyiguanosine, 8-oxo-guanosine. 7-methyl-8-oxo-guanosine, 1 -metliyl-6-tliio- guanosine, N2-methyl-6-thio-guanosine, andN2,^'N2-dimethy!-6-thio-guanosine.

[0066] Other components of nucleic acid are optional, and are beneficial in some

embodiments. For example, a 5' -untranslated region (UTR) and/or a 3'UTR are provided, wherein either or both may independently contain one or more different nucleoside

modifications. In such embodiments, nucleoside modifications may also be present in the translatable region. Also provided are nucleic acids containing a Kozak sequence.

[0067] Additionally, nucleic acids encoding anti-microbial polypeptides (e.g., anti-bacterial polypeptides), e.g., anti-microbial polypeptides described herein, and containing one or more intronic nucleotide sequences capable of being excised from the nucleic acid are provided herein, f 00681 Further, nucleic acids encoding anti-microbial polypeptides (e.g., anti-bacterial polypeptides), e.g., anti-microbial polypeptides described herein, and containing an internal ribosome entry site ( IRES) are provided herein. An IRES may act as the sole ribosome binding site, or may serve as one of multiple ribosome binding sites of an mRNA. An mRNA containing more than one functional nbosome binding site may encode several peptides or polypeptides that are translated independently by the ribosonies ("muiticistronic mRNA"), When nucleic acids are provided with an IRES, further optionally provided is a second translatable region, Examples of IRES sequences that can be used according to the invention include without limitation, those from picornaviruses (e.g., FMDV), pest viruses (CFFV), polio viruses (PV),

encephalomyocarditis viruses (ECMV), foot-and-mouth disease viruses (FMDV), hepatitis C viruses (HCV), classical swine fever viruses (CSFV), murine leukemia virus (MLV), simian immune deficiency viruses (SIV) or cricket paralysis viruses (CrPV).

Prevention or redaction of imiate cel far immune response activation ¾smg modified

H _icjelc_iiiacids.

[0069] The term "innate immune response" includes a cellular response to exogenous single s tranded nucleic acids, generally of viral or bacterial origin, which involves the induc tion of cytokine expression and release, particularly the interferons, and cell death. Protein synthesis is also reduced during the innate cellular immune response. While it is advantageous to eliminate the innate immune response in a cell, the invention provides modified mRNAs that substantially reduce the immune response, including interferon signaling, without entirely eliminating such a response. In some embodiments, the immune response is reduced by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 99%, 99.9%, or greater than 99.9% as compared to the immune response induced by a corresponding unmodified nucleic acid. Such a reduction can be measured by expression or activi ty level of Type 1 in terferons or the expression of interferon- regulated genes such as the toll-like receptors (e.g., TLR7 and TLR8). Reduction of innate immune response can also be measured by decreased cell death following one or more administrations of modified RNAs to a cell population; e.g., cell death is 10%, 25%», 50%, 75%, 85%, 90%, 95%, or over 95% less than the cell death frequency observed with a corresponding unmodified nucleic acid. Moreover, cell death may affect fewer than 50%, 40%, 30%, 20%, 10%, 5%, 1%, 0.1%, 0.01%) or fewer than 0.01% of cells contacted with the modified nucleic acids.

[0070] The invention provides for the repeated introduction (e.g., transfection) of modified, nucleic acids into a target cell population, e.g., in vitro, ex vivo, or in vivo. The step of contacting the cell population may be repeated one or more times (such as two, three, four, five or more than five times). In some embodiments, the step of contacting the cell population with the modified nucleic acids is repeated a number of times sufficient such that a predetermined efficiency of protein translation in. the cell population is achie ved. Gi ven the reduced cytotoxicity of the target cell population provided by the nucleic acid modifications, such repeated transfections are achievable in a diverse array of cell types.

Polypeptide variants. [0071] Provided are nucleic acids that encode variant polypeptides, which have a certain identity with a reference polypeptide (e.g., an anti-microbial polypeptide (e.g,, an anti-bacterial polypeptide), e.g., an anti-microbial polypeptide described herein) sequence. The term "identity" as known in the art, refers to a relationship between the sequences of two or more peptides, as determined by comparing the sequences. In the art, "identity" also means the degree of sequence relatedness between peptides, as determined by the number of matches between strings of two or more amino acid residues, "identity" measures the percent of identical matches between the smal ler of two or more sequences with gap alignments (if any) addressed by a particular mathematical model or computer program (i.e., "algorithms"). Identity of related peptides can be readily calculated by known methods. Such methods include, but are not limited to, those described in Computational Molecular Biology, Lesk, A. M., ed., Oxford University Press, New York, 1988; Biocomputing: Informatics and Genome Projects, Smith, D. W,, ed., Academic Press, New York, 1993: Computer Analysis of Sequence Data, Part 1, Griffin, A. M., and Griffin, H, G., eds., Humana Press, New Jersey, 1994; Sequence Analysis in Molecular Biology, von Heinje, G., Academic Press, 1987: Sequence Analysis Primer, Gribskov, M. and Devereux, J., eds., M, Stockton Press, New York, 1991: and Carillo et a!., SIAM J, Applied Math. 48, 1073 (1988).

[0072] In some embodiments, the polypeptide variant has the same or a similar activity as the reference polypeptide. Alternatively, the variant has an altered activity (e.g., increased or decreased) relative to a reference polypeptide. Generally, variants of a particular polynucleotide or polypeptide of the invention will have at least about 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 91%, 92%», 93%, 94%, 95%, 96%, 97%, 98%, 99% or more sequence identity to that particular reference polynucleotide or polypeptide as determined by sequence alignment programs and parameters described herein and known to those skilled in the art,

[Θ073] As recognized by those skilled in the art, protein fragments, functional protein domains, and homol ogous proteins are also considered to be within the scope of this invention. For example, pro vided herein is any protein f agment of a reference protein (meaning a polypeptide sequence at least one amino acid residue shorter than a reference polypeptide sequence but otherwise identical) 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 70, 80, 90, 100, or greater than 100 amino acids in length In another example, any protein that includes a stretch of about 20, about 30, about 40, about 50, or about 100 amino acids which are about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, about 95%, about 98%, or about 100% iden tical to any of the sequences described herein can be utilized in accordance with, the invention. In certain embodiments, a protein sequence to be utilized in accordance with the invention includes 2, 3, 4, 5, 6, 7, 8, 9, 10, or more mutations as shown in any of the sequences provided or referenced herein.

Polyiiacleqtide libraries.

[0074] Also provided are polynucleotide libraries containing nucleoside modifications, wherein the polynucleotides individually contain a first nucleic acid sequence encoding a polypeptide, such as an anti -microbial polypeptide (e.g,, an anti-bacterial polypeptide), e.g., an anti-microbial polypeptide described herein. Preferably, the polynucleotides are mRNA in a form suitable for direct introduction into a target cell host, which in turn synthesizes the encoded polypeptide.

[0075] In certain embodiments, multiple variants of a protein, each with different amino acid modifications), are produced and tested to determine the best variant in terms of

pharmacokinetics, stability, bioeompatibiiity, and/or biological activity, or a biophysical property such as expression level. Such a library may contain 10, 10^*, 10^J, 10\ 10⁵, 10\ 10 ', 10⁸, 10^'', or over 10⁹ possible variants (including substitutions, deletions of one or more residues, and insertion of one or more residues).

Polypeptide-nucleic acid complexes.

[0076] Proper protein translation involves the physical aggregation of a number of polypeptides and nucleic acids associated with the mRNA. Provided by the invention are complexes containing conjugates of protein and nucleic acids, containing a translatable mRNA encoding an anti-microbial polypeptide (e.g., an anti-bacterial polypeptide), e.g., an antimicrobial polypeptide described herein), and having one or more nucleoside modifications (e.g., at least two different nucleoside modifications) and one or more polypeptides bound to the mRNA. Generally, the proteins are provided in an amount effective to prevent or reduce an innate immune response of a cell into which the complex is introduced.

Targeting Moieties.

[0077] In embodiments of the invention, modified nucleic acids are pro vided to express a protein-binding partner or a receptor on the surface of the cell, which functions to target the cell to a specific tissue space or to interact with a specific moiety, either in vivo or in vitro. Suitable protein-binding partners include antibodies and functional fragments thereof, scaffold proteins, or peptides, Additionally, modified nucleic acids can be employed to direct the synthesis and extracellular localization of lipids, carbohydrates, or other biological moieties.

[0078] As described herein, provided are mRNAs having sequences that are substantially not translatable. Such mRNA is effective as a vaccine when administered to a mammalian subject.

[0079] Also provided are modified nucleic acids that contain one or more noncodmg regions. Such modified nucleic acids are generally not translated, but are capable of binding to and sequestering one or more translational machinery component such as a ribosomal protein or a transfer RNA (tRNA), thereby effectively reducing protein expression i the ceil. The modified nucleic acid may contain a small nucleolar RNA (sno-RNA), micro RNA (miRNA), small interfering RNA (siRNA), or Piwi-interaeting RNA (piRNA).

[0080] Additionally, certain modified nucleosides, or combinations thereof, when introduced into modified nucleic acids activate the innate immune response. Such activating modified nucleic acids, e.g., modified RNAs, are useful as adjuvants when combined with polypeptides (e.g., anti-microbial polypeptides) or other vaccines. In certain embodiments, the activated modified mRNAs contain a translatable region which encodes for a polypeptide (e.g., an antimicrobial polypeptide (e.g., an anti-microbial polypeptide described herein)) sequence useful as a vaccine, thus providing the ability to be a self-adjuvant.

Modified

f008l| Nucleic acids for use in accordance with the invention may be prepared according to any available technique including, but not limited to chemical synthesis, enzymatic synthesis, which is generally termed in vitro transcription, enzymatic or chemical cleavage of a longer precursor, etc. Methods of synthesizing RNAs are known in the art (see, e.g., Gait, M.J. (ed.) Oligonucleotide synthesis: a practical approach, Oxford (Oxfordshire), Washington, DC: IRL Press, 1984; and Herdewijn, P, (ed.) Oligonucleotide synthesis: methods and applications.

Methods in Molecular Biology, v. 288 (Clifton, N.J.) Totowa, N.J.: Humana Press, 2005; both of which are incorporated herein by reference).

[0082] Modified nucleic acids need not be uniformly modified along the entire length of the molecule. Different nucleotide modifications and/or backbone stnictures may exist at various positions in the nucleic acid. One of ordinary skill in the art will appreciate that the nucleotide analogs or other may be located at any position(s) of a nucleic acid such that the function of the nucleic acid is not substantially decreased. A modification may also be a 5' or 3' terminal modification. The nucleic acids may contain at a minimum one and at maximum 100% modified nucleotides, or any intervening percentage, such as at least 50% modified nucleotides, at least 80% modified nucleotides, or at least 90% modified nucleotides.

[0083] Generally, the length of a modified mRNA of the present invention is greater than 30 nucleotides in length. In another embodiment, the RNA molecule is greater than 35, 40, 45, 50, 60, 75, 100, 125, 150, 175, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1800, 2000, 3000, 4000, 5000 nucleotides, or greater than 5000 nucleotides.

Uses of m^_^

Therapeutic Agents.

[0084] The modified nucleic acids described herein can be used as therapeutic agents to treat or prevent microbial infections and/or diseases, disorders, or conditions associated with microbial infections. Provided herein are compositions (e.g., pharmaceutical compositions), formulations, methods, kits, dressings (e.g., wound dressings), bandages (e.g., adhesive bandages), and reagents for treatment or prevention of diseases, disorders, or conditions, e.g., diseases, disorders, or conditions associated with microbial infections (e.g., bacterial infections), in humans and other animals (e.g., mammals). The active therapeutic agents of the invention include modified nucleic acids, cells containing modified nucleic acids or polypeptides translated from the modified nucleic acids, polypeptides translated from modified nucleic acids, and cells contacted with cells containing modified nucleic acids or polypeptides translated from the modified nucleic acids.

[0085] Provided are methods of inducing translation of a recombinant polypeptide (e.g. , an anti-microbial polypeptide described herein) in a cell population using the modified nucleic acids described herein. Such translation can be in vivo, ex vivo, in culture, or in vitro. The cell population is contacted with an effective amount of a composition containing a nucleic acid that has at least one nucleoside modification, and a translatable region encoding the recombinant polypeptide. The population is contacted under conditions such that the nucleic acid is localized into one or more cells of the cell popul ation and the recombinant polypeptide is translated in the ceil from the nucleic acid. [0086] An effective amount of the composition is provided based, at least in part, on the target tissue, target cell, type, means of administration , physical characteristics of the nucleic acid (e.g., size, and extent of modified nucleosides), and other determinants. In general, a effective amount of the composition provides efficient protein production in the cell, preferably more efficient than a composition containing a corresponding unmodified nucleic acid. Increased efficiency may be demonstrated by increased cell transfection (i.e., the percentage of cells transfected with the nucleic acid), increased protein translation from the nucleic acid, decreased nucleic acid degradation (as demonstrated, e.g., by increased duration of protein translation from a modified nucleic acid), or reduced innate immune response of the host cell

[0087] Aspects of the discl osures are directed to methods of inducing in vivo translation of a recombinant polypeptide (e.g., an anti-microbial polypeptide described herein) in a human or animal (e.g., mammalian) subject in need thereof. Therein, an effective amount of a composition containing a nucleic acid that has at least one nucleoside modification and a translatable region encoding the recombinant polypeptide (e.g., an anti-microbiai polypeptide described herein) is administered to the subject using the delivery methods described herein. The nucleic acid is provided in an amount and under other conditions such that the nucleic acid is localized into a cell of the subject and the recombinant polypeptide is translated in the cell from the nucleic acid, The cell in which the nucleic acid is localized, or the tissue in which the cell is present, may be targeted with one or more than one rounds of nucleic acid administration.

[0088] Other aspects of the disclosures relate to transplantation of cells containing modified nucleic acids to a human or animal (e.g., mammalian) subject. Administration of cells to human or animal (e.g., mammalian) subjects is known to those of ordinary skill in the art, such as local implantation (e.g., topical or subcutaneous administration), organ delivery or systemic injection (e.g., intravenous injection or inhalation), as is the formulation of cells in pharmaceutically acceptable carrier. Compositions containing modified nucleic acids are formulated for administration intramuscularly, transarterialiy, intraocularly, vaginally, rectally,

intraperitoneal.lv, intravenously, intranasally, subcutaneously, endoscopically, transdermal!)_'', or intrathecally. In some embodiments, the composition is formulated for extended release.

[0089] The subject to whom the therapeutic agent is administered suffers from or is at risk of developing a disease, disorder, or deleterious condition. Provided are methods of identifying, diagnosing, and classifying subjects on these bases, which may include clinical diagnosis, biomarker levels, genome-wide association studies (GWA8), and other methods known in the art,

f 0090 [ in certain embodiments, nucleic acids encoding an anti-microbiai polypeptide (e.g., an anti-bacterial polypeptide), e.g., an anti-microbial polypeptide described herein, are administered to subjects in need of anti-microbial polypeptide (e.g., an anti-bacteria! polypeptide) administration.

[0091] In certain embodiments, the administered modified nucleic acid directs production of one or more recombinant polypeptides that provide a functional activity which is substantially absent in the cell in which the recombinant polypeptide is translated , For example, the missing functional activity may be enzymatic, structural, or gene regulatory in nature, in related embodiments, the administered modified nucleic acid directs production of one or more recombinant polypeptides that increases (e.g., synergistically) a functional activity which is present but substantially deficient in the cell in which the recombinant polypeptide is translated.

[0092] In other embodiments, the administered modified nucleic acid directs production of one or more recombinant polypeptides that replace a polypeptide (or multiple polypeptides) that is substantially absent in the cell in which the recombinant polypeptide is translated. Such absence may be due to genetic mutation of the encoding gene or regulatory pathway thereof. In some embodiments, the recombinant polypeptide increases the level of an endogenous protein in the cell to a desirable level; such an increase may bring the level of the endogenous protein from a subnormal level to a normal level, or from a normal level to a super-normal level,

f 00931 Alternatively , the recombinant polypeptide functions to antagonize the acti vity of an endogenous protein present in, on the surface of, or secreted from the cell. Usually, the activity of the endogenous protein is deleterious to the subject, for example, due to mutation of the endogenous protein resulting in altered activity or localization. Additionally, the recombinant polypeptide antagonizes, directly or indirectly, the activity of a biological moiety present in, on the surface of, or secreted from the ceil. Examples of antagonized biological moieties include lipids (e.g., cholesterol), a lipoprotein (e.g., low density lipoprotein), a nucleic acid, a carbohydrate, a protein toxin such as shiga and tetanus toxins, or a small molecule toxin such as botulinum, cholera, and diphtheria toxins. Additionally, the antagonized biological molecule may be an endogenous protein that exhibits an undesirable activity, such as a cytotoxic or cytostatic activity, [0094] The recombinant proteins described herein are engineered for localization within the cell, potentially within a specific compartment such as the nucleus, or are engineered for secretion from the cell or translocation to the plasma membrane of the cell

[0095] As described herein, a useful feature of the modified nucleic acids of the invention is the capacity to reduce the innate immune response of a cell to an exogenous nucleic acid.

Provided are methods for perforniing the titration, reduction or elimination of the immune response in a cell or a population of cells. In some embodiments, the cell is contacted with a first composition that contains a first dose of a first exogenous nucleic acid including a translatable region and at least one nucleoside modification, and the level of the innate immune response of the cell to the first exogenous nucleic acid is determined. Subsequently, the ceil is contacted with a second composition, which includes a second dose of the first exogenous nucleic acid, die second dose containing a lesser amount of the first ex ogenous nucleic acid as compared to the first dose. Alternatively, the cell is contacted with a first dose of a second exogenous nucleic acid. The second exogenous nucleic acid may contain one or more modified nucleosides, which may be the same or different from the first exogenous nucleic acid or, alternatively, the second exogenous nucleic acid may not contain modified nucleosides. The steps of contacting the cell with the first composition and/or the second composition may be repeated one or more times. Additionally, efficiency of protein production (e.g., protein translation) in the cell is optionally determined, and the cell may be re-transfected with the first and/or second composition repeatedly until a target protein production efficiency is achieved.

Topical delivery applied to the skin.

[0096] The skin is a desirable target site for nucleic acid delivery. It is readily accessible, and gene expression may be restricted not only to the skin, potentially avoiding nonspecific toxicity, but also to specific layers and cell types within the skin. The site of cutaneous expression of the delivered nucleic acid will depend on the route of nucleic acid delivery. Three routes are commonly considered to deliver nucleic acids to the skin: (i) topical application (e.g. for local/regional treatment); (ii) intradermal injection (e.g. for local/regional treatment); and (iii) systemic delivery (e.g., for treatment of dermatoiogic diseases that affect both cutaneous and extracutaneous regions). Nucleic acids can be delivered to the skin by several different approaches. Most have been shown to work for D A, such as, topical application of non- cationic liposome-DNA complex, cationic liposome-DNA complex, particle-mediated (gene gun), puncture-mediated gene transfections, and viral delivery approaches. After gene delivery, gene products have been detected in a number of skin cell types, including but not limited to, basal keratinocytes, sebaceous gland cells, dermal fibroblasts and dermal macrophages.

[0097] In certain embodiments, dressing compositions comprising a modified nucleic acid encoding for an anti-microbia! polypeptide (e.g., an anti-bacterial polypeptide), e.g., an antimicrobial polypeptide described herein, precursor or a partially or fully processed form are pro vided herein.

[0098] In certain embodiments, the composition described herein is formulated for administration via a bandage (e.g. , adhesive bandage).

[0099] The modified nucleic acids encoding for an anti-microbial polypeptide (e.g., an antibacterial polypeptide), e.g., an anti-microbial polypeptide described herein, precursor or a partially or fully processed form described herein may be intermixed with the dressing compositions or may be applied separately, e.g. by soaking or spraying.

Targeting Moieties.

[00100] In embodiments of the disclosure, modified nucleic acids are provided to express a protein-binding partner or a receptor on the surface of the cell, which functions to target the cell to a specific tissue space or to interact with a specific moiety, either in vivo or in vitro. Suitable protein-binding partners include antibodies and functional fragments thereof, scaffold proteins, or peptides. Additionally, modified nucleic acids can be employed to direct the synthesis and extracellular localization of lipids, carbohydrates, or other biological moieties.

Methods of treating diseases and conditions.

[00101] Provided are methods for treating or preventing a microbial infection (e.g., a bacterial infection) and/or a disease, disorder, or condition associated with a microbial infection (e.g., a bacterial infection), and/or a symptom thereof, by providing an anti-microbial (e.g., antibacterial) activity. Because of the rapid initiation of protein production following introduction of modified mRNAs, as compared to viral DNA vectors, the compounds of the present invention are particularly advantageous in treating acute or chronic diseases such as microbial infections and sepsis. Moreover, the lack of transcriptional regulation of the modified mRNAs of the invention is advantageous in that accurate titration of protein production is achievable, In some embodiments, modified mRNAs and their encoded polypeptides in accordance with the present invention may be used for therapeutic purposes. [00102] In some embodiments, modified ni NAs and their encoded polypeptides in accordance with the present disclosure may be used for treatment of microbial infections and/or any of a variety of diseases, disorders, and/or conditions associated with microbial infections. Microbial infections can include, but not limited to, bacterial infections, viral infections, fungal infections, and protozoan infections.

[00103] In one embodiment, modified mR As and their encoded polypeptides in accordance with the present disclosure may be useful in the treatment of inflammatory disorders coincident with or resulting from infection.

[00104] Exemplary diseases, disorders, or conditions associated with bacterial infections include, but not limited to one or more of the following: abscesses, actinomycosis, acute prostatitis, aeromonas liydrophila, annual ryegrass toxicity, anthrax, baciliary peliosis, bacteremia, bacterial gastroenteritis, bacteria! meningitis, bacterial pneumonia, bacterial vaginosis, bacterium-related cutaneous conditions, bartonellosis, BCG-oma, botryomycosis, botulism, Brazilian purpuric fever, Brodie abscess, brucellosis, Buruli ulcer, campyiobacieriosis, caries, Carrion's disease, cat scratch disease, cellulitis, chlamydia infection, cholera, chronic bacterial prostatitis, chronic recurrent multifocal osteomyelitis, clostridial necrotizing enteritis, combined periodontic-endodontic lesions, contagious bovine leuropneumonia, diphtheria, diphtheritic stomatitis, ehrlichiosis, erysipelas, pigiottitis, erysipelas, Fitz-Hugh-Curtis syndrome, flea-borae spotted fever, foot rot (infectious pododermatitis), Garre's sclerosing osteomyelitis, Gonorrhea, Granuloma inguinale, human granulocytic anaplasniosis, human monocytotropic ehrlichiosis, hundred days' cough, impetigo, late congenital syphilitic oculopathy, legioneilosis, Lemierre's syndrome, leprosy (Hansen's Disease), leptospirosis, listeriosis, Lyme disease, lymphadenitis, melioidosis, meningococcal disease, meningococcal septicaemia, methiciilin-resistant Staphylococcus aureus (MRSA) infection, mycobacterium avium-intracellulare (MAI), mycoplasma pneumonia, necrotizing fasciitis, nocardiosis, noma (cancram oris or gangrenous stomatitis), omphalitis, orbital cellulitis, osteomyelitis,

overwhelming post-splenectomy infection (OPSI), ovine brucellosis, pasteureilosis, periorbital cellulitis, pertussis (whooping cough), plague, pneumococcal pneumonia, Pott disease, proctitis, pseudomonas infection, psittacosis, pyaemia, pyomyositis, Q fever, relapsing fever (typhinia), rheumatic fever, Rocky Mountain spotted fever (RMSF), rickettsiosis, salmonellosis, scarlet fever, sepsis, serratia infection, shigellosis, southern tick-associated rash illness, staphylococcal scalded skin syndrome, streptococcal pharyngitis, swimming pool granuloma, swine brucellosis, syphilis, syphilitic aortitis, tetanus, toxic shock syndrome (TSS), trachoma, trench fever, tropical ulcer, tuberculosis, tularemia, typhoid fever, typhus, urogenital tuberculosis, urinary tract infections, vancomycin-resistant Staphylococcus aureus infection, Waterhouse-Friderichsen syndrome, pseudotuberculosis (Yersinia) disease, and yersiniosis. Other diseases, disorders, and/or conditions associated with bacterial infections can include, for example, Alzheimer's disease, anorexia nervosa, asthma, atherosclerosis, attention deficit hyperactivity disorder, autism, autoimmune diseases, bipolar disorder, cancer (e.g. , colorectal cancer, gallbladder cancer, lung cancer, pancreatic cancer, and stomach cancer), chronic fatigue syndrome, chronic obstructive pulmonary disease, Crohn's disease, coronary heart disease, dementia, depression, Guillain-Barre syndrome, metabolic syndrome, multiple sclerosis, myocardial infarction, obesity, obsessive-compulsive disorder, panic disorder, psoriasis, rheumatoid arthritis, sarcoidosis, schizophrenia, stroke, thromboangiitis obliterans (Buerger's disease), and Tourette syndrome.

[00105] The bacterium described herein can be a Gram-positive bacterium or a Gram-negative bacterium. Exemplary bacterial pathogens include, but not limited to, Acinetobacter baumannii, Bacillus anthracis. Bacillus subtilis, Bordetella pertussis, Borrelia burgdorferi, Brucella abortus, Brucella cards, Brucella melitensis, Brucella suis, Campylobacter jejuni, Chlamydia pneumoniae, Chlamydia trachomatis, Chlamydophila psittaci, Clostridium botulinum,

Clostridium difficile, Clostridium perfringens, Clostridium tetani, coagulase Negative

Staphylococcus, Corynebacterium diphtheria, Enterococcus faecalis, Enterococcus faecium, Escherichia coli, enterotoxigenic Escherichia coli (ETEC), enteropathogenic E. coli, E. coli 0157:H7, Enterohacter sp,, Francisella tularensis, Haemophilus influenzae, Helicobacter pylori, Klebsiella pneumoniae, Legionella pneumophila, Leptospira interrogans, Listeria

monocytogenes, Moraxeila catarralis, Mycobacterium leprae, Mycobacterium tuberculosis, Mycoplasma pneumoniae, Neisseria gonorrhoeae, Neisseria meningitides, Preteus mirabilis, Proteus sps., Pseudomonas aeruginosa, Rickettsia rickettsii, Salmonella typhi, Salmonella typhimurium, Serratia rnarcesens, Shigella flex eri, Shigella sonnei, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophytics, Streptococcus agalactiae,

Streptococcus rnutans, Streptococcus pneumoniae, Streptococcus pyogenes, Treponema pallidum, Vibrio choierae, and Yersinia pestis. Bacterial pathogens may also include bacteria that cause resistant bacterial infections, for example, cl idamycin-resistant Clostridium difficile, fluoroqumolon-resistant Clostridium difficile, Slφhyioco(xιts aureus (MRSA), mu!tidrag-resistant Enterococcus faecalis, multidrug-resistant Enterococcus faecium, multidrug-resistance Pseudomonas aeruginosa, multidrug-resistant Acinetobacter baumannii, and vancomycin-resistant Staphylococcus aureus (VRSA).

[00106] Exemplary diseases, disorders, or conditions associated with viral infections include, but not limited to, acute febrile pharyngitis, pharyngoconjunctival fever, epidemic

keratoconjunctivitis, infantile gastroenteritis, Coxsackie infections, infectious mononucleosis, Burkiti lymphoma, acute hepatitis, chronic hepatitis, hepatic cirrhosis, hepatocellular carcinoma, primary HSV-1 infection (e.g., gingivostomatitis in children, tonsillitis and pharyngitis in adults, keratoconjunctivitis), latent HSV-1 infection (e.g., herpes labialis and cold sores), primary HSV- 2 infection, latent HSV-2 infection, aseptic meningitis, infectious mononucleosis, Cytomegalic inclusion disease, Kaposi sarcoma, multicentric Castleman disease, primary effusion lymphoma, AIDS, mfluenza, Reye syndrome, measles, postinfectious encephalomyelitis, Mumps, hyperplastic epithelial lesions (e.g., common, flat, plantar and anogenital warts, laryngeal papillomas, epidermodysplasia verruciformis), cervical carcinoma, squamous cell carcinomas, croup, pneumonia, bronchiolitis, common cold, Poliomyelitis, Rabies, bronchiolitis, pneumonia, influenza-like syndrome, severe bronchiolitis with pneumonia, German measles, congenital rubella, Varicella, and herpes zoster.

[00107] Exemplary viral pathogens include, but not limited to. adenovirus, coxsackievirus, dengue virus, encephalitis virus, Epstein-Barr virus, hepatitis A virus, hepatitis B virus, hepatitis C virus, herpes simplex virus type 1, herpes simplex virus type 2, cytomegalovirus, human herpesvirus type 8, human immunodeficiency virus, influenza virus, measles virus, mumps virus, human papillomavirus, parainfluenza virus, polioviras, rabies vims, respiratory syncytial virus, rubella virus, varicella-zoster virus, West Nile virus, and yellow fever virus. Viral pathogens may also include viruses that cause resistant viral infections.

[00108] Exemplary diseases, disorders, or conditions associated with fungal infections include, but not limited to, aspergilloses, blastomycosis, candidasis, coccidioidomycosis, cryptococcosis, histoplasmosis, mycetomas, paracoccidioidomycosis, and tinea pedis,

Furthermore, persons with immuno-deficiencies are particularly susceptible to disease by fungal genera such as Aspergillus, Candida, Cryptoccocus, Histoplasma, and Pneumocystis. Other fungi can attack eyes, nails, hair, and especially skin, the so-called dermatophyte fungi and keratmopbilie fungi, and cause a variety of conditions, of which ringworms such as athlete's foot are common. Fungal spores are also a major cause of allergies, and a wide range of fungi from different taxonomic groups can evoke allergic reactions in some people,

[00109] Exemplary fungal pathogens include, but not limited to, Ascomycota (e.g., Fusarium ox sporum, Pneumocystis jirovecii, Aspergillus spp., Coccidioides immitis/posadasii , Candida albicans), Basidiomycota (e.g., Filobasidiella neoformans, Trkhosporon), Microsporidia (e.g., Encephalitozoon cuniculi, Enterocytozoon bieneusi), and Mucoromycotina (e.g., Mucor circinelloides, Rhizopus oryzae, Lichtheimia corymbifera).

[00110] Exemplar/ diseases, disorders, or conditions associated with protozoal infections include, but not limited to, amoebiasis, giardiasis, trichomoniasis, African Sleeping Sickness, American Sleeping Sickness, leishmaniasis (Kala-Azar), balantidiasis, toxoplasmosis, malaria, acanthamoeba keratitis, and babesiosis.

[001 1] Exemplary protozoal pathogens include, but not limited to, Entamoeba histolytica, Giardia lambila, Trichomonas vaginalis, Trypanosoma br cei, T cruzi, Leishmania donovani, Balantidium coli, Toxoplasma gondii, Plasmodium spp. , and Babesia microti.

[00112] Exemplar}' diseases, disorders, or conditions associated with parasitic infections include, but not limited to, acanthamoeba keratitis, amoebiasis, ascariasis, babesiosis, balantidiasis, bavlisascariasis, chagas disease, clonorchiasis, cochiiomyia, cryptosporidiosis, diphyllobothriasis, dracunculiasis, echinococcosis, elephantiasis, enterobiasis, fascioliasis, fasciolopsiasis, filariasis, giardiasis, gnathostomiasis, hymenolepiasis, isosporiasis, katayama fever, leishmaniasis, lyme disease, malaria, metagonimiasis, myiasis, onchocerciasis, pediculosis, scabies, schistosomiasis, sleeping sickness, strongyloidiasis, taeniasis, toxocariasis, toxoplasmosis, trichinosis, and trichuriasis.

[00113] Exemplary parasitic pathogens include, but not limited to, Acanthamoeba, Anisakis, Ascaris lumbricoides, botfly, Balantidium coli, bedbug, Cestoda, chiggers, Cochiiomyia hominivorax, Entamoeba histolytica, Fasciola hepatica, Giardia lamblia, hookworm,

Leishmania, Linguatula serrata, liver fluke, Loa loa, Paragonimus, pinworm, Plasmodium falciparum, Schistosoma, Strongyloides stercoralis, mite, tapeworm, Toxoplasma gondii, Trypanosoma, whipworm, Wuchereria hancrofti.

[001 4] Exemplary diseases, disorders, or conditions associated with prion infections include, but not limited to Creutzfeldt- Jakob disease (CJD), iatrogenic Creutzfeldt- Jakob disease (iCJD), variant Creutzfeldt-Jakoh disease (vCJD), familial Creutzfeldt-Jakob disease (fCJD), sporadic Creutzfeldt--- Jakob disease (sCJD), Gerstmann-Straussler-Sclieinker syndrome (GSS), fatal familial insomnia (FFI), Kuru, Scrapie, bovine spongiform encephalopathy (BSE), mad cow disease, transmissible mink encephalopathy (TME), chronic wasting disease (CWD), feline spongiform encephalopathy (FSE), exotic ungulate encephalopathy (EUE), and spongiform encephalopathy,

100115] Provided herein, are methods to prevent infection and/or sepsis in a subject at risk of developing infection and/or sepsis, the method comprising administering to a subject in need of such prevention a composition comprising a modified nucleic acid precursor encoding an antimicrobial polypeptide (e.g., an anti-bacterial polypeptide), e.g., an anti-niicrobial polypeptide described herein, or a partially or fully processed form thereof in an amount sufficient to prevent infection and/or sepsis, In certain embodiments, the subject at risk of developing infection and/or sepsis is a cancer patient. In certain embodiments, the cancer patient has undergone a conditioning regimen. In some embodiments, the conditioning regiment comprises

chemotherapy, radiatio therapy, or both.

[001 6] Further provided herein, are methods to treat infection and/or sepsis in a subject, the method comprising administering to a subject in need of such treatment a composition comprising a modified nucleic acid precursor encoding an anti-microbial polypeptide (e.g., an anti-bacterial polypeptide), e.g., an anti-microbial polypeptide described herein, or a partially or fully processed form thereof in an amount sufficient to treat an infection and/or sepsis. In certain embodiments, the subject in need of treatment is a cancer patient. In certain embodiments, the cancer patient has undergone a conditioning regimen. In some embodiments, the conditioning regiment comprises chemotherapy, radiation therapy, or both,

[00117] In one embodiment, the modified mRN As of the present in ven tion may be administered in conjunction with one or more antibiotics. These include, but are not limited to Aknilox , Ambisome, Amoxycillin, Ampicillin, Augmentm, Avelox, Azithromycin, Bactroban, Betadine, Betnovate, Blephamide, Cefaclor, Cefadroxil, Cefdinir, Cefepime, Cefix, Cefixime, Cefoxitin, Ceipodoxime, Cefprozil, Cefuroxime, Cefzil, Cephalexin, Cephazolin, Ceptaz, Chloramphenicol, Chlorhexidine, Chloromycetin, Chlorsig, Ciprofloxacin, Clarithromycin, Clindagel, Clindamycin, Clindatech, Cloxaciilin, Colistin, Co-trimoxazole, Demeclocycline, Diclocil, Dicloxaciliin, Doxycycline, Duricef, Erythromycin, Flamazine, Floxin, Framycetin, Fueidm, Furadantm, Fusidic, Gatifioxaem, Gemifloxaciii, Gemifioxachi, Ilosone, Iodine, Levaquin, Levofioxacin, Lomefloxacin, Maxaquin, Mefoxin, Meronem, Minocycline,

Moxifloxacin, Mvambiitol, Mycostatin, Neosporin, Netromycin, Nitrofurantoin, Norfloxacin, Norilet, Ofloxacin, Omnicef, Ospamox, Oxytetracycline, Paraxin, Penicillin, Pneumovax, Polyfax, Povidone, Rifadin, Rifampin, Rifaximin, Rifmah, Rimactane, Rocephin,

Roxithromycin, Seromyciri, Soframycin, Sparfloxacin, Staphlex, Targocid, Tetracycline, Tetradox, Tetraiysal, tobramycin. Tobramycin, Trecator, Tygacil, Vancocin, Velosef,

Vibramycin, Xifaxan, Zagam, Zitrotek, Zoderm, Zymar, and Zyvox.

[00118] In certain embodiments, the subject exhibits acute or chronic microbial infections (e.g., bacterial infections). In certain embodiments, the subject has received or is receiving a therapy. In certain embodiments, the therapy is radiotherapy, chemotherapy, steroids, ultraviolet radiation, or a combination thereof. In certain embodiments, the patient suffers from a microvascular disorder. In some embodiments, the microvascular disorder is diabetes. In certain embodiments, the patient has a wound. In some embodiments, the wound is an ulcer. In a specific embodiment, the wound is a diabetic foot ulcer, In certain embodiments, the subject has one or more burn wounds, In certain embodiments, the administration is local or systemic. In certain embodiments, the administration is subcutaneous. In certain embodiments, the administration is intravenous. In certain embodiments, the administration is oral In certain embodiments, the administration is topical. In certain embodiments, the administration is by inhalation. In certain embodiments, the administration is rectal. In certain embodiments, the administration is vaginal,

Combination Therapy

[00119] Provided are methods for treating or preventing a microbial infection (e.g., a bacterial infection) and/or a disease, disorder, or condition associated with a microbial infection (e.g. , a bacterial infection), or a symptom thereof, in a subject, by administering a modified nucleic acid encoding an anti-microbiai polypeptide (e.g., an anti-bacterial polypeptide), e.g., an antimicrobial polypeptide described herein in combination with an anti-microbiai agent (e.g., an anti-bacterial agent), e.g., an anti-microbial polypeptide or a small molecule anti-microbiai compound described herein. The anti-microbial agents include, but not limited to, anti-bacterial agents, anti-viral agents, anti-fungal agents, anti-protozoal agents, anti-parasitic agents, and anti- prion agents,

[00120] The agents can be administered simultaneously, for example in a combined unit dose (e.g., providing simultaneous deliver)/ of both agents). Alternatively, the agents can be administered at a specified time interval, for example, an interval of minutes, hours, days or weeks. Generally, the agents are concurrently bioavailable, e.g., detectable, in the subject. In some embodiments, the agents are administered essentially simultaneously, for example two unit dosages administered at the same time, or a combined unit dosage of the two agents. In other embodiments, the agents are delivered in separate unit dosages. The agents can be administered in any order, or as one or more preparations that includes two or more agents. In a preferred embodiment, at least one administratio of one of the agents, e.g., the first agent, is made within minutes, one, two, three, or four hours, or even within one or two days of the other agent, e.g. , the second agent. In some embodiments, combinations can achieve synergistic results, e.g., greater than additive results, e.g., at least 25, 50, 75, 100, 200, 300, 400, or 500% greater than additive results,

[00121] Exemplary anti-bacterial agents include, but not limited to, aminoglycosides (e.g., amikacin (A IKIN®), gentamicin (GARAMYCIN®), kanamycin ( ANTREX®), neomycin (MYCiFRADIN®), netilmicin (NETROMYCIN®), tobramycin (NEBCIN®), Paromomycin (HUMATIN®)), ansamycins (e.g., geldanamycin, herbimycin), carbacephem (e.g., loracarbef (LORABID®), Carbapenems (e.g., ertapenem (INVANZ®), doripenem (DORIBAX®), imipenem/cilastatin (PRIMAXIN®), meropenem (MERREM®), cephalosporins (first generation) (e.g., cefadroxi! (DURICEF®), cefazolin (ANCEF®), cefalotin or cefalothin (KEFLIN®), cefalexin (KEFLEX®), cephalosporins (second generation) (e.g., cefaclor

(CECLOR®), cefamandole (MANDOL®), cefoxitin (MEFOXIN®), cefprozil (CEFZIL®), cefuroxime (CEFTTN®, ZINNAT®)), cephalosporins (third generation) (e.g., cefixime

(SUPRAX®), cefdinir (O NICEF®, CEFDIEL®), cefditoren (SPECTRACEF®), cefoperazone (CEFOBID®), cefotaxime (CLAFORAN®), cefpodoxime (VANTIN®), ceftazidime

(FORTAZ®), ceftibuten (CEDAX®), ceftizoxime (CEFIZOX®), ceftriaxone (ROCEPHIN®)), cephalosporins (fourth generation) (e.g., cefepime (MAXIPIME®)), cephalosporins (fifth generation) (e.g., ceftobiproie (ZEFTERA®)), glycopeptides (e.g., teicoplanin (TARGOCID®), vancomycin (VA COCIN®), telavancin (VIBATIV®)), lincosamides (e.g., clindamycin (CLEOCIN®), lincomycin (LINCOCIN®)), lipopeptide (e.g., daptomycin (CUBICIN®)), macrolides (e.g., azithromycin (ZITHROMAX®, SIJMAMED®, ZITROCIN®), clarithromycin (BIAXIN®), dirithromycin (DYNABAC®), erythromycin (ERYTHOCIN®,

ERYTHROPED®), roxithromycin, ^oleandomycin (TAO®), telithromycin ( ETE ®), spectinomycin (TROBICIN®)), monobactanis (e.g., aztreonam (AZACTAM®)), nitrofurans (e.g., furazolidone (FUROXONE®), nitrofurantoin (MACRODANTIN®, MACROBID®)), penicillins (e.g., amoxicillin (NOVAMOX®, AMOXIL®), ampicillin (PRINCIPEN®), azIociUm, carbenicillin (GEOCILLIN®), cloxacillin (TEGOPEN®), dicloxacillin

(DYNAPEN®), flucloxaciilin (FLOXAPEN®), mezlocillin (MEZLIN®), metbicillin

(STAPHCILLIN®), nafcillin (UNIPE ®), oxacillin (PROSTAPHLIN®), penicillin G

(PENTIDS®), penicillin V (PEN-VEE-K®), piperacillin (PIPRACIL®), temocillin

(NEGABAN®), ticarcillm (TICAR®)), penicillin combinations (e.g., amoxicillin/clavulanate (AUGMENTED®), ampiciilin sulbactam (IJNA8YN®), piperaci!lin/tazobactam (ZOSYN®), ticarcillin'clavulanate (TIMENTIN®)), polypeptides (e.g., bacitracin, colistm (COLY-MYCIN- 8®}, polymyxin B, quinolones (e.g., ciprofloxacin (CIPRO®, CIPROXIN®, CIPROBAY®), enoxacin (PENETREX®), gatifloxacin (TEQUIN®), levofloxacin (LEVAQUi ®),

lomefloxacin (MAXAQU1N®), moxifJoxaein (AVELOX®), nalidixic acid (NEGGRAM®), norfloxacin (NOROXIN®), ofloxacin (FLOXIN®, OCUFLOX®), trovafloxacfri (TROVAN®), grepafloxacin (RAXAR®), sparfloxacm (ZAGAM®), temafloxacin (OM IFLOX®)), sulfonamides (e.g., mafenide (SULFAMYLON®), sulfonamidochrysoidine (PRONTOSIL®), sulfacetamide (SULAMYD®, BLEPH-10®), sulfadiazine (MICRO-SULFON®), silver sulfadiazine (SILVADENE®), sulfamethizole (THIOSULFIL FORTE®), sulfamethoxazole (GANTANOL®), suifanilimide, sulfasalazine (AZULFIDINE®), sulfisoxazole

(GANTRISIN®), trimethoprim (PROLOPRIM®), TRIMPEX®), trimethoprim- sulfamethoxazole (co-trinioxazole) (TMP-SMX) (BACTRIM®, SEPTRA®)), tetracyclines (e.g., demeclocycline (DECLOMYCIN®), doxycycline (VIBRAMY CIN®), minocycline

(MINGCIN®), oxytetracycline (TERRAMYCIN®), tetracycline (SUMYCIN®,

ACHROMYCIN® V, STECLIN®)), drugs against mycobacteria (e.g., clofazimine

(LAMPRENE®), dapsone (AVLOStlLFON®), capreomycin (CAPASTAT®), cycloserine (SEROMYCIN®). ethambutol (MYAMBUTOL®), ethionamide (TRECATOR®), isoniazid (LN.l-L®), pyrazinamide (ALDINAMIDE®), rifampin (RIFADIN®, RIMACTANE®), rifabutin (MYCOBUTIN®), rifapentine (PRIFTIN®), streptomycin), and others (e.g., arsphenaniine (SALVARSAN©), chloramphenicol (CHLOROMYCETI ©), fosfomycm (MONUROL®), fusidic acid (FUCIDIN®), linezolid (ZYVOX®), metronidazole (FLAGYL.©), mupirocin (BACTROBA ®), platensimycin, quinuprisiin,''dalfopristin (SY ERCI D®), rifaximin

(XIFAXAN©), thiarnphenicol, tigecycline (TIGACYL®), imidazole (TTNDAMAX®,

FAS1GYN®)).

[00122] Exemplary anti-viral agents include, but not limited to, abacavir (ZIAGEN®), abacavir/lamivudine/zidovudine (trizivir®), aeiclovir or acyclovir (CYCLQVIR®, HERPEX®, ACTVIR®, AC i v IRAX n . ZOVIRAX®, ZOVIR®), adefovir (Preveon®, Hepsera®), amantadine (SYMMETREL®), amprenavir (AGENERA8E®), ampligen, arbidol, atazanavir (REYATAZ®), boeeprevir, cidofovir, damnavir (PREZISTA®), delavirdine (RESCRiPTOR®), didanosine (VIDEX®), docosanol (ABREVA®), edoxudine, efavirenz (SUSTIVA®,

STOCRiN®), emtricitabine (EMTRIVA®), emtricitabine/tenofovir/efavirenz (ATRIPLA®), enfuviriide (FUZEON®), entecavir (BARACLUDE®, ENTAVIR®), famciclovir (FAMVTR®), fomivirsen (VITRAVENE®), fosamprenavir (LEXIVA®, TELZIR®), foscamet

(FOSCAVIR®), fosfonet, ganciclovir (CYTOVENE®, CYMEVENE®, VITRASERT®), GS 9137 (ELVITEGRAVIR®), imiquimod (ALDARA®, ZY CLARA®, BESELNA®), indinavir (CRIXIVAN®), inosine, inosine pranobex (IMIJNOVIR®), interferon type I, interferon type II, interferon type III, kutapressin (NEXAVIR®), lamivudine (ZEFFIX®, HEPTOVIR®,

EPIV R®), lamivudine/zidovudine (COMBIVIR®), lopinavir, ioviride, maraviroc

(SELZENTRY®, CELSENTRI®), methrsazone, MK-2048, moroxydine, nelfinavir

(VIRACEPT®), nevirapine (ViRAMUNE® ), oseltamivir (TA 1FLU®), peginterferon alfa-2a (PEGASYS®), penciclovir (DENAVIR®), perarnivir, pleconaril, podophyllotoxin

(CONDYLOX®), raltegravir (ISENTRESS®), ribavirin (COPEGUs®, REBETOL®, mBASPHERE®, VILONA® AND VIRAZOLE®), rimantadine (FLUMADINE®), ritonavir (NORV1R®), pyramidine, saquinavir (INVIRASE®, FORTOVASE®), siavudine, tea tree oil (melaleuca oil), tenofovir (VIREAD®), tenofovir/emtricitabine (TRUVADA®), tipranavir (APTTVUS®), trifluridine (YIROPTIC®), tromantadine (VIRU-MERZ®), valaciclovir

(VALTREX®), valganciclovir (VALCYTE®), vicriviroc, vidarabine, viramidine, zalcitabine, zanamivir (RELENZA®), and zidovudine (azidothymidine (AZT), RETROVIR®,

RETROViS®).

[00123] Exemplary anti-fungal agents include, but not limited to, polyene antifungals (e.g., natamycin, rimocidin, fiiipin, nystatin, amphotericin B, candicin, hamycin), imidazole antifungals (e.g., miconazole (MICATIN®, DAKTARIN®), ketoconazole (NIZORAL®, FUNGORAL®, SEBIZOLE®), clotrimazole (LOTRIMIN®, LOTRIMIN® AF, CANESTEN®), econazole, omoconazole, bifonazole, butoconazole, fenticoiiazole, isoconazole, oxiconazole, sertaconazole (ERTACZO®), suiconazole, tiocotiazole), triazole antifangais (e.g., aibaconazoie fluconazole, itraconazole, isavuconazole, ravuconazole, posaconazole, voriconazole,

terconazole), thiazole antifungals (e.g., abafungin), allylamines (e.g., terbinafirie (LAMISIL®), naftifme (NAFTIN®), butenafine (LOTRIMIN® Ultra)), echinocandins (e.g., anidulafungin, caspofungin, micafungin), and others (e.g,, polygodial, benzoic acid, ciclopirox, tolnaftate (TTNACTIN®, DESENEX®, AFTATE®), undecylenic acid, flucytosine or 5-fluorocytosme, griseofulvin, haloprogin, sodium bicarbonate, allicin).

[00124] Exemplary anti-protozoal agents include, but not limited to, eflor ithine, furazolidone (FUROXONE®, DEPEND AL-M®), melarsoprol, metronidazole (FLAGYL®), ornidazole, paromomycin sulfate (HUMATiN®), pentamidine, pyrimethamine (DARAPRIM®), and imidazole (TINDAMAX®, FASIGYN®).

[00125] Exemplary anti-parasitic agents include, but not limited to, antinematodes (e.g. , mebendazole, pyrantel pamoate, thiabendazole, dietliylcarbamazine, ivermectin), anticestodes (e.g., niclosamide, praziquantel, albendazole), antitrematodes (e.g., praziquantel), antiamoebics (e.g., rifampin, amphotericin B), and antiprotozoals (e.g., melarsoprol, eflornithine,

metronidazole, imidazole) .

10012 1 Exemplary anti -prion agents include, but not limited to, flupirtine, pentosan polysuphate, quinacrine, and tetracyclic compounds.

Targeting of pathogenic organisms; purification of biological materials.

[00127] Provided herein are methods for targeting pathogenic microorganisms, such as bacteria, yeast, protozoa, parasites, prions and the like, using modified mRNAs that encode cytostatic or cytotoxic polypeptides, e.g., anti-microbial polypeptides described herein.

Preferably the mRNA introduced into the target pathogenic organism contains modified nucleosides or other nucleic acid sequence modifications that the mRNA is translated

exclusively, or preferentially, in the target pathogenic organism, to reduce possible off-target effects of the therapeutic. Such methods are useful for removing pathogenic organisms from biological material, including blood, semen, eggs, and transplant materials including embryos, tissues, and organs.

Targeting of diseased cells.

[00128] Provided herein are methods for targeting pathogenic or diseased cells, particularly cells that are infected with one or more microorganisms (e.g., bacteria) or cancer cells, using modified mR As that encode cytostatic and/or cytotoxic polypeptides, e.g., anti-microbial polypeptides described herein, Preferably the mRN A introduced into the target pathogenic cell contains modified nucleosides or other nucleic acid sequence modifications that the mRNA is translated exclusively, or preferentially, in the target pathogenic ceil, to reduce possible off- target effects of the therapeutic. Alternatively, the invention provides targeting moieties that are capable of targeting the modified mRNAs to preferentially bind to and enter the target pathogenic cell.

Methods of protein production.

[00129] The methods provided herein are useful for enhancing protein (e.g., an anti-microbial polypeptide described herein) product yield in a ceil culture process. In a ceil culture containing a plurality of host cells, introduction of the modified mRNAs described herein results in increased protein production efficiency relative to a corresponding unmodified nucleic acid. Such increased protein production efficiency can be demonstrated, e.g., by showing increased cell transfection, increased protein translation from the nucleic acid, decreased nucleic acid degradation, and/or reduced innate immune response of the host cell. Protein production can be measured by ELISA, and protem activity can be measured by various functional assays known in the art. The protein production may be generated in a continuous or a fed-batch mammalian process.

[00130] Additionally, it is useful to optimize the expression of a specific polypeptide (e.g., an anti-microbial described herein) in a cell line or collection of cell lines of potential interest, particularly an engineered protein such as a protein variant of a reference protein having a known acti vity. In one embodimen t, provided is a method of optimizing expression of an engineered protein in a target ceil, by providing a plurality of target ceil types, and independently contacting with each of the plurality of target cell types a modified mRNA encoding an engineered polypeptide. Additionally, culture conditions may be altered to increase protein production efficiency. Subsequently, the presence and/or level of the engineered polypeptide in the plurality of target cell types is detected and/or quantitated, allowing for the optimization of an engineered polypeptide's expression by selection of an efficient target cell, and cell culture conditions relating thereto. Such methods are particularly useful when the engineered polypeptide contains one or more post-translationai modifications or has substantial tertiary structure, situations which often complicate efficient protein production.

[00131] The rapid translation of modified mRNAs introduced into cells provides a desirable mechanism of modulating target biological pathways, e.g., biological pathways associated with microbial infections (e.g., bacterial infections) and/or diseases, disorders or conditions associated with microbial infections (e.g., bacterial infections). Such modulation includes antagonism or agonism of a given pathway. In one embodiment, a method is provided for antagonizing a biological path way in a cell by contacting the cell with an effective amount of a composition comprising a modified nucleic acid encoding a recombinant polypeptide, under conditions such that the nucleic acid is localized into the cel l and the recombinant polypeptide is capable of being translated in the cell from the nucleic acid, wherein the recombinant polypeptide inhibits the activity of a polypeptide functional in the biological pathway,

[00132] Alternatively, provided are methods of agonizing a biological pathway in a ceil by contacting the ceil with an effective amount of a modified nucleic acid encoding a recombinant polypeptide under conditions such that the nucleic acid is localized into the cell and the recombinant polypeptide is capable of being translated in the cell from the nu cleic acid, and the recombinant polypeptide induces the activity of a polypeptide functional in the biological pathway. Exemplary agonized biological pathways include pathways that modulate antibacterial activity. Such agonization is reversible or, alternatively, irreversible.

Methods of cellular nucleic acid delivery.

Methods of the present invention enhance nucleic acid delivery into a cell population, in vivo, ex vivo, or in culture. For example, a cell culture containing a plurality of host ceils (e.g., eukaryotic cells such as yeast or mammalian cells) is contacted with a composition that contains an enhanced nucleic acid having at least one nucleoside modification and, optionally, a translatable region encoding an anti-microbial polypeptide (e.g., an anti-bacterial polypeptide), e.g., an antimicrobial polypeptide described herein. The composition also generally contains a transfection reagent or other compound that increases the efficiency of enhanced nucleic acid uptake into the host cells. The enhanced nucleic acid exhibits enhanced retention in the cell population, relative to a corresponding unmodified nucleic acid, The retention of the enhanced nucleic acid is greater than the retention of the unmodified nucleic acid, in some embodiments, it is at least about 50%, 75%, 90%, 95%, 100%, 150%, 200%, or more than 200% greater than the retention of the unmodified nucleic acid. Such retention advantage may be achieved by one round of transfection with the enhanced nucleic acid, or may be obtained following repeated rounds of transfection.

| 00134] in some embodiments, the enhanced nucleic acid is delivered to a target cell population with one or more additional nucleic acids. Such delivery may be at the same time, or the enhanced nucleic acid is delivered prior to del ivery of the one or more additional nucleic acids. The additional one or more nucleic acids may be modified nucleic acids or unmodified nucleic acids, it is understood that the initial presence of the enhanced nucleic acids does not substantially induce an innate immune response of the cell population and, moreover, that the innate immune response wil l not be activ ated by the later presence of the unmodified nucleic acids. In this regard, the enhanced nucleic acid may not itself contain a translatable region, if the protein desired to be present in the target cell population is translated from the unmodified nucleic acids.

[00135] The present invention provides enhanced nucleic acids (e.g., nucleic acids described herein), and complexes containing enhanced nucleic acids associated with other deliverable moieties. Thus, the present invention provides pharmaceutical compositions comprising one or more enhanced nucleic acids, or one or more such complexes, and one or more pharmaceutically acceptable excipients. Pharmaceutical compositions may optionally comprise one or more additional therapeutically active substances. In some embodiments, compositions are administered to humans, For the purposes of the present disclosure, the phrase "active ingredient" generally refers to an enhanced nucleic acid to be delivered as described herein.

[00136] Alth ough the descriptions of pharmaceutical compositions pro vided herein are principally directed to pharmaceutical compositions which are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with merely ordinary, if any, experimentation. Subjects to which administration of the pharmaceutical compositions is contemplated include, but are not limited to, humans and/or other animals (e.g., primates, mammals), including commercially relevant mammals such as cattle, pigs, horses, sheep, cats, dogs, mice, and/or rats; and/or birds, including commercially relevant birds such as chickens, ducks, geese, and/or turkeys,

[00137] Formulations of the pharmaceutical compositions described herein may be prepared by any method known or hereafter developed in the ail of pharmacology. In general, such preparatory methods include the step of bringing the active ingredient into association with an excipient and/or one or more other accessory ingredients, and then, if necessary and/or desirable, shaping and/or packaging the product into a desired single- or multi-dose unit.

[00138J A pharmaceutical composition in accordance with the invention may be prepared, packaged, and/or sold in bulk, as a single unit dose, and/or as a plurality of single unit doses. As used herein, a "unit dose" is discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and/or a convenient fraction of such a dosage such as, for example, one-half or one-third of such a dosage.

[00139] Relative amounts of the active ingredient, the pharmaceutically acceptable excipient, and/or any additional ingredients in a pharmaceutical composition in accordance with the invention wall vary, depending upon the identity, size, and/or condition of the subject treated and further depending upon the route by which the composition is to be administered. By way of example, the composition may comprise between 0.1 % and 100% (w/w) active ingredient.

[00140] Pharmaceutical formulations may additionally comprise a pharmaceutically acceptable excipient, which, as used herein, includes any and all solvents, dispersion media, diluents, or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired. Remington's The Science and Practice of

Pharmacy, 21^st Edition, A. R, Gennaro (Lippincott, Williams & Wilkins, Baltimore, MD, 2006; incorporated herein by reference) discloses various excipients used in formulating

pharmaceutical compositions and known techniques for the preparation thereo Except insofar as any conventional excipient medium is incompatible with a substance or its derivatives, such as by producing any undesirable biological effect or otherwise interacting in a deleterious manner with any other components) of the pharmaceutical composition, its use is contemplated to be within the scope of this invention.

[0014 J j In some embodiments, a pharmaceutically acceptable excipient is at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% pure, In some embodiments, an excipient is approved for use in humans arid for veterinary use. In some embodiments, an excipient is approved by United States Food and Drug Administration, In some embodiments, an excipient is pharmaceutical grade. In some embodiments, an excipient meets the standards of the United States Pharmacopoeia (USP), the European Pharmacopoeia (EP), the British

Pharmacopoeia, and/or the International Pharmacopoeia.

[00142 J Pharmaceutically acceptable excipients used in the manufacture of pharmaceutical compositions include, but are not limited to, inert diluents, dispersing and/or granulating agents, surface active agents and/or emuisifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and/or oils. Such excipients may optionally be included in pharmaceutical formulations. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and/or performing agents can be present in the composition, according to the judgment of the formulator,

[00143] Exemplary diluents include, but are not limited to, calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, etc., and/or combinations thereof.

[00144] Exemplar/ granulating and/or dispersing agents include, but are not limited to, potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vmyl-pyrrolidone)

(crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (croscamieilose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium iauryl sulfate, quaternary ammonium compounds, etc., and/or combinations thereof,

f 001451 Exemplary surface active agents and/or emuisifiers include, but are not limited to, natural emuisifiers (e.g. acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays {e.g. bentonite [aluminum silicate] and Veegum^®' [magnesium aluminum silicate]), long chain amino acid derivatives, high molecular weight alcohols {e.g. stearyl alcohol, cetyl alcohol, oieyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), earhomers {e.g. carhoxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer), carrageenan, cellulosic derivatives e.g. carboxyrnethyicellulose sodium, powdered cellulose, hydroxymethyi cellulose, hydroxypropyl cellulose, hydroxypropyi methyicelluSose, methylcellulose), sorbitan fatty acid esters (e.g. polyoxyethylene sorbitan monolaurate [Tween^<¾'20], polyoxyethylene sorbitan [Tween^®60], polyoxyethylene sorbitan monooleate [Tween.^80], sorbitan

monopalmitate [Span^O], sorbitan monostearate [Span^O], sorbitan tristearate [Span^¾65], glyceryl monooleate, sorbitan monooleate [Span^&80]), polyoxyethylene esters (e.g.

polyoxyethylene monostearate Myr ^S], polyoxyethylene hydrogenated castor oil,

polyethoxylated castor oil, polyoxymethylene stearate, and Solutol^®'), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g. Cremophor*), polyoxyethylene ethers, (e.g.

polyoxyethylene lauryl ether [Brij"30]), polyfvinyl-pyrrolidone), diethylene glycol monolaurate, triethanolaniine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Piuronic³F 68, Poloxamer*188, cetrimonium bromide, cetylpyridiniimi chloride, benzaSkonium chloride, docusate sodium, etc. and/or combinations thereof.

[00146] Exemplar/ binding agents include, but are not limited to, starch (e.g. cornstarch and starch paste); gelatin; sugars (e.g. sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol,); natural and synthetic gums (e.g. acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethyicellulose, methylcellulose, ethylcelluiose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, micro crystalline cellulose, cellulose acetate, poly(vmyl-pyrrolidone), magnesium aluminum silicate (Veegum*), and larch arabogalactan); alginates; polyethylene oxide; polyethylene glycol; inorganic calcium salts: silicic acid; poiyniethaerylates; waxes; water; alcohol; etc.; and combinations thereof.

1001471 Exemplary preservatives may include, but are not limited to, antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives, and/or other preservatives. Exemplary antioxidants include, but are not limited to, alpha tocopherol, ascorbic acid, acorbyi palmitate, butylated hydroxyanisole, butylated hydroxy toluene, monolhioglycerol, potassium metabisuifite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisuifite, and/or sodium sulfite. Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA), citric acid monohydrate, disodium edetate, dipotassium edetate, edetic acid, fumaric acid, malic acid, phosphoric acid, sodium edetate, tartaric acid, and/or trisodium edetate. Exemplary antimicrobial preservatives include, but are not limited to, benzalkonium chloride, henzethonrum chloride, benzyl alcohol bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chiorocresol, chloroxylenol, cresol, ethyl, alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenyimercuric nitrate, propylene glycol, and/or thimerosai. Exemplary antifungal preservatives include, but are not limited to, butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and/or sorbic acid. Exemplary alcohol preservatives include, but are not limited to, ethanol, polyethylene glycol, phenol, phenolic compounds, bisplienol, chlorobutanol, hydroxybenzoate, and/or phenylethyl alcohol. Exemplary acidic preservatives include, but are not limited to, vitamin A, vitamin C, vitamin E, beta- carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and/or phytic acid. Other preservatives include, but are not limited to, tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT), ethylenediamme, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisuifite, potassium sulfite, potassium metabisuifite, Glydant Plus^®, Phenonip^®, methyl paraben, Genrnall^® 15, Germaben* !!, Neolone ", Katho™, and/or Euxyl*.

[001481 Exemplary buffering agents include, but are not limited to, citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium giubionate, calcium giuceptate, calcium gluconate, D- gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium ievulinate, pentaiioic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, etc., and/or combinations thereof.

[00149] Exemplary lubricating agents include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, etc., and combinations thereof.

[00150] Exemplary oils include, but are not limited to, almond, apricot kernel, a vocado, babassu, bergamot, black current seed, borage, cade, camomile, canola, caraway, caniauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea buckthorn, sesame, shea butter, silicone, soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut, and wheat germ oils. Exemplar oils include, but are not limited to, butyl stearate, capryiic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil,

octyldodecanol, oleyl alcohol, silicone oil, and/or combinations thereof.

[00151] Liquid dosage forms for oral and parenteral administratio include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and/or elixirs. In addition to active ingredients, liquid dosage forms may comprise inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formarnide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofuriuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof, Besides inert, diluents, oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and/or perfuming agents. In certain embodiments for parenteral administration, compositions are mixed with solubilizing agents such as Cremophor\ alcohols, oils, modified oils, glycols, polysorbates, cyc!odextrins, polymers, and/or combinations thereof.

[00152] Injectable preparations, for example, sterile mjectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing agents, wetting agents, and/or suspending agents. Sterile injectable preparations may be sterile injectable solutions, suspensions, and/or emulsions in nontoxic parenterally acceptable diluents and/or solvents, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S. P., and isotonic sodium chloride solution. Sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. Fatty acids such as oleic acid can be used in the preparation of injectables.

[00153] Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, and/or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[00154] In order to prolong the effect of an active ingredient, it is often desirable to slow the absorption of the active ingredient from subcutaneous or intramuscular injection . This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle. Injectable depot forms are made by forming microencapsuie matrices of the drug in biodegradable polymers such as polylactide-polyglycoli.de. Depen din g upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and polyi anhydrides). Depot injectable formulations are prepared by entrapping the drug in liposomes or microemuisions which are compatible with body tissues. [00155] Compositions for rectal or vaginal administration are typically suppositories which can be prepared by mixing compositions with suitable non-irritating excipients such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient. Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, an active ingredient is mixed with at least one inert, pharmaceutically acceptable excipient such as sodium citrate or dicalcium phosphate and/or fillers or extenders (e.g. starches, lactose, sucrose, glucose, mannitoi, and silicic acid), binders (e.g. carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidmone, sucrose, and acacia), humectants (e.g. glycerol), disintegrating agents (e.g. agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate), solution retarding agents (e.g. paraffin), absorption accelerators (e.g. quaternary' ammonium compounds), wetting agents (e.g. cetyl alcohol and glycerol monostearate), absorbents (e.g. kaolin and bentonite clay), and lubricants (e.g. talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium iauryi sulfate), and mixtures thereof, in the case of capsules, tablets and pills, the dosage form may comprise buffering agents.

[00156] Solid compositions of a similar type may be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well, as high molecular weight polyethylene glycols and the like. Solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or

preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes. Solid compositions of a similar type may be employed as fillers in soft and hard- filled gelatin capsules using such excipients as lactose or milk sugar as weli as high molecular weight polyethylene glycols and the like.

[00157] Dosage forms for topical, and/or transdermal administration of a composition may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants and/or patches. Generally, an active ingredient is admixed under sterile conditions with a

pharmaceutically acceptable excipient and/or any needed preservatives and/or buffers as may be required. Additionally, the present invention contemplates the use of transdermal patches, which often have the added advantage of providing controlled deliver}' of a compound to the body. Such dosage forms may be prepared, for example, b dissolving and/or dispensing the compound in the proper medium. Alternatively or additionally, rate may be controlled by either providing a rate controlling membrane and/or by dispersing the compound in a polymer matrix and/or gel.

[00158] Suitable devices for use in delivering intradermal pharmaceutical compositions described herein include short needle devices such as those described in U.S. Patents 4,886,499; 5,190,521; 5,328,483; 5,527,288; 4,270,537; 5,015,235; 5,141,496; and 5,417,662. intradermal compositions may be administered by devices which limit the effective penetration length of a needle into the skin, such as those described in PCT publication WO 99/34850 and functional equivalents thereof. Jet injection devices which deliver liquid compositions to the dermis via a liquid jet injector and/or via a needle which pierces the stratum comeum and produces a jet which reaches the dermis are suitable. Jet injection devices are described, for example, in U.S. Patents 5,480,381 ; 5,599,302; 5,334,1.44; 5,993,412; 5,649,912; 5,569,189; 5,704,911 ;

5,383,851; 5,893,397; 5,466,220; 5,339,163; 5,312,335; 5,503,627; 5,064,413; 5,520,639;

4,596,556; 4,790,824; 4,941,880; 4,940,460; and PCT publications WO 97/37705 and WO 97/13537. Ballistic powder/particle delivery devices which use compressed gas to accelerate vaccine in powder form through the outer layers of the skin to the dermis are suitable.

Alternatively or additionally, conventional syringes may be used in the classical mantoux method of intradermal administration.

[0015 j Formulations suitable for topical administration include, but are not limited to, liquid and/or semi liquid preparations such as liniments, lotions, oil in water and/or water in oil emulsions such as creams, ointments and/or pastes, and/or solutions and/or suspensions.

Topically-administrable formulations may, for example, comprise from about 1% to about 10% (w/w) active ingredient, although the concentration of active ingredient may be as high as the solubility limit of the active ingredient in the sol vent. Formulations for topi cal administration may further comprise one or more of the additional ingredients described herein.

[00160] A pharmaceutical composition may be prepared, packaged, and/or sold in a formulation suitable for pulmonary administration via the buccal cavity, Such a formulation may comprise dry particles which comprise the active ingredient and which have a diameter in the range from about 0.5 nm to about 7 nm or from about i nm to about 6 nm, Such compositions are suitably in the form of dry powders for administration using a device comprising a dry powder reservoir to which a stream of propellant may be directed to disperse the powder and/or using a self propelling solvent powder dispensing container such as a device comprising the active ingredient dissolved and/or suspended in a low-boiling propellant in a sealed container, Such powders comprise particles wherein at least 98% of the particles by weight have a diameter greater than 0,5 nm and at least 95% of the particles by number have a diameter less than 7 nm. Alternatively, at least 95% of the particles by weight have a diameter greater than 1 nm and at least 90% of the particles by number have a diameter less than 6 nm, Dry powder compositions may include a solid fine powder diluent such as sugar and are conveniently provided in a unit dose form.

[00161] Low boiling propellants generally include liquid propellants having a boiling point of belo 65 °F at atmospheric pressure. Generally the propellant may constitute 50% to 99.9% (w/w) of the composition, and active ingredient may constitute 0.1% to 20% (w/ ) of the composition, A propellant may further comprise additional ingredients such as a liquid non- ionic and/or solid anionic surfactant and/or a solid diluent (which may have a particle size of the same order as particles comprising the active ingredient),

[00162] Pharmaceutical compositions formulated for pulmonary delivery may provide an active ingredient in the form of droplets of a solution and/or suspension. Such formulations may be prepared, packaged, and/or sold as aqueous and/or dilute alcoholic solutions and/or suspensions, optionally sterile, comprising active ingredient, and may conveniently be administered using any nebulization and/or atomization device. Such formulations may further comprise one or more additional ingredients including, but not limited to, a fla voring agent such as saccharin sodium, a volatile oil, a buffering agent, a surface active agent, and/or a preservative such as methyihydroxybenzoate. Droplets provided by this route of administration may have an average diameter in the range from about 0.1 nm to about 200 nm,

[00163] Formulations described herein as being useful for pulmonary delivery are useful for intranasal delivery of a pharmaceutical composition. Another formulation suitable for intranasal administration is a coarse powder comprising the active ingredient and having an average particle from about 0.2 μπι to 500 μηι. Such a formulation is administered in the manner in which snuff is taken, i.e. by rapid inhalation through the nasal passage from a container of the powder held close to the nose. [001 4] Formulations suitable for nasal administration may, for example, comprise from about as little as 0.1% (w/w) and as much as 100% (w/w) of active ingredient, and may comprise one or more of the additional ingredients described herein. A pharmaceutical composition may be prepared, packaged, and/or sold in a formulation suitable for buccal administration. Such formulations may, for example, be in the form of tablets and/or lozenges made using

conventional methods, and may have, for example, 0.1% to 20% (w/w) active ingredient, the balance comprising an orally dissolvable and/or degradab!e composition and, optionally, one or more of the additional ingredients described herein. Alternately, formulations suitable for buccal administration may comprise a powder and/or an aerosolized and/or atomized solutio and/or suspension comprising active ingredient. Such powdered, aerosolized, and/or aerosolized formulations, when dispersed, may have an average particle and/or droplet size in the range from about 0.1 nm to about 200 ran, and may further comprise one or more of any additional ingredients described herein.

(00165] A pharmaceutical, composition may be prepared, packaged, and/or sold in a formulation suitable for ophthalmic administration. Such formulations may, for example, be in the form of eye drops including, for example, a 0.1/1.0% (w/w) solution and/or suspension of the active ingredient in an aqueous or oily liquid excipient. Such drops may further comprise buffering agents, salts, and'or one or more other of any additional ingredients described herein. Other opthalmically-administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form and/or in a liposomal preparation. Ear drops and/or eye drops are contemplated as being within the scope of this invention.

[00166] Genera l considerations in the formulation and/or manufa cture of pharmaceutical agents may be found, for example, in Remington: The Science and Practice of Pharmacy 21" ed., Lippincott Williams & Wilkins, 2005 (incorporated herein by reference),

[00167] The present invention provides methods comprising administering modified mR As and their encoded proteins or complexes in accordance with the invention to a subject in need thereof. Nucleic acids, proteins or complexes, or pharmaceutical, imaging, diagnostic, or prophylactic compositions thereof, may be administered to a subject using any amount and any route of administration effective for preventing, treating, diagnosing, or imaging a disease, disorder, and/or condition (e.g., a disease, disorder, and/or condition relating to microbial infections). The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the disease, the particular composition, its mode of administration, its mode of activity, and the like, Compositions in accordance with the invention are typically formulated in dosage unit form for ease of administration and uniformity of dosage, it will be understood, however, that the total daily usage of the compositions of the present in vention will be decided by the attending physician within the scope of sound medical judgment, The specific therapeutically effective,

prophylactially effective, or appropriate imaging dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and ra te of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or comcidental with the specific compound employed; and like factors well known in the medical arts.

[00168] Devices may also be used in conjunction with the present invention. I one embodiment, a device is used to assess levels of a protein which has been administered in the form of a modified mRNA. The de vice may comprise a blood, urine or other biofiuidie test. It may be as large as to include an automated central lab platform or a small decentralized bench top device.

Kits.

[00169] The invention provides a variety of kits for conveniently and/or effectively carrying out methods of the present invention. Typically kits will comprise sufficient amounts and/or numbers of components to allow a user to perform multiple treatments of a subject(s) and/or to perform multiple experiments.

[00170] In one embodiment, the levels of a modified mRNA of the present invention may be measured by immunoassay, In this embodiment, the assay may be used to assess levels of modified mRNA or its activated form or a variant delivered as or in response to the

administration of the modifi ed mRN A,

Dressings and b¾nd¾ges,

[00171] The invention provides a variety of dressings (e.g., wound, dressings) or bandages (e.g., adhesive bandages) for conveniently and/or effectively carrying out methods of the present invention. Typically dressings or bandages will comprise sufficient amounts of pharmaceutical compositions and/or modified nucleic acids described herein to allow a user to perform multiple treatments of a subjeet(s).

Animal models.

[00172] Anti-microbial agents (e.g. , anti-microbial polypeptides) can be tested in healthy animals (e.g., mice) exposed to specific microbial pathogens (e.g., bacteria). Anti-microbial agents (e.g., anti-microbial polypeptides) can also be tested in immunodeficient animal (e.g., mouse) models to test infection process without interference from other immune mechanisms except innate immunity.

[00173] Severe Combined Immunodeficiency (SCID) is a severe immunodeficiency genetic disorder that is characterized by the compl ete inability of the adaptive immune system to mount, coordinate, and sustain an appropriate immune response, usually due to absent or atypical T and B lymphocytes. Scid mice are important tools for researching hematopoiesis, innate and adapti ve immunity, autoimmunity, infectious diseases, cancer, vaccine development, and regenerative medicine in vivo.

[00174] Strain NQO.Cg-Prkdc ^c,d 112rg^{!mI jl} !Sz] (005557 Jacson Lab), commonly known as NOD scid gamma (NSG), is the latest breakthrough in the development of immunodeficient models, It combines the innate immunity deficiencies of the NOD/ShiLtJ background, the scid mutation, and IL2 receptor gamma chain (H2rg) deficiency. The latter two deficiencies combine to eliminate mature T cells, B ceils, and NK cells. Because the l rg knockout prevents the development of lymphoma, NSG mice survive longer than other scid strains, enabling long-term experiments.

[00175] The B6 scid- strain B6.CB17- rWc^iC"7SzJ (001913, Jacson Lab), B6 sea/ mice lack most B and T cells. B6 scid is more severely immunodeficient and supports better engraftment of allogeneic and xenogeneic cells, tissues, and tumors than Foxnf mutant strains.

[00176] The humanized mouse model of HIV infection to investigate mechanisms of viral dissemination, of HIV-induced immune activation, and of HI V-induced immune dysfunction can be used too MGH. Another mouse model - EcoHIV infected about 75 percent of the mice tested, an efficiency rate comparable with that of HIV in humans. The EcoH IV infection was present in immune cells and white blood cells, the spleen, abdominal cavity and brain.

[00177] CSTBLie-Bttf"¹*"* 9723-F- mouse model for Bruton's disease. Barton's tyrosine kinase (Btk) is a member of the Tec kinase family and has been implicated in the primary immunodeficiency X-linked agammaglobulinemia. Btk is thought to play multiple roles in the haematopoietic system, including B-cell devel opment, stimulatio of mast cells and the onset of autoimmune diseases. The Btk (Bruton's tyrosine kinase) inaseSwitch mouse strain carries point mutations at the genomic level at positions T474A S538A in the ATP binding pocket of the Btk kinase domain (BtkT474A. /S538A).

Definitions

|00178] Therapeutic Agent: The term "therapeutic agent" refers to any agent that, when administered to a subject, has a therapeutic, diagnostic, and/or prophylactic effect and/or elicits a desired biological and/or pharmacological effect.

[001791 Administered in combination: As used herein, the term "administered in

combination" or "combined administration" means that two or more agents (e.g., a modified nucleic acid encoding an anti-microbial polypeptide (e.g. , an anti-bacterial polypeptide), e.g., an anti-microbial. polypeptide described herein and an anti-microbial agent (e.g., an anti-microbial polypeptide or a small molecule anti-microbial compound described herein)) are administered to a subject at the same time or within an interval such that there is overlap of an effect of each agent on the patient, In some embodiments, they are administered within about 60, 30, 15, 10, 5, or 1 minute of one another. In some embodiments, the administrations of the agents are spaced sufficiently close together such that a combinatorial (e.g., a synergistic) effect is achieved.

[001801 Animal: As used herein, the term "animal" refers to any member of the animal kingdom, in some embodiments, "animal" refers to humans at any stage of de velopment. In some embodiments, "animal" refers to non-human animals at any stage of development. In certain embodiments, the non-human animal is a mammal (e.g., a rodent, a mouse, a rat, a rabbit, a monkey, a dog, a cat, a sheep, cattle, a primate, or a pig). In some embodiments, animals include, but are not limited to, mammals, birds, reptiles, amphibians, fish, and worms. In some embodiments, the animal is a transgenic animal, genetically-engineered animal, or a clone,

[001 1] Approximately: As used herein, the term "approximately" or "about," as applied to one or more values of interest, refers to a value that is similar to a stated reference value. In certain embodiments, the term "approximately" or "about" refers to a range of values that fall within 25%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 1 1%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater than or less than) of the stated reference value unless otherwise stated or otherwise evident from the context (except where such number would exceed 100% of a possible value).

1001821 Associated with: As used herein, the terms "associated with," "conjugated," "linked," "attached," and "tethered," when used with respect to two or more moieties, means that the moieties are physically associated or connected with one another, either directly or via one or more additional moieties that serves as a linking agent, to form a structure that is sufficiently stabl e so that the moieties remain physically associated under the conditions in which the structure is used, e.g., physiological conditions. As used herein, the terms "associated with," when used with respect to a microorganism (e.g., a bacterium) and a disease, disorder, or condition, means the microorganisms (e.g., bacterium) is found more frequently (e.g., at least 10%, 25%, 50%, 75%, 100%, 200%, 500%, 1000% more frequently) in atients with the disease, disorder, or condition than in healthy controls and/or there is a frequent co-occurrence of the microorganisms (e.g., bacterium) in the disease, disorder, or condition. In some embodiments, the microorganisms (e.g., bacterium) can be a direct and/or singular cause of the disease, disorder, or condition. In some embodiments, the microorganisms (e.g., bacterium) can be a necessary, but not sufficient, cause of the disease, disorder, or conditio (e.g., only causes the disease, disorder or condition in combination with one or more other causal factors (e.g., genetic factors, or toxin exposure)). In some embodiments, the bacterium can predispose to the development of or increase the risk of getting the disease, disorder, or condition. In some embodiements, the microorganisms (e.g., bacterium) can also be an "innocent bystander" that plays no significant role in the etiology of the disease, disorder, or condition but is more prevalent in patients with the disease, disorder, or condition for some reason such as the compromised immune response caused by the disease, disorder, or condition.

[00183] Biologically active: As used herein, the phrase "biologically active" refers to a characteristic of any substance that has activity in a biological system and/or organism. For instance, a substance that, when administered to an organism, has a biological effect on that organism, is considered to be biologically active. In particular embodiments, where a nucleic acid is biologically active, a portion of that nucleic acid that shares at least one biological activity of the whole nucleic acid is typically referred to as a "biologically active" portion.

1001841 Conserved: As used herein, the term "conserved" refers to nucleotides or amino acid residues of a polynucleotide sequence or amino acid sequence, respectively, that are those tha occur unaltered in the same position of two or more related sequences bei g compared.

Nucleotides or amino acids that are relatively consen'ed are those that are consen'ed amongst more related sequences than nucleotides or amino acids appearing elsewhere in the sequences. In some embodiments, two or more sequences are said to be "complete ly conserved" if they are 100% identical to one another. In some embodiments, two or more sequences are said to be "highly conserved" if they are at least 70% identical, at least 80% identical, at least 90%) identical, or at least 95%> identical to one another. In some embodiments, two or more sequences are said to be "highly conserved" if they are about 70% identical, about 80%) identical, about 90% identical, about 95%, about 98%, or about 99% identical to one another. In some embodiments, two or more sequences are said to be "conserved" if they are at least 30%> identical, at least 40% identical, at least 50%) identical, at least 60% identical, at least 70% identical, at least 80% identical, at least 90% identical, or at least 95% identical to one another. In some embodiments, two or more sequences are said to be "conserved" if they are about 30% identical, about 40% identical, about 50% identical, about 60% identical, about 70% identical, about 80%» identical, about 90% identical, about 95%) identical, about 98% identical, or about 99% identical to one another.

[00185] Cytostatic: As used herein, "cytostatic" refers to inhibiting, reducing, suppressing the growth, division, or multiplication of a cell (e.g., a mammalia ceil (e.g., a human cell)), bacterium, vims, fungus, protozoan, parasite, prion, or a combination thereof.

[00186] Cytotoxic: As used herein, "cytotoxic" refers to killing or causing injurous, toxic, or deadly effect on a cell (e.g., a mammalian ceil (e.g., a human cell)), bacterium, virus, fungus, protozoan, parasite, prion, or a combination thereof.

[001 7] Expression: As used herein, "expression" of a nucleic acid sequence refers to one or more of the following events: (1) production of an RNA template from a DNA. sequence (e.g., by transcription); (2) processing of an RNA transcript (e.g. , by splicing, editing, 5' cap formation, and/or 3' end processing); (3) translation of an RNA into a polypeptide or protein; and (4) post-translational modification of a polypeptide or protein.

[001 8] Functional: As used herein, a "functional" biological molecule is a biological molecule in a. form in which it exhibits a property and/or activity by which it is characterized. 10018 1 Homology: As used herein, the term "homology" refers to the overall relatedness between polymeric molecules, e.g. between nucleic acid molecules (e.g. DNA molecules and/or RNA molecules) and/or between polypeptide molecules. In some embodiments, polymeric molecules are considered to be "homologous" to one another if their sequences are at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 99% identical. In some embodiments, polymeric molecules are considered to be

"homologous" to one another if their sequences are at least 25%, at least 30%), at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%), at least 80%», at least 85%, at least 90%, at least 95%., or at least 99% similar. The term "homologous" necessarily refers to a comparison between at least two sequences

(nucleotides sequences or amino acid sequences). In accordance with the invention, two nucleotide sequences are considered to be homologous if the polypeptides they encode are at least about 50% identical, at least about 60% identical, at least about 70% identical, at least about 80%) identical, or a t least about 90% identical for at least one stretch of at least about 20 amino acids. In some embodiments, homologous nucleotide sequences are characterized by the ability to encode a stretch of at least 4-5 uniquely specified amino acids. Both the identity and the approximate spacing of these amino acids relative to one another must be considered for nucleotide sequences to be considered homologous. For nucleotide sequences less than 60 nucleotides in length, homology is determined by the ability to encode a stretch of at least 4-5 uniquely specified amino acids. In accordance with the invention, two protein sequences are considered to be homologous if the proteins are at least about 50% identical, at least about 60% identical, at least about 70% identical, at least about 80% identical, or at least about 90% identical for at least one stretch of at least about 20 amino acids.

[001 01 Identity: As used herein, the term "identity" refers to the overall relatedness between polymeric molecules, e.g., between nucleic acid molecules (e.g. D A molecules and/or RNA molecules) and/or between polypeptide molecules. Calculation of the percent identity of two nucleic acid sequences, for example, can be performed by aligning the two sequences for optimal comparison purposes (e.g. , gaps can be introduced in one or both of a first and a second nucleic acid sequences for optimal alignment and non-identical sequences can be disregarded for comparison purposes). In certain embodiments, the length of a sequence aligned for comparison purposes is at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%), at least 95%, or 100% of the length of the reference sequence. The nucleotides at corresponding nucleotide positions are then compared. When a position in the first sequence is occupied by the same nucleotide as the corresponding position in the second sequence, then the molecules are identical at that position. The percent identity between the two sequences is a function of the number of identical positions shared by the sequences, taking into account the number of gaps, and the length of each gap, which needs to be introduced for optimal alignment of the two sequences. The comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm , For example, the percent identity between two nucleotide sequences can be determined using methods such as those described in Computational Molecular Biology, Lesk, A, M,, ed., Oxford University Press, New York, 1988; Biocomputing: Informatics and Genome Projects, Smith, D. W., ed., Academic Press, New York, 1993; Sequence Analysis in Molecular Biology, von Heiiije, G., Academic Press, 1987; Computer Analysis of Sequence Data, Part I, Griffin, A. M, and Griffin, H. G., eds., Humana Press, New Jersey, 1994; and Sequence Analysis Primer, Gribskov, M. and Devereux, J., eds,, M Stockton Press, New York, 1991 ; each of which is incorporated herein by reference. For example, the percent identity between two nucleotide sequences can be determined using the algorithm of Meyers and Miller (CABIOS, 1989, 4: 1 1-17), which has been incorporated into the ALIGN program (version 2.0) using a PAM120 weight residue table, a gap length penalty of 12 and a gap penalty of 4. The percent identity between two nucleotide sequences can, alternatively, be determined using the GAP program in the GCG software package using an NWSgapdna.CMP matrix. Methods commonly employed to determine percent identity between sequences include, but are not limited to those disclosed in Carillo, FL, and Lipman, D., SIAM J Applied Math., 48: 1073 (1988): incorporated herein by reference.

Techniques for determining identity are codified in publicly available computer programs.

Exemplary computer software to determine homology between two sequences include, but are not limited to, GCG program package, Devereux, J,, et ah, Nucleic Acids Research, 12(1), 387 (1984)), BLAST?, BLASTN, and FASTA Atschul, S. F, et al, J. Voice. Biol, 215, 403 (1990)).

[00191] Inhibit expression of a gene: As used herein, the phrase "inhibit, expression of a gene" means to cause a reduction in the amount of an expression product of the gene. The expression product can be an RNA transcribed from the gene (e.g., an mRNA) or a polypeptide translated from an mRNA transcribed from the gene. Typically a reduction in the level of an mRNA results in a reduction in the level of a polypeptide translated therefrom. The level of expression may be determined using standard techniques for measuring mRNA or protein, f 001921 in vitro: As used herein, the term "/« vitro^'" refers to events that occur in an artificial environment, e.g., in a test tube or reaction vessel, in cell culture, in a Petri dish, etc., rather than within an organism (e.g., animal, plant, or microbe).

[00193] In vivo: As used herein, the term "in vivo^'" refers to events that occur within an organism (e.g., animal, plant, or microbe).

| 00194] isolated: As used herein, the term "isolated" refers to a substance or entity that has been (1) separated from at least some of the components with which it was associated when initially produced (whether in nature or in an experimental setting), and/or (2) produced, prepared, and/or manufactured by the hand of man. Isolated substances and'or entities may be separated from at least about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or more of the other components with which they were initially associated. In some embodiments, isolated agents are more than about 80%, about 85%, about 90%, about 91 %, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or more than about 99% pure. As used herein, a substance is "pure" if it is substantially free of other components.

[001 5] Preventing: As used herein, the term "preventing" refers to partially or completely delaying onset of a microbial infection; partially or completely delaying onset of one or more symptoms, features, or clinical manifesta tions of a particular disease, disorder, and/or condition associated with a microbial infection; partially or completely delaying onset of one or more symptoms, features, or manifestations of a particular disease, disorder, and/or condition prior to an identifiable microbial infection; partially or completely delaying progression from an latent microbial infection to an active microbial infection or a particular disease, disorder and/or condition; and/or decreasing the risk of developing pathology associated with the microbial infection or the disease, disorder, and/or condition.

[001 6] Similarity: As used herein, the term "similarity" refers to the overall relatedness between polymeric molecules, e.g. between nucleic acid molecules (e.g. DNA molecules and/or RNA molecules) and/or between polypeptide molecules. Calculation of percent similarity of polymeric molecules to one another can be performed in the same manner as a calculation of percent identity, except that calculation of percent similarity takes into account conservative substitutions as is understood in the art,

1001971 Subject: As used herein, the term "subject" or "patient" refers to any organism to which a composition in accordance with the invention may be administered, e.g., for

experimental, diagnostic, prophylactic, and/or therapeutic purposes. Typical subjects include animals (e.g., mammals such as mice, rats, rabbits, non-human primates, and humans) and/or plants.

|00198] Substantially: As used herein, the temi "substantially" refers to the qualitative condition of exhibiting total or near-total extent or degree of a characteristic or property of interest. One of ordinary skill in the biological arts will understand that biological and chemical phenomena rarely, if ever, go to completion and/or proceed to completeness or achieve or avoid an absolute result. The term "substantially" is therefore used herein to capture the potential lack of completeness inherent in many biological and chemical phenomena,

[001 9] Suffering from: An individual who is "suffering from" a disease, disorder, and/or condition has been diagnosed with or displays one or more symptoms of a disease, disorder, and/or condition.

[00200] Susceptible to: An individual who is "susceptible to" a disease, disorder, and/or condition has not been diagnosed with and/or may not exhibit symptoms of the disease, disorder, and/or condition. In some embodiments, an individual who is susceptible to a disease, disorder, and/or condition (for example, cancer) may be characterized by one or more of the following: (1) a genetic mutation associated with development of the disease, disorder, and/or condition; (2) a genetic polymorphism associated with development of the disease, disorder, and/or condition; (3) increased and/or decreased expression and/or activity of a protein and/or nucleic acid associated with the disease, disorder, and/or condition; (4) habits and/or lifestyles associated with development of the disease, disorder, and/or condition; (5) a family history of the disease, disorder, and/or condition; and (6) exposure to and/or infection with a microbe associated with development of the disease, disorder, and/or condition. In some embodiments, an individual who is susceptible to a disease, disorder, and/or condition will develop the disease, disorder, and/or condition. In some embodiments, an individual who is susceptible to a disease, disorder, and/or condition will not develop the disease, disorder, and or condition. [00201] Therapeutically effective amount: As used herein, the term "therapeutically effective amount" means an amount of an agent to be delivered (e.g., nucleic acid, drug, therapeutic agent, diagnostic agent, prophylactic agent, etc.) that is sufficient, when administered to a subject suffering from or susceptible to a disease, disorder, and/or condition, to treat, improve symptoms of, diagnose, prevent, and/or delay the onset of the disease, disorder, and/or condition.

[00202] Transcription factor: As used herein, the term "transcription factor" refers to a DNA- binding protein that regulates transcription of DNA into RNA, for example, by activation or repression of transcription. Some transcription factors effect regulation of transcription alone, while others act in concert with other proteins. Some transcription factor can both activate and repress transcription under certain conditions. In general, transcription factors bind a specific target sequence or sequences highly similar to a specific consensus sequence in a regulatory region of a target gene. Transcription factors may regulate transcription of a target gene alone or in a complex with other molecules.

[00203] Treating As used herein, the term "treating" refers to partially or completely alleviating, ameliorating, improving, relieving, delaying onset of, inhibiting progression of, reducing severity of, and/or reducing incidence of one or more symptoms, features, or clinical manifestations of a particular disease, disorder, and/or condition. For example, "treating" microbial infections may refer to inhibit or reduce the survi val, growth, and/or spread of the microbial pathogens. "Treating" cancer may refer to inhibiting survival, growth, and/or spread of a tumor. Treatment may be administered to a subject who does not exhibit signs of a disease, disorder, and/or condition (e.g., prior to an identifiable microbial infection) and/or to a subject who exhibits only early signs of a disease, disorder, and/or condition for the puipose of decreasing the risk of developing pathology associated with the disease, disorder, and/or condition,

[Θ0204] Unmodified; As used herein, "unmodified^"' refers to the protein or agent prior to being modified.

Equivalents and Scope

[00205] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments, described herein. The scope of the present invention is not intended to be limited to the above Description, but rather is as set forth in the appended claims. [00206] Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments in accordance with the invention described herein. The scope of the present invention is not intended to be limited to the above Description, but rather is as set forth in the appended claims,

[00207] In the claims articles such as "a," "an," and "the" may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include "or" between one or more members of a group are considered satisfied if one, more than o e, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The invention includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The invention includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process. Furthermore, it is to be understood that the invention encompasses all variations, combinations, and permutations in which, one or more limitations, elements, clauses, descriptive terms, etc., from one or more of the listed claims is introduced into another claim, For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Furthermore, where the claims recite a composition, it is to be understood that methods of using the composition for any of the purposes disclosed herein are included, and methods of making the composition according to any of the methods of making disclosed herein or other methods known in the art are included, unless otherwise indicated or unless it would be evident to one of ordinary skill in the art that a contradiction or inconsistency would arise.

[00208] Where elements are presented as lists, e.g., in Markush group format, it is to be understood that each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the invention, or aspects of the invention, is/are referred to as comprising particular elements, features, etc., certain embodiments of the invention or aspects of the invention consist, or consist essentially of, such elements, features, etc. For purposes of simplicity those embodiments have not been specifically set forth in haec verba herein. It is also noted that the term "comprising" is intended to be open and permits the inclusion of additional elements or steps. [00209] Where ranges are given, endpoints are included. Furthermore, it is to he understood that unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or subrange within the stated ranges in different embodiments of the invention, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise.

[00210] In addition, it is to be understood that any particular embodiment of the present invention that falls within the prior art may be explicitly excluded from any one or more of the claims. Since such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the compositions of the invention (e.g., any nucleic acid or protein encoded thereby; any method of production; any method of use; etc. ) can be excluded from any one or more claims, for any reason, whether or not related to the existence of prior art.

[00211] All cited sources, for example, references, publications, databases, database entries, and art cited herein, are incorporated into this application by reference, even if not expressly stated in the citation. In case of conflicting statements of a cited source and the instant application, the statement in the instant application shall control .

EXAMPLES

[00212] Modified mRNAs (mmRNAs) according to the invention can be made using standard laboratory methods and materials. The open reading frame (ORF) of the gene of interest is flanked by a 5' untranslated region (UTR) containing a strong Kozak translational initiation signal and a 3' UTR (e.g., an alpha-globin 3' UTR) terminating with an oligo(dT) sequence for tem lated addition of a poly A tail. The mmRNAs can be modified with pseudouridine (ψ) and 5- methyl-cytidine (5meC) to reduce the cellular innate immune response, Kariko K et al. Immunity 23:165-75 (2005), anko ei al. Mol Ther 16: 1833-40 (2008), Anderson BR et al. NAR.

(2010).

[002 3] The cloning, gene synthesis and vector sequencing ca be performed by DNA2.0 Inc. (Menlo Park, CA). The ORFs can be restriction digested and used for cDNA synthesis using tailed-PCR, This tailed-PCR cDNA product can be used as the template for the modified mRNA synthesis reaction using 25mM each modified nucleotide mix (modified U/C was manufactured by TriLink Biotech, San Diego, CA, unmodifed A'^'G was purchased from Epicenter Biotechnologies, Madison, WI) and CeilScript MegaScript™ (Epicenter Biotechnologies, Madison, WI) complete raRNA synthesis kit, The in vitro transcription reaction can be run for 3- 4 hours at 37°C. PGR reaction can use HiFi PGR 2X Master Mix™ (Kapa Biosystems, Woburn, MA), The in vitro transcribed mRNA product can be run on an agarose gel and visualized, mRNA can be purified with Ambion/ Applied Biosystems (Austin, TX) MEGAClear RNA™ purification kit. PGR reaction can be purified using PureLink™ PGR purification kit

(Invitrogen, Carlsbad, CA) or PGR cleanup kit (Qiagen, Valencia, CA). The product can be quantified on Nanodrop™ XJV Absorbance (ThermoFisher, Waltham, MA), Quality, UV absorbance quality and visualization of the product can be performed on a 1.2% agarose gel. The product can be resuspended in TE buffer,

[00214] When transfected into mammalian cells, the modified mRNAs may have a stability of between 12-18 hours.

[00215] For animal experiments, the IV delivery solution can be 150mM NaCl, 2 mM CaC12, 2 mM a+-phosphate, and 0.5 mM EDTA, pH 6.5 and 10μΙ lipofectamine (RNAiMax™, Invitrogen, Carlsbad, CA).

Example 1: Use of synthetic modified mRNAs to produce functional anti-rnicrohial peptides and proteins by human cells

[0021 ] The goal of this example is to express several functional AMPs from modified RN A in several human cell lines to test antibacterial effect of AMPs with distinct patterns of natural distribution and activities.

[00217] Each AMP (hBD-2, LL-37, or RNAse-7) is cloned into propagation piasmid in connection with sequences required for efficient translation and prolonged life of mRNA in cell with globin 5' and 3' UTRs and poly A tail. The mRNAs containing modified nucleotides and/or backbone modifications are transcribed using a standard T7 RNA polymerase-dependent transcription system from piasmid templates. Those mRNAs are transfected into a panel of primary human ceil lines including keratinocytes and fibroblasts using a lipophilic carrier. The intensive optimization of expression is performed in matrix-type experiments focusing on dose, media and delivery reagents selection. Then a dose titration curve of AMI⁵ expression can be established, in a repeat administration protocol, As a positive transfection control, each construct encodes the EGFP gene for visualization. The expressed and secreted polypeptides are detected by corresponded antibodies by ELISA and Western blots. The specific antimicrobial activity is tested in corresponded microbiological plate assays or antibacterial neutralization assays required for the selection of targeted microorganisms. The strain collection can be tested for sensitivity to AMPs by determining their minimal inhibitor)' concentration (MIC) using those methods.

Apoplosis is monitored using FACS with Annexin VCy5.5 and DAPI staining, Apoptotic DNA fragmentation can also be observed by agarose gel electrophoresis, interferon production is assayed from the cell supernatant using s tandard ELISA techniques and qPC of inflammatory gene products. Experiments can be carried out with a collection of different microorganisms including Listeria monocytogenes strains and Staphylococcus aureus strains representing different lineages and serotypes (L, monocytogenes), spa types (S, aureus), and origins (food processing environment, food products, and human clinical isolates).

Example 2: The combinatory effect of modified. mRNAs for polypeptides with different antimicrobial mechanisms on bacterial resistance

[00218] The goal of this example is to show increase in anti-bacterial po tency of AMP by co- expression of combination of several functional AMPs with distinct patterns of natural distribution and activities in human cell lines and test antibacterial effect of combination of AMPs on microorganisms partially resistant against one of AMP.

[00219] AMPs can interact with the membrane lipids and form a channel through which ions can escape, upsetting homeostasis and eventually leading to cell lysis. However, other mechanisms for AMP activity may include activation of autolysis as well as nonlytic

mechanisms such as inhibition of protein synthesis, degradation of proteins required for DNA replication, and interference with the transport and energy metabolism 7(Gob). The approach described in this example is to reduce bacterial resistance and cover a wider variety of pathogenic microorganisms by applying the desired mixture of two and more in viYro-generated, modified synthetic niR As encoded AMPs (e.g., hBD-2, LL-37, RNAse-7). The library of AMPs with most studied and different mechanisms of action can be cloned and transcribed as above. Following by the developed optimal protocol for modified mRNA transfection, many possible combinations of target AMPs can be expressed in a panel of human ceil lines including keratinocytes and fibroblasts using a lipophilic carrier in described anti-bacterial assays in a systematic manner looking for the lowest possible dose for bacteriostatic effect on selected panel of microorganisms.

!Δ Example 3: The combinatory effect of modified mRNA for AMP and conventional antibiotic on bacterial resistance

j 00220 j The goal of this example is to show increase in antibacterial potency of AMP distinct patterns of natural distribution and activities expressed in human cell lines from modified RNA by combination with one or more traditional antibiotic drugs test antibacterial effect of combination of AMPs on microorganisms partially resistant against those antibiotic drugs, [00221] Human peptide antibiotics, in combination with wide variety of other natural polypeptides from other species and conventional antibiotics can be used as therapeutic agents, avoiding the problems of acquired resistance, The approach described in this example is to reduce bacterial resistance and cover a wi der variety of pathogenic microorganisms by applying the desired mixture of one or more in vitro-generated, modified synthetic niRNAs encoded AMPs and one or more traditional antibiotics and to show synergetic effect of combination of panel of traditional antibiotics and panel of AMPs, For example, the fiBD-2, LL-37, and R Ase-7 can be used along and in all possible combinations. The following exemplary antibiotics can be used in this example: penicillins such as penicillin and amoxicillin;

cephalosporins such as cephalexin (Keflex); macrolides such as erythromycin (E-Mycin), clarithromycin (Biaxin), and azithromycin (Zithromax); fluoroquinolones such as ciprofloxacin (Cipro), levofioxacin (Levaquin), and ofloxacin (Floxin); sulfonamides such as co-trimoxazole (Bactrim) and trimethoprim (Proloprim); tetracyclines such as tetracycline (Sumycm, Panmycin) and doxycycline (Vibramycin); and aminoglycosides such as gentamicin (Garamycin) and tobramycin (Tobrex). The library of AMPs with most studied and different mechanisms of action can be cloned and transcribed as above. Following by the developed optimal protocol for modified mRNA transfection, many possible combinations of target AMPs can be expressed in a panel of human cell lines including keratinocytes and fibroblasts using a lipophilic carrier in described antibacterial assays in a systematic manner looking for the lowest possible dose for bacteriostatic effect on selected panel of microorganisms including microorganisms known to be resistant to one or more traditional antibiotics.

Example 4: ^'The modified mRNA technology as a tool for developing novel antibiotic activity

[00222] The goal of this example is to develop efficient protocol for discovery, validation and development of ne w AMPs. [00223] The AMP validation protocol in high throughput manner can be developed. There have been many new AMPs recently discovered, but their mechanisms of action and utility for therapeutic applications remain unknown. Modified RNA technology allows for the

simultaneous testing of new AMPs for human cell toxicity and antimicrobial activities, The sequence of newly discovered candidates can be cloned for in vitro RNA synthesis and testing in high throughput screens without actual peptide expression. Following by the optimal protocol for modified mRNA transfeeuon, several new AMPs expressed in human cells against a panel of microorganisms can be tested. The AMP improvement protocol can be developed. 2-3 known AMPs are selected and a systematic walkthrough mutagenesis by PGR and clone resulting constructs in plasmid vectors are performed. The library of those mutants can be tested one-by- one in a high throughput screen according to developed protocols in comparison to wild type peptides. Functional domains in testing proteins and peptides associated with human cytotoxicity and domains linked to certain mechanisms of antimicrobial activities can be identified. The results of those scanning efforts can allow engineering AMPs with optimal non-toxic but rapid bacteriostatic activities.

Example : The effect of synthetic modified mRN As coding intracellular communication factors on the expression of AMPs in human cells

[00224] The goal of this example is to use modified mRN As coding intracellular

communication factors to induce innate immune system including expression of AMPs,

[0022S] The expression of AMP genes in a variety of epithelial cells can be enhanced using specific nutrients, vitamins (D) and other short chain fatty acids as therapeutic treatment. The opportunity for more specific signal for expression of AMP can be investigated. hBD-2 messenger RNA expression in foreskin-derived keratinocytes was greatly up-regulated wdth TNF-a within 1 h of stimulation and persisted for more than 48 h. The TNF-a gene can be used for synthesis of modified mRNA and transfected into a panel of primary human cell lines including keratinocytes and fibroblasts using a lipophilic carrier. It can be used to test expression of several AMPs including hBD-2 in human cells. The expressed TNF-a and secreted AMPs can be detected by corresponded antibodies by ELISA and Western blots. The specific anti-microbial activity can be tested in corresponded microbiological plate assays or anti-bacterial

neutralization assays required for the selection of targeted microorganisms. Apoptosis can be monitored using FACS with Amiexin VCy5.5 and DAPI staining, Apoptotic DNA fragmentation can also be observed by agarose gel electrophoresis. Interferon production can be assayed from the cell supernatant using standard ELISA techniques and qPCR of inflammatory gene products. Example 6: Use of synthetic modified mRNAs to produce functional antimicrobial peptides and proteins by animal cells for development of antibiotics for agriculture industry

[00226] The goal of this example is to express several functional AMPs from modified RNA in several animal cell lines to test anti-bacterial effect of AMPs with distinct patterns of natural distribution and activities to test possibility to use modified RNAs as antibiotics in agriculture. | 00227] Each AMP (hBD-2, LL-37, and RNAse-7) can be cloned into propagation plasmid in connection with sequences required for efficient translation and prolonged life of mRNA in cell with globin 5' and 3' UTRs and polyA tail. The mRNAs containing modified nucleotides and/or backbone modifications can be transcribed using a standard T7 RNA polymerase-dependent transcription system from plasmid templates. Those mRNAs are transfected into a panel of primary human cell lines including keratinocytes and fibroblasts using a lipophilic carrier. The intensive optimization of expression can be performed in matrix-type experiments focusing on dose, media and delivery reagents selection, A dose titration curve of AMP expression can be established in a repeat administration protocol. As a positive transfection control, each construct encodes the EGFP gene for visualization. The expressed and secreted polypeptides can be detected by corresponded antibodies by ELISA and Western blots. The specific antimicrobial activity can be tested in corresponded microbiological plate assays or antibacterial neutralization assays required for the selection of targeted microorganisms. Apoptosis is monitored using FACS with Annexin VCy5.5 and DAP I staining. Apoptotic D^'NA fragmentation can also be observed by agarose gel electrophoresis. Interferon production can be assayed from the cell supernatant using standard ELIS A techniques and qPCR of inflammatory gene products.

Example 7: In vitro selection of anti-viral inhibitory peptides encoded by synthetic modified mRNA

100228] The viral lifecycie may be inhibited by antibody mimetic anti-viral peptides at a number of points. Viral entry into the host cell can be pre vented by inhibitory peptides that ameliorate the proper folding of the viral hairpin fusion complex. Alternatively, intracellular viral propagation may be inhibited by antiviral peptides directed against viral capsid assembly thereby preventing the formation of functional infectious viral particles. The goal of this example is to identify anti-viral peptides using niRNA-display technology directed against specific viral capsid proteins or viral envelope proteins from HIV, herpes or influenza viruses. The mRNA display in vitro selection can be performed similar to previously described methods (Wilson et ol, PNAS USA, 2001, 98(7):375). Briefly, a synthetic oligonucleotide library is constructed containing ~10^lj unique sequences in a 30-nt randomized region for selection of a lOaa antiviral peptide. The oligonucleotide library is synthesized containing a 3'-puromycin nucleotide analog used to covently attach the nascent peptide chain to its encoded mRNA during the in vitro translation step in rabbit reticulocyte lysate, A pre-selection round can filter the mRNA peptide-display library over a ligand-free column to remove non-specific binding partners from the pool. The selection rounds can then proceed through passage and incubation over a target viral-protei functionalized selection column followed by a wash through selection buffer (20 niM Tris-HCl, pH7.5; 100 mlvl NaCl). The bound peptides are eluted with an alkaline elution buffer (0.1M KOH) and the sequence information in the peptide is reco vered through RT-PCR of the attached mRNA. Mutagenic PGR may be performed between selection rounds to further optimized binding affinity and peptide stability. Based on previous mRNA-display selections (Wilson et αί, PNAS USA, 2001, 98(7):375), this selection is expected to recover high affinity (¾ ~50pM-50n ) anti-viral peptides after 15-20 rounds of selection , To test in vivo functionality of the anti-viral peptide, synthetic modified mRNAs encoding the anti-viral peptide are transfected into target cells. Post-transfection culture transduction with infectious virus or mock-virus are performed and viral propagation can be monitored through standard pfu counts and qPCR of viral genomic material. Cells transfected with synthetic mRNAs encoding the appropriate anti-viral peptide inhibitor are expected to reduce viral propagation, display reduced pfu counts, reduced viral RNA or DNA in culture, and. increase ceil survival. In vivo efficacy, P and toxicology can be studied in appropriate animal models.

LENGTHY TABLE

[00229 ] The patent application contains a lengthy table section, A copy of the table is available in electronic form from the US PTO web site. An electronic copy of the table will be available from the USPTO upon request and payment of the fee set forth in 37 CFR

1.19(b)(3).

BIMBD-i ; [cattle. Peptide, 38 aa]

nn

71

29 Brevinin -2I⁾Yd ail 160380518!spjP0C5X4.1 B2DYD RAND GiFDVVKGYIJCCiVGKNVAGSL 84 V! i 6038051 8]Brevini -2I⁾Yd LEOLKCKLSGGC

Brevinin-2DYe / gil 1603805 Ϊ isp|P0C5X5. I]B2DYE RAND GLFSVVTGVLKAVG VA NV 85

Dvbowskin-5 Y [ 16038051 |Breviiim-2DYe GG SLLEOL C iSGGC

Brevinin-2E gil416725|splP32413.1|BR2E RANE814167 GIMDTLKNL AKT A GKGALO SL

251RecNaroe: Full=Brevinin-2E LNKASCKL8GOC

Brevinin-2Ea ri!728979isp!P40837, liBR2EA RANESI 728 GILDTLKNLAISAAKGAAOGLV 87

979iBrevinin-2Ea NKASCKLSGGC

Brevinin-2Eb gi|728980|solP40838. ! IBR2EB RANES1728 G1LDTLKNLAKTAGKGALOGL 88

9801Brevinin-2Eb VKMASC LSGOC

Brevinin-2Ec £il72898 i |splP40839,l|BR2EC RANESf728 GILLDKLKNFA TAG GVLOSL 9

981 ]Brevinin-2Ec LNTASCKLSGOC

Brevmin-2Ed rii728982|spiP40840.1 IBR2ED RANESf728 GiLDSL NLAKNAGOiLL AS 20

982]Brevinin-2Ed C LSGOC

Brevinin -2Ee gi!728985jsp!P40841.1 BR2EE RANESi 728 GIFDKLKNFAKGVAOSLLNKAS 21

985]Brevii]ii]-2Ee CKLSGOC

Brevinin-2Ef rii 728983 jsp!P40842jBR2EF RANES GIMDTLKNLAKTAGKGALOSL 92

Breviniri-2Ef rec ursor VKMASCKLSGOC

Brevmm-2GHa gi! 122056007!sp|P84860|BR2GA RANGU GFSSLFKAGAKYLLK8VGKAG 93 fAMP-1) Brevinin-2GHa (A P-1) AQQLACKAA NCA

Brevinin-2GHb sii l22056008lsp|A0AEI5IBR2GB RANGU GVITDALKGAAKTVAAELLRK 94 precursor ( AMP-2 ) Brevinin-2GHb precursor fAMP-2) AHCKLTNSC

Brevinin-2GHc gi! 122056010 ! sp AO A ET6 IBR2GC RANGU STWEGIKNAGKGFLVSILDKVR 95 precursor iAMP-4) Brevinirj-2GHc precursor i^'A P-4) CKVAGGCNP

Brevinin~2H8a Brevinin-2HSa GLLDSL NLAINAAKGAGOSVL 96

TLSCKLSKTC

Brevinin-2HSb Brevinin-2HSb GLLDTLKNMA1NAAKGAGOSV 97

LNTLSCKLSKTC

Brevinin-2PTa Brevinin-2PTa GAIKDALKGAAKTVAVELLKK 98

AQCKLEKTC

Brevinin-2PTb Brevinin-2PTb GFKGAFK VMFG1AKSAGKSA 99

LN ALA CKIDKSC

Brevmiti-2PTc Brevinin-2PTc CJLLDSFKNAMIGIAKSACTKTAL 100

KIACKTDKTC

Brevinin-2PTd Brevinin-2PTd GFLDSFKNAM1GVAKSAGKTAL 101

NTLACKIDKTC

Brevinin -2PTe Brevinin-2PTe GFLDSF NAMIGVAKSVGKTAL 302

STLAC JDKSC

Brevinin- Breviniti-2SKa[Rana sakuraii] FLPVILPViGKLLNGIL 103

2SKajRana

sakuraii]

Brevinin- Brev inin-28Kb [Rana sakura ii] GLFNVFKKVGKNVLK VAGSL 104

2SKb[Rarsa MDNLKCKVSGEC

sakuraii]

Brevin.in.-2Tc gi!4 ί 016801 !sp|P82234|BR2TC RANTE GLWETIKNFGKKFTLNILH LK 305

Brevinin-2Tc CKiGGGC

Brevinin-2Td ei!41016802!spjP82235|BR2TD RANTE GLWETIKNFGKKFTLNILHNLK 106

Brevinin-2Td CKiGGGC

Brevinin -2TSa Brevinin- 2TSa GiMSLFKGVLKTAGKHVAGSL 307

VDOLKCKITGGC

Si Buforin - ί ί Buforin gii2495i 38!spiPS5897!H2A BUFBG Histone AGRGKOGGKVRAKAKTRSS A 108

I) H2A Contains: Buforin- 1 (Buforin I); GLOFPVGRVHRLLRKGNY

Buforin-2 (Buforin ID]

Buforiti-2 (Buforin si|2495 Ϊ 38|spiP558 7iH2 A BUFBG Histone TRSSRAGLQFPVGRVHRLLRK 109 m H2A [Contains: Buforin- 1 (Buforin 1);

Buforin-2 (Buforin li ]

Canine beta- eil66864905lref|NP 001019812, 1! beta- CW LRGSCREKCIK EKLYIF 1 10 defensin defensin ί ί Cants lupus familiaris] CTSGKLCCLKPK.

Cecropm-Pl ill Π ϋ~ > P O i ( HU }^■<( , Cecropm- SWLSKTAKKLEMSAK RlSEGi i l l

Pl ALAiOGGPR

Chain A, The gi| 157872589lpdb| lD6X|Ari578725891Chai RRRFPWVCWPFLRRR 1 12

Stnicture Of The n A, The Stnicture Of The Antimicrobial

Antimicrobial Peptide Tritrpticin Bound To Micelles-A

Peptide Tritrpticin Distinct Membrane-Bound Peptide Fold

Bound To (peptide2)

Micelles-A Distinct

Membrane-Bound

Peptide Fold

(peptide2)

Chain A. The e(U 57872589lpdbilD6XIAF1578725891Chai FPWWWPF 1 13

Structure Of The n A, The Structure Of The Antimicrobial

Antimicrobial Peptide Tritrpticin Bound To Micelles-A

Peotide Tritrpticin Distinct Membrane-Bound Peptide Fold

Bound To (peptide4)

Micelles -A Distinct

Membrane-Bound

Peptide Fold

(peptide4)

Chain AJbtruciure si! 40889465 !pdb i 10^"X9I A Cham A, Structure ICLKKWPWWPWRRCKX 114

Of A Cvchc Of A Cyclic indolicidin Peptide Derivative

iiidolicidiri Peptide With Higher Charge

Derivaiive

WifhHigher Charge

Chain A. Structure Eil40889472lpdb| lOXO|A Chain A. Stnicture ILKKWPWWPWRRKX 115

Of An indolicidin Of An Indolicidin Peptide Derivative With

Peptide Derivative Higher Charge

With Higher

Charge

Clavanin-A gi!3121854!sp!P80710!CLAVA STYCL VFOFLGKITHHVG FVHGFSHV 1 16

Clavanin-A precursor F

Clavanin-B gi|3121864ispjP807 ϊ Ϊ iCLAVB STYCL WQFLGRilHHVGNFVHGFSHVF 117

Clavanin-B

Ciavaniii-C gi!3 I2 i863|sp!OI 84 3!CLAVC STYCL VFHLLG KliHH VGNF VYGF SHV 118

Clavanin-C precursor F

Ciavaniii-D gi!3121865!sp!P80713!CLAVD STYCL AFKLLGRIIHHVGNF VYGF SHV 1 19

Clavanin-D precursor F

Defense-related gi!20I39322!spjP8I929jPSt3i PEA Defense- KTCEHLADTYRGVCFTNASCD 120 peptide 1 related peptide I (Defensin- 1) (Antifungal DHC NKAHLISGTCHNW CFC i^'Defensm ^') protein Psdl) TQ C

ί ^'Antifungal protein

Psdi) Defensin MGD- ί Defensin MGD-1 precursor GFGCP NYOCHRHCKSTPGRCG 140 precursor GYCGGWHRLRCTCYRC defensin NP-1 - rat g i ! 483220 fpir ! ! D6 Ϊ 0 Ϊ.4 defensin ΝΡ-Ϊ - rat VTCYCR TRCGFRERLSGACGY 141

RGRIYRLCCR

Defensin precursor Defensin precursor AHCLAIGR 142

Defensin- i Defensin- 1 AAKPMGITCDLLSLWKVGHAA 143

CAAHCLVLGDVGGYCTKEGLC VC E

Defensin- i Defensin- 1 RICRCRIGRCLGLEVYFGVCFLH 144

GRLARRCCR

Defensin- i ei! 1 1 8414|splP11477.2|DEFl MOUSE11 184 LRDLVCYCRSRGCKGRERMNG 145 precursor 14]Defensin- 1 precursor (Defensin, alpha 1) TCRKGHLLYTLCCR

(Defensin, alpha Γι iDefensin-related cryptdin peptide) fDEFCR)

(Defensin-related f Cryptdin- 1)

crvptddin peptide)

(DEFCR)

(Crvptdin- i )

Defensin-3 Defensin-3 RTCRCRLGRCSRRESYSGSC I 146

NGR1YSLCCR

Defensin-A gi!46395690|sp|P917 3. Ϊ iDEFA AEDAEf46 ATCDLLSGFG VGDSACAAHCIA 147

395690]Defensin-A precursor (AaDef) RGNRGG Y CNSK VCVCRN

Defensin-A ei!6225249!si)iP81610 iDEFA MYTED GFGCPNDYPCHRHCKSiPGRXG 148

Defensin-A GYCGGXHRLRCTCYR

Defensin-A Defensin-A VTCDLLSFEAKGFAANHSICAA 149

HCLA1GRKGGSCO GVCVCRN

Defensin-B gii 6225251 !si>iP8161 1 !DEFB MYTED GFGCPNDYPCHRHC SIPGRYG 150

Defensin-B GYCGGXHRLRCTC

Defensin-B Defensin-B VTCDLLSFEAKGFAANHSICAA 151

HCLV1GRKGGACONG VCVCR

Defensin-like eil 156630496lsp|P85215.1 IDEF2 GALME l DKL1G SC V WGATNYT SDCNAE 152 peptide 56630496]Defensin-like peptide CKRRGYKGGHCGSFWNVNCW

CEE

Defensin-related gi!2829412!sp|P50714!DEF 16 MOUSE LRDLVCYCRSRGCKGRERMNG 153 crvptdin 1 6 Defensin-related cryptdin 16 precursor TCRKGHLMYTLCCR

precursor

Defensin-related gil 1706339!SP!P28309!DEF2 MOUSE LRDLVCYCRTRGCKRRERMNG 154 crvptdin 2 Defensin-related crvptdin 2 precursor TCRKGHLMYTLCCR

precursor

Defensin-related sii i?06340!soiP28310iDEF3 MOUSE LRDLVCYCRKRGC RRERMNG 155 cryptdin 3 Defensin-related crvptdin 3 precursor TCRKGHLMYTLCCR

precursor

Defensin-related Defe n sin -related cryptdin-6/ ί 2 DLVCYCRARGCKGRERMNGTC 156 cryptdin-6/12 RKGHLLYMLCCR

Dermaseptin-01 Dermaseptin-01 (DS 01 ) GLWSTIKOKGKEAAIAAAKAA 157 (DS 01) GOAALGAL Dermaseptiii- 1 (DS gil29337160lsp|P24302|DMSl PHYSA ALWKTMLKKLGTMALHAGKA 158 I) Dermaseptin-1 (DS i) ALGAAADTISOGTO

Dermaseptm- gi| 1 14i49278isp|P84596. riDMSl ΡΗΫΉΥΓΪ ' GLW STIKNVGKEAA1AAGKAA 159 KDShypo 01 ) 14149278 ]Dermaseptm-l precursor (DShypo LGAL

(DPh-1 ) 01 ) (DPh- 1 )

Dermaseptm-2 (DS ei!461936|splP80278IDMS2 PHYSA ALWFT LKKLGTMALHAGKA 160 iii Dermaseptiti-2 (DS II) ALGAAANTISOGTO

Dermaseptra-3 Dermaseptin-3 ALWKT1IKGAGKMIGSLAKNLL 161

GSOAOPES

Dermaseptiii- 3 (DS gi|461937isp!P80279!DMS3 PHYSA AL WKNMLKGIGKLAGKAALG 162

111) (Dermaseptin- Dermaseptin-3 (DS 111) (Dermaseptin-S3) AVKKLVGAES

S3) (DS3) (DS3)

Dermaseptiii- 4 (DS sii461938|splP80280IDMS4 PHYSA ALWMTLLKKVLKAAAKALNA 163 IV) iDerrnaseptiii- Demiaseptin-4 (DS IV) (Dennaseptin-S4) VLVGA.NA

S4) i DS4) (DS4)

Dermaseptin-5 (DS Eii461939|splP80281 IDMS5 PHYSA ( i l .WSK I K^'i \( ,K S\ Λ Λ \ Λ .Λ \ 164 Y) Demiaseptiii-5 CDS V) VKAVTNAV

Dermaseptin-B3 gi! 13959342isolP8 I 485IDMS3 PHYBi ALWK MLKGTGKLAGOAALG 165 (Dermaseptiri Bill) Dermaseptin-B3 precursor (Dermaseptiri AVKTLVGA

Bill)

Dermasepiit3-B4 gi! i 3959343!spiP81486, l iDMS4 PHYBIN 3 AL WKDILKNV GKAA GKAVLNT 166

(Dermaseptiii BiV) 959343]Derrnaseptiii-B4 precursor VTDMVNO

(Dennaseptin. BIV)

Dermaseptin-B5 gi!3913493!sp|P81487!DMS5 PHYBI GLWNK1KE AA SK A AGK A ALGF 167 (Dermaseptin-BV) Dermaseptin-B5 (Dermaseptin-BV) VNEMV

Dertnaseptit3-H4 Derma sept -H4 GLWSTIKNVGKEAAIAAGKAA 168

LGAL

Dermaseptin-HS Dermaseptiii-H5 GLWSTIKm¾KEAAL AGKAV 169

LGSL

dermaseptm-like ri!29123270!¾bjAAQ62958, l!L29123270]der GLVTSLI GAG LLGGLFGSVT 170

PBN2 maseptin-like precursor PBN2 GGQS

[PlivUomediisa bicoiorj

Dermcidin gi|20341302|sp|P81605IDCD HUMAN SSLLEKGLDGAK A.VGGLG L 171

(.Preproieoiysin) Dermcidi ^'precursor (Preproteolysin) GKD AVEDLE S VGKG AVHDVKD [Contains: f Contains: Survival-promoting peptide; VLDSV

Survival-promoting DCD-1]

peptide; DCD-1 ]

Diptericin Diptericin DLHiPPPDN I WPOLSGGGGG 172

SPKTGYDININAOO .

Diptericin-A Diptericin-A DEKPKLILPTPAPP LPOLVGGG 173

GG RKDGFGVSVD A HOKVWT SDNGGHSIGVSPGYSOHLPGPY GNSRPDYRIGAGYSYNF Hi statin- 3 gii i23143jsp!P15516!ffiS3 HUMAN DSHAKRHHGYKRKFHEKHHSH 1 88 Hissatin-3 precursor iHistidi e-rich protein RGYRS YLYDN 3) fPBi (Basic histidine-rich protein) (list)

[Contains: Hissatin-3; Histatin- 1 /25

iHistatin-6); Histatin-3 1/24 flfciatin -5);

Hissatin-3 1/13; Histatin-3 1/12; Histasin-3

1/1 1 ; Hissatin-3 5/13; Hissatin-3 5/12

iHistatin-1 1); Hi statin- 3 5/11 ί Histatin- 12);

Hissatin-3 6/13; Histatin-3 6/11 ; Histatitt-3

7/13; Hisiatin-3 7/12; Hissatin-3 7/11 ;

Hissatin-3 12/32 i^'Hissatin-4 ; Histatin-3

12/25 (Histatin-9); Histatin-3 12/24

(Histatin-7); Histatin-3 13/25 (Histatin- 10);

Histatin-3 13/24 (Histatin-8); Histatin-3

14/25; Histatin-3 1 /24; Histatin-3 15/25;

Histatin-3 15/24; Histatin-3 26/32; Histatin-3

28/32; Histatin-3 29/32]

Histatin-5 Histatin-5 DSHAKRHHGYKRKFHEKHHSH 1 89

RGY

Human Afpha- Human Alpha-Defensin-6 AFTCHCRRSC Y STEY S YGI^'CTV 190 Defensin-6 MG1MHRFCCL

Hitman beta Human beta defensin 2; G26M hBD-2 DPVTCLKSGAICHPVFCPRRYK 191 defensm 2; G26M OIGTCGLPGTKCCKKPP

hBD-2

Human besa- gil4826692|ref|NP 004933, i i[4826692]defen G1GDPVTCLKSGAICHPVFCPRR 192 defensin-2 WT sin, beta 4 precursor [Homo sapiens] YKOIGTCGLPGTKCC KP hBD - 2

Human Defensm Eil l0348513^"9irefiNP 525 Ϊ28.2 j [ 103485139] ELDRICGYGTARCRKKCRSOEY 193 beta 104A f Beia- defensin^ beta 104 A precursor [Homo RiGRCPNTYACCLRKWDESLLN defensin 4) saaiens] RTKP human defensin 1 human defensin 1 ACYCRIPACIAGERRYGTCIYOG 194

RLWAFCC

Human Defensin-5 Human Defensin-5 ATCYCRTGRCATRESLSGVCEIS 195

GRLYRLCCR

Human Human lactoferricin FOWORNMRKVR 196 lactoferricin

Irsdolicidisi indolicidin ILPWKWPWWPWRX 197 indolicidin gii246037jspjAAB21 94.1 i indolicidin ILPWKWPWWPWRR 198

,antimierobiai peptide [cattle, neutrophils,

Peptide, 13 aaj Indolicidin Peptide Indoiicidin Peotide Derivative With P-a ILAWKWAWWAWRX 199

Derivative With P- Substitution

>a Siibstiiuiion

Lactotransferrin gi!418131 |sp!P24627.2|T FL BOVi [418 i3 ' FKCRRWOWRMKKLGAPSITCV 200 precursor 1 jLactotransferrin precursor (Lactoferrin) RRAF

(Lactoferrin) {Contains: Lactoferricin B (Lfcin BjJ

(Contains:

LactoferriciriB

(Lfcin B)]

Metchnikowin gi!2493581 !sD!024395!MT . DROME HRHOGP1FDTRPSPF PNOPRPG 201

Metchnikowin precursor ΡΪΥ

Metchnikowin-2 Metchnikowin-2 RROGPiFDTRPSPFNPNQPRPGPI 202

I.

Modified defensin Modified defensin ALRLAIR R 203

Modified defensin Modified defensin ALLLAIRKR 204

Modified defensin Modified defensin AWLLAiR R 205

Modified defensin Modified defensin ALYLAIRKR 206

Modified defensin Modified defensin ALWLAiR R 207 moriein-like gi! 146737992|gb|AB042574.1 If 146737992] GKiPVKAIK GGOiiGKALRGFMI 208 peptide B moricin-like peptide B FGalleria mellonella] ASTAHDiiSOFKPK KX H moronecidiii »| 17529687|Kb|AAL40409.1|AF 332621 if X FFHHIFRGIVHVGKTIHKLVTGG 209

7529687 Jmoronecidin prepropep!ide

[Morone chrvsoDs] moronecidin si! 17940 i i 8isbjAAL49496. 1 ! AF385583 1 ! ί FFHHIFRGIVHVG TiHRLVTGG 210

7940118 ^"jmoronecidin. precursor [Morone

saxatilis] mor necidin gii ! 8034013igb|AAL57318.1 |AF394243 1[ i FFHH1FRGIVHVGRTIHKLVTGG 211

8034013]moronecidin precursor [Morone

chrysons] moronecidin gii l 8034015!abjAAL573 i9Ji! i 80340I5]mor FFHHlFRGiVHVGRTIHRLVTGG 212 oneeidin precursor [Morone saxatiiisj

Moronecidin gi|37999868|sp|08UUG2. i IMORO MORC FFHH1FRGIVHVGKT1HKLVTG 213

H[37999868]Moronecidin precursor

Moronecidin gi!55775527!gb|AAV65044, i!! 55775527]mo IFHHIFK GIVHVG TIHRLVTG 214

ronecidin f Siniperca chuatsi] Moroaecidin gi!37999867!sp!O8UUG0, ljMORO MORSA FFHHIFRGIVFIVGKTiHRLVTG 2.15 fPiscidin- H 37999867^"jMoronecidin precursor (Piscidm-

Neutrophil gi!2494046|sp|O62715IDEF2 RAT VTCYCR STRCGFRERLSGACGY 216 antibiotic peptide Neutrophil antibiotic peptide NP-2 precursor RGRiYRLCCR

NP-2 precursor fNeutrophil defensin 2) (RatNP-2

(Neutrophil

defensin 2)

( atNP-2)

Neutrophil Eil2494047|solO62713|DEFA RAT CSCRTSSCRFGERLSGACRLNG 217 antibiotic peptide Neutrophil antibioiic peptide NP-3 precursor RIYRLCC

NP-3 precursor fNeutrophil defensin 3) fRatNP-3a)

fNeutrophil

defensin 3)

fRaiNP-3a)

Neutrophil gii2494048|spiO62714|DEF4 RAT ACYCRIGACVSGERLTGACGLN 218 antibiotic peptide Neutrophil antibiotic peptide NP-4 precursor GR1YRLCCR

NP-4 precursor (Neutrophil defensin 4) (RatNP-4)

fNeutrophil

defensin 4)

fRatNP-4)

neutroolrii beta- ei!2884994 ! IreflNP 777200. Ι ΙΓ288499411^ηε ORVRNPOSCRWNMGVC1PFLC 2 ! 9 defensin 4 [Bos utrophil beta-defensin 4 Bos taurus] RVGMROTGTCFGPRVPCCRR taursi

neutrophil beta- _ei!4102644 gb!AADO 1523.1 j 14102644]neutro NPOSCRWNMGVCiPiSCPGNMR 220 defensin 5.[Bos phii beta-defeasin 5 [Bos iaurusj OiGTCS

taurus]

Neutrophil defensin gi!3913450!spjP81465!DEF 3 MESAU VTCFCRRRGCASRERHIGYCRF 221

1 (HANP-1 ) Neutrophil defensin 1 (ΗΑΝΡ-Π GNTiYRLCCRR

Neutrophil defensin gil38502875lsp|P60030|DEFl MACMU ACYCRIPACLAGERRYGTCFYL 222 1 i^'RMAD- i ) Neutrophil defensin 1 precursor (RMAD- 1 ) GRVWAFCC

Neutrophil defensin Neutrophil defensin 2 fHANP-2 ) CFCKRPVCDSGETOIGYCRLGN 223 2 (ΉΑΝΡ-2 ) TFYRLCCRO

Neutrophil defensin Neutrophil defensin 2 fRMAD-2 ) ACYCRTPACI.AGERRYGTCFYM 224

2 fRMAD-2 ) GRVWAFCC

Neutrophil defensin gi!30316323ispiP59666iDEF3 HUMAN DCYCRIPACIAGERRYGTCIYOG 225 3 fHNP-3) (ΉΡ-3 Neutrophil defensin 3 precursor fHNP-3) RLWAFCC

(HP3) (Defensin, fHP-3) fHP3 ) fDefensin, alpha 3) [Contains:

aloha 3 ) HP 3-56; Neutrophil defensin 2 fHNP-2

fHP-2) fHP2)|

Neutrophil defensin ri!3913452!sp!P81467iDEF3 MESAU VTCFCRRRGCASRERLIGYCRF 226 3 (HANP-3) Neutrophil defensin 3 iHANP-3) GNTiYGLCCRR Phormicin ειί 1 18432|spiP10891.2|DEFI PROTE! i 1843 ACAAHCLLRG RGGYC GKG 2.41 precursor (Insect 2]Phonniciu precursor (insect defensin A/B)

defensin A B)

Pleurocidin gij 38017 ί 84! sp |P8194 i jPLE ! P8EAM GWGSFFKK AAHVG H VGKAA 242

Pleurocidin precursor LTHYL pleurocidin-iike ei!32396178kb|AAP55793.1! 32396178]T3leu 243 peptide API rocidin-like peptide A I [Hippoglossoides DHYLG

platessoides] pleurocidia-like gi!32396 i 80!sb|AAP55794.1 ΙΓ323961 SOlnleu GWKKWFNRAKJiVG TVGGLA 244 peptide AP2 rocidin-like peptide AP2 [^"Hippoglossoides VDHYLG

platessoides] pleurocidin- iike pleurocidin-like peptide AP3 GWRTEL KAEVKTVG IALKH 2.45 peptide AP3 XL

pleurocidia-like εϋ32396192i eb| AAP55800.11 Γ323961921oleu GWKKWFTKGERLSORHFA 246 peptide GC3.2 rocidin-like peptide GC3.2 [GivDtocephalus

cvaoelossus] pleurocidin-iike gi!32396188igb|AAP55798.1ii32396188Meu FWGKLLKLGMHGIGLLHOHLG 247 peptide GcSc4B7 rocidin-like peptide GcSc4B7

[GlYptocephalus cynoglossus] pleurocidin-iike a i! 32396186 ! eb| A APS 5797. i ! Γ323961861oleu GWGSIF HIF A GKFIHGAIOAH 248 peptide GcSc4C5 rocidin-like peptide GcSc4C5 DG

[Glyptocephalus cynoglossus] pleurocidin-like gii32396196igbjAAP55802.1ii323961961pleu GFLGILFHGVHHGRK ALOM 249 peptide Hb 1 8 rocidin-like peptide Hb l 8 [Hippoglossus SERRS

hippoglossus] pleurocidin-like gii 32396194 j gbl AAP5580 L I j ί 32396194 eu FLGLLFHGVHHVG WIHGLIHG 250 peptide Hb26 rocidin-like peptide Hb26 1 Hippoglossus HH

hippoglossus] pleurocidin-like pleurocidin-iike peptide WFX RSTEDilKSISGGGFL AMNA 251 peptide WFX pleurocidin-like gij32396184jgb|AAP55TO6i|[323%iM^'|pieu RWGKWFKKATHVGKHVG AA 252 peptide YT2 ( rocidin-like peptide YT2 j Limanda LTAYL

YellovVtail flounder ferrugineaj

YT2 ¾

21 Proenkephaliti A giil29769|spiP0121 ! . i |PENK ΒΟΥΙΝΠ 297 FAEPTBSEEEGESYSKEVPEME 253 precursor 691Proenkephalm A precursor [Contains: KRYGGFM

[Contains; Synenketihalm; Met-enkepbalin [Opioid

Synenkephahn; growth factor) [OGF); Met- enkephalin -Arg- Met-enkephalin Gly-Leu; Leu-enkephaliii; Enkelytin; Met- [Opioid growth enkephalin- ArR-Phe]

factor) [OGF);

Met-enkephalin- Arg-Glv-Leu: Leu- enkephalin;

Enkelvtin.; Met- enkepbalin-Arg- Phej

Proteerin-l Proie^grin-l RGGRLCYCRRRFCVC VGR 254

Proteerin-2 Proiegrin-2 RGGRLCYCRRRFCICV 255

Proteerin-3 Protegrin-3 RGGGLCYCRRRFCVCVGR 2.56

Pyrrhoeoriein gij585769ispiP37362jPYRRH PYRAP VDKGSYLPRPTPPRPTYNRN 257

Pyrrbocoricin

Ranatuerin- 1 T gi|41017603isp|P82740|RNlT RANTE GLLSGLKKVG HVA NVAVSL 258

CBrevinin-2T) Ranatuerin- IT [Rrcvinin-2T) MDSLKC ISGDC

Recombinant Recombinant Crassostrea Gigas Defensin GFGCPG OLKC NHCKSiSCRA 259

Crassostrea Gieas GYCDAATL LRCTCTDCNGK Defensin

Reptilian Defensin Reptilian Defensin EKKCPGRCTLKCGKHERPTLPY 260

NCGKYICCVPVKV

Rhesus theta gi!52783432|sp|P82270|RTD l A MACMU GFCRCICTRGFCR.CICTR 261 defers sin -1/3, Rhesus theta defensin- 1 /3, subunit A

subunit A precursor precursor (RTD-la) RTD-1 subunit A)

ί RTD-3 ) (RTD-3) [Demidefensin-2)

Ribonuclease 7 Ribonuclease 7 (RNase-7) P GMTSSOWFKIOHMOPSPO 262

[Rnase-7) AOS) S A MKNFNKHTKRCKDL T

FLHEPFSSVAATCOTPKIAC NG D NCHOSHG A VSLTMCKLT SG HP CRYKE RONKSYVVACK PPOKKDSOOFHLVPVHLDRVL

Royalisin precursor eii i 706354ISBIP17722IDEFI AP1ME VTCDLLSFKGOVTSfDSA.CAA.NC 263

[Defensin ) Royalisin precursor [Defensin) LSLGKAGGHCEKVGCICRKTSF

KDLWDKYF

salivary glands dl 12 279 )23igb|AB028926.11[ 1292790231s NCiOOCVS GAOGGYC^'F EKC 264 defensin alivary glands defensin [Haemaphysalis ICY

lo gicornisj

Shepherin I Shepherin I GYGGHGGHGGHGGHGGHGGH 265

GHGGGGHG

Sherjiierm ii Shepherin Π GYHGGHGGHGGGYNGGGGHG 266

GHGGGYNGGGHHGGGGHG

Styelin-A eil3915049lst>IP81469ISTYA STYCL GXFGKAFXSVS FA KU TA 267

Styelin-A Sryelin-C gi!3915043!ss)iO l 8494jSTYC STYCL GWFG AFRSVSNFYKKH TYi 2.68 Stvelin -C precursor HAGLSAATLL

Stvelin-D si!50401306!spjO18495!STYD STYCL GWLRKAAKSVGKFYYKHKYYI 269

Styelin-D precursor AAWOIGKHAL

Tachvcitin Tachycitin YL AFRCGRY SPCLDDGPN VNLY 270

SCCSFYNCHKCLARLENCPKGL HY AYLKVCDWPSKAGCTSVN KECHLWKT

Tachyplesin-l Tach plesin-1 {Tachvplesin I ) WCFRVCYRG1CYRRCR 271 fTachyplesin Ϊ ) si! i 35266|spiP 142 i 3 jTAC I TACTR

T chjiglesirb Ei! l35267|splP14214ITAC2 TACTR RWCFRVCYRGICYRKCR 272 fTacbvnlesii! TD Tachyplesin-2 precursor (Tachyplesin ID

Tachyplesin-3 isii 1352 8fsp|P 18252ITAC3 TACGl KWCFRVCYRGICYRKCR 273

(Tachyplesin HI) Tachvpiesin- 3 (Tachyplesin 111)

Thanatin gii2493582|spiP55788iTHA PODMA GSKKPVPllYCNRRTGKCORM 274

Thanatin

Tritrpiicin gi!157872589lpdbilD6XIA[ ! 578725891Chai VRRFPWWWPFLRR 2.75 is A, The Structure Of The Antimicrobial

Peptide Tritroticin Bound To Micelles-A

Distinct Membrane-Bound Peptide Fold

White cloud bean White cloud bean defensin (plant defensin) KTCENLADTFRGPCFATSNCDD 276 defensin (plant HCKN EHLLSGRCRDDFRCWC defensin) FRX

K4-S4f l- 13 a Chain A, Solution Structure Of Dermaseptin ALWKTLLKKVLKAX 277

Antimicrobial Peptide Truncated, Mutated

Analog, K4-S4(l-i 3)a

RD-1 Chain A, Nrnr Structure Of The M . YK K i K K i .i .K Si .K Ri ( i 278

Antimicrobial Peptide Rp-l Bound To|Dpc

Micelles,

! l i 08189291possibl [13081 8929]rjossihk baeterioein protein M.HRNLAPVTEVAWG01GEEA 279 e baeterioein [Rhodococcus sp. RH A 3 ] ARTFKRHVAGRRWDVAGPFG protein YSYSAHNLGRVTPIKTSDSRIRA

[Rhodococcus sp. OOROVNPLVELRFPFTLSRAEV RHA11 DDVARGSLDSDWOPVKDAAK

AVAFAEDOSIFOGFDEAGIRGL

GPSSDNPVLSLPEDPLLIPDAVA

SALSALRLAGVEGPYSWLDAD

AYTAVSETRDEGHPVFHHLRDL

VAGDIIWA AISGGYVLSTRGG

DNQLTLGTDLSIGYDSHTATDV

TLYLEETFTFASLTAEA Γ11 1255051beta- [ 1 1125505]beta-defensin [Bos taurus] NPOSCRWNMGVCIPiSCPGNMR 2.80 defensin [Bos OIGTCFGPRVPCCR

taurusl

1 119852241 Iprepro [ i 19852241 ipreprotemporin-1 SKd [Rana FLPMLAKLLSGFLGK 281 temporiii- lS d sakuraii]

[Rana sakuraii f

Γ 1198522431prepro [1 19852243]preprobradvkinin {Rana RLPPGFTPWRIAPATV 282 bradykiniti [Rana sakuraii]

sakuraii]

f l33778666]beta [133778666 jbeta defensin 4 [Bos taurus] NPOSCRWNMGVCiPISFLVNMR 283 defensin 4 [Bos OiGTCFGPRV

taurus]

1149388929]Nucle [ 1493889291Nucleoporiii JP49/NSP49 RVGDLPPAIROELEEFDRYINKO 284 oporin (Nuclear pore protein NUP49/NSP49 ) HLVATTLOADYGKHDOLINTIP

N JP49/NSP49 [Pichia stipitis CBS 60541 KDiNYLI-iN I.MST OAI.i FE⁾S (^"Nuclear pore GOLVHLKELNNEiTDDlSKIMOL protein ILOLSTPGTRLSSSFOLNEFFV

NUP49/NSP49 KI KYYEILR.OYEGVVAELDS1L [Pichia stipitis CBS GGLERSCTEGFGNLFNIVEVIK S 6054 | OYHLFMELCETMAOLHNEVN

L8.K

[149930883 jputativ [149930883]rjutative antimicrobial peptide A ALRGAL.RAVARVGKA1LPHVAI 285 e antimicrobial Northern Europe Heligoland variant [Ciona ANPYVRTPYVHNNPDWSLWRS peptide A Northern intestinalis] RRRSGNOOPTSOAEiLEDALEA Europe Heligoland OAIEALMOEO

variant FCiona

mtestinalis]

H4993G885iDutativ [149930885]putative antimicrobial peptide A ALRSAVRTVARVGRAVLPHVAI 286 e antimicrobial Pacific variant [Ciona intestinalis] ADPYVRTPYVH NPDWSLWRR peptide A Pacific RWNOOPTSOADMLEDALEAO variant [ Ciona AiEALMOEO

intestinalis]

r i615224461Linoci [1615224461Linocin Mi 8 bacteriocin -INNIJ-IRELAPISSAAWEOIEEE 287 n M18 bacteriocin protein [Burkholderia multivorans ATCC VARTFKRSVAGRRWDVEGPK pjojein 176161 GPELSAVGTGHLRDVAAPREH

[Burkboldena VDARLRE TTVELTVPFELDR multivorans ATCC AAIDSVERGARDADWOAAKEA 17616] AOREAFAEDSAiFDGYPAAGIV

GIREGTSNRKLTLPSDVGAYPD

AISD ALEALRLA GVDGPYSVLL

GADAYTALSEARDOGYPV1EHI

KRIVSGEIIWAPAISGGCVLSTR

GGDYELHLGEDV SiGY ASHTDK

VVRLYLRETLTFLMLTSEA

[27800725]catk-:lic [27806725]cathelicidin antimicrobial peptide ALSYREAVLRAVDRINERSSEA 288 idin antimicrobial [Bos taurus] LYRLLELDPPPKDVEDRGARK peptide [Bos PTSFTVKETVCPRTSPOPPEOCDau us

1 Bos taurus Ri|289396|gb|AAA72363.1|[2893961l^'Bos NPVSCVR KGICVPIRCPGSMK 289 antimicrobial taurus antimicrobial protein exons 1-2, OIGTCVGRAVKCCR

protein exons 1 -2, complete cds. I, gene product

complete cds,],

gene product Uncharacterized ]Uncharacterized protein, Hnocin/CFP29 MDLLKRELAPILPAAWDLIDHE 2.90 protein, homolog ATRVL LHLAGRKWDFRGPF linocin/CFP29 GWEVAAVNTGRLRA1ERKEGP homoloe AVSAGVELVRPLVEFRAPIRLEL

AELDAVGRGAOEP IEDWRA

AEHAARFEDGAIF GLAAAGIE

GILEVAPHKPWIPAPEAWPRA

VAEAREVLRAAGVDGPYALAL

GPKAYDELAAAAEDGYPLRKHI

EGOLIDGPIVWAPALEGGVLLS

TRGGDFELTVGEDLSiGYDGHD

ROWELFLTESFTF

50S ribosomal sr!25002 ί 8!si)!P56029, i l . i HELPYi25002 A VFKRLE LFSKIO DK 291 rotein LI 18 ]50S ribosomal protein L I

ABF-1 ABF-1 EASCARMDVPVMOR1AOGLCT 292

SSCTAQKCMTGICKKVDSHPTC FCGGCSNANDVSLDTLISQLPH

ABF-2 ABF-2 DiDF STCARMDVPIL KAAOGL 293

CITSCSMO CGTGSCK RSGRP TCVCYRCANGGGDIPLGALTKR G

Acanthoscurrin-l Acanthoscurrin- 1 DVYKGGGGGRYGGGRYGGGG 294

GYGGGLGGGGLGGGGLGGGK

GLGGGGLGGGGLGGGGLGGG

GLGGGKGLGGGGLGGGGLGG

GGLGGGGLGGGKGLGGGGLG

GGGLGGGRGGGYGGGGGYGG

GYGGGYGGGKYK

Acanthoscurrin-2 Acanthoscurrin-2 DVYKGGGGGRYGGGRYGGGG 295

GYGGGLGGGGLGGGGLGGG

GLGGGGLGGGGLGGGGLGGG

GLGGGKGLGGGGLGGGGLGG

GGLGGGGLGGGKGLGGGGLG

GGGLGGGRGGYGGGGYGGGY

GGGYGGGKYKG

Acidic venom Acidic venom peptide Ka2 { BmKa2 ] YPASMDNYDDALEELD LDLD 296 peptide Ka2 DYFDLEPADFVLLDMWA MLE BmKa2 i SSDFDDME

Actinoxaiitliiti Actiiioxanthra APAFSVSPASGASDGOSVSVSV 297

AAAGETYYIAOCAPVGGODAC PATATSFTTDASGAA SFSFTVR KSYAGOTPSGTPVGSVDCATDA

CNLGAGNSGLNLGHVALTFG

Agrocyhin Agrocybin ANDPQCLYGNVAAKF 298

Alliumin Alliumin DDFLCAGGCL 299

Alloferon-i ei!32363 i20lsp|P83412.1iAFN CALVIF3236 HGVSGHGOHGVHG 300

3120]Alloferon-i [Contains: Alloferon-2]

Alpha-basrubrin il l 26391707|sp|P83186|BRA BASAL GADFQECMKEHSQKQHOHQG 301

Alpha-basrubrin Aluha-bemticasin gil50401829!spjP83960.1 !BNCA ΒΕΝΗΙΓ50 RDWERREFERRQNELRREOEO 302

401829]Alpba-benincasin RREELL

Alveolarin Alveolarin GVCDMADLA 303 amino acid amino acid adenvlation domain PRiTiDRWLARESWRFTVTGLG 304 adenylation domain FATLTGOGDRFRRVORWOHAH

GLPRHLFGWTPMEERPFSLDLT SPA S VDVL AGALRRT

amolopin-l a gil l 10348515|gb|ABG72909. i p 103485151a FLPMLAGLAANFLPKLFCKITK 305 molopin-la antimicrobial peptide precursor C

[Amoiops ioioensis]

amolopin-la arnolopin- la antimicrobial peptide FLPMLAGLAANFLPKLFCKITK 306 antimicrobial KC

peptide

amoio in-lb eii 110348517|gb|ABG72910.11[ Ϊ 10348517ia FLPLAVSLAANFLPKLFCKITKK 307 moiopin-l b antunierobial peptide precursor c

j Amoiops Ioioensis]

amolo in-lc ai! l l 0348519|gb|ABG7291 1. i p 103485191 FLPMLAGLAANLLPKLFCKITK 308 amolopin-lc antimicrobial peptide precursor KC

[Amoiops ioioensis]

amoiopin-ld gii 1 10348521 igb] ABG72912.1 \\l 10348521 ! FLPMLAGLAANFLPELFCKITK 309 amoiopin-ld antimicrobial peptide precursor Q

[Amoiops ioioensis]

amoiopin-2a gil l 10348525igb|ABG72914. 1 ([1 103485251a FLPIVG LLSGLSGLL 310 molopia-2a antimicrobial peptide precursor

[Amoiops Ioioensis]

amoiopin-2b til i 1034853 ligb|ABG72917.11[ 1 10348531] FLPrVGKLLSGLL 311 amolopin-2b antimicrobial peati !e precursor

[Amoiops loloensisj

amolopin-2c gil l 10348533|gb|ABG7291 8.1111 103485331a LLPTVGKLLSGLL 312 molopin-2c antimicrobial peptide precursor

[Amoiops ioioensis]

amolopin-2e amolopm-2e antimicrobial pepiide precursor MFTM KSLLLLFFLGTiHLSLC^'E 313 antimicrobial [Amoiops ioioensis]. OERNAEEERRDDLGEROAEVE peptide KRFLPIAGKLLSGLSGLLGK amoio in-2f amol o in-2f antimicrobial peptide precursor MFTLKK SLLLLFFLGTINLSLCE 314 antimicrobial [Amoiops Ioioensis]. OERNAEEERRDEPDERNAEVEK peptide RFFPIVGKLLFGLSGLLGK amolopin-2g amolopin-2g antimicrobial peptide precursor MFTLKK SLLLLFFLGTINLSLCE 315 antimicrobial [Amoiops Ioioensis], OERNAEEERRDEPDERNAEVEK peptide RFFPIVGKLLSGLSGLLGK amoio in-2h amolopin-2h antimicrobial peptide MFTLKKSLLLLFFLGT1NLSLCE 316 antimicrobial QERNAEEER DDLGERQAEVE peptide KRFFPIVGKLLFGLFGLLGK amolopin-2i amolopin-2i antimicrobial peptide precursor MFPLKKSLLLLFFLATINLSLCE 317 antimicrobial [Amoiops ioioensis]. OERNAEEERRDEPDERNAEVEK peptide RFFP.1VGKLLSGLLGK

amolopin-2k amolopin-2k antimicrobial peptide precursor MFTLKKSLLLLFFLATFNLSFCE 318 antimicrobial [Amoiops ioioensis] OERNAEEERRDEPDERNAEVEK. peptide RFFPIVGKLLFGLLGK

amolopin-3a amolopin-3a antimicrobial pepiide FLPPSPW ETFRTT 319 antimicrobial

Sg rtidfi amolopin-5a amolopin-Sa antimicrobial peptide precursor FTMKKSLLLLFFLGAISLSLCE 320 antimicrobial [Amolops loloensis] OERDADEEETEGGAKVETVKR peptide ASVPPGFTPFRVAPEIV

amolopin-6a amolopin-6a antimicrobial peptide precursor MFTMKKSLLLLFFLGMISLSLC 321 antimicrobial [Amolops loloensis] KQERDANEERRDDPDENEENG e tide GEAKVEEIKRAARPPLGCKAAF

C

amolopin.-6b amolopin-6b antimicrobial peptide precursor MFTMKKSLLLLFFLGMISLSLC 322. antimicrobial [Amolops loloensis] OERDANEERRDDPDENEENG peptide GEAKVEEIKRAARPPLRCKAAF

c

amolopin-7a amolopin-7a antimicrobial peptide precursor MFTMKKSLLLLFFLGAISLSLCE 323 antimicrobial [Amolops ioioensisj OERDADEEDGGEVTEEEVKRA peptide AFRGCWTKNYSPKPCLGKR amolopin-8a amolopin-8a antimicrobial peptide precursor MFTMKKSLLLLFFLGMISLSLC 324 antimicrobial [Amolops loloensis] KOERDANEERRDDPDENEENG peptide GEAKVEEIORGARPPLRCKAAL

C

amolopin-9a amolopm-9a antimicrobial peptide precursor MFTL KSMLLLFFLGTiSLSLCE 325 antimicrobial [Amolops loloensis] EERNADEDDGEKEVKRGIFALI peptide KTAAKFVGKNLLKOAGKAGLE

HLACKANNOC

amolopin-9b amolopin-9b antimicrobial peptide precursor MFTMKKSLLLLFFLGTISLSLCE 326 antimicrobial [Amolops loloensis]. EERSADEDDGEKGVKRGTFSLIK peptide TAAKFVGKNLLKOAGKAGVEH

LACKANNOC

amoiopin-nl amolopin-iil antimicrobial peptide precursor MFTLKKSLLLLFFLGTINLSLCE 327 antimicrobial [Amolops loloensis] OERNAEEERRDDLGEROAEVE pegtide RFFPIVGKLLSG

amolopin-n2 amolopin-!i2 antimicrobial peptide precursor FTMKKSLLLLFFLGTINLSLCEO 328 antimicrobial [Amolops loloensis] ERNAEEERRDDLGEROAEVEK peptide R

amoiopin- i amolppin-ϋΐ antimicrobial peptide precursor MFPMKKSLLLLFFFGPISLSFCD 329 antimicrobial [Amolops loloensis] OERGADEEENGGEVTEOEVKR peptide NILS SrV GINRALSFFG

amolopin-p2 amolopin-p2 antimicrobial peptide precursor MFTLKKSLLLLFFLGTISLSLCE 330 antimicrobial [Amolops loloensis] OERGADEEENGGEVTEOEVKR peptide N VLS S VANG IN RAL SFFG

Anionic eil 156630460lsp|P85216.1 IAP2 GALME! 15 ETESTPDYLKNIOOOLEEYTKN 331 antimicrobial 6630460]Attionic antimicrobial peptide 2 FNTOVONAFDSDKJKSEVNNFIE peptide 2 SLGKILNTEKKEAPK

Anionic peptide Anionic peatide clone 10 YPASYDGDFDALDDLDDLDLD 332 clone 10 DLLDLEPADLVLLDMWANMLD

SQDFEDFE

Anionic peptide Anionic peptide clone 7 YPTSYDDDFDALDDLDDLDLD 333 clone 7 DLLDLEPADLVLLDMWANMLD

SQDFEDFE

Anionic peptide Anionic peptide clone 8 YPASYDDDFDALDDLDDLDLD 334 clone 8 DLLDLEPADLVLLDMWANMLD

SODFEDFE

peptide 7 (XT-7) Antimicrobial peptide 7 (XT-7) Antimicrobial Antimicrobial peptide Alo- 1 CiKNGNGCOPDGSQGNCCSRYC 380 peptide Aio- 1 HKEPGWVAGYCR

Antimicrobial Antimicrobial peptide Alo-2 CIANRNGCOPDGSOGNCCSGYC 381 peptide Alo-2 HKEPGWVAGYCR

Antimicrobial Antimicrobial peptide Aio-3 CI NGNGCOP GSOGNCCSGY 382 peptide Aio-3 CHKOPG W V AG YCRRK

Antimicrobial Antimicrobial peptide Ar-AMP AGECVOGRCPSGMCCSOFGYC 383 peptide Ar-AMP GRGPKYCGR

Antimicrobial Antimicrobial peptide attacin AttA MOSF ICFFISCLSWLVKGOFG 384 peptide attacin GTVSSNPNGGLDVNARLSKTIG AttA DPNANVVGGVFAAGNTDGGPA

TRGAFLAAN DGHGLSLQHSK

TDNFGSSLTSSAHAHLFND TH

KLDANAFHSRTHLDNGFKFDR

VGGGLRYDHVTGHGASLTASRI

PQLDMNTLGLTGKANLWSSPN

RATTLDLTGGVSKI-IFGGPFDGQ

TNKQIGLGL SRF

Antimicrobial Antimicrobial peptide BAMP- i OAEESNLOSLVSOYFOTVADYG 385 peptide BAMP- 3 KDLVEKAKGSELOTOAKAYFE

KTOEELTPFFKKAGTDLL FLSS FIDPK OPAT

antimicrobial antimicrobial peptide brevinin-lE-OG7 FFPLIAGLAA^'NFLPOILC IARK 386 peptide brevinin- precursor j^' ana graliamij c

1 E-OG7

antimicrobial antimicrobial peptide cecropin [Piutella M LSNIFFFVFMAFFAVASVSA 387 peptide cecropin xylostella] APRWKPFKKLEKVGRNIRNGII

RYNGPAVAViGOATSiARPTG antimicrobial antimicrobial peptide Defl-1 [Nasouia MKLLLVVAFIAVAVTAGLSIPL 388 peptide Defi-l vitripennis] NEFEDLVDFODWDEAAVDEDA

GVRORRVTCDLLSFGGVVGDS

ACAANCLSMGKAGGSCNGGIC

ECRKTTFKELWDORFG

antimicrobial antimicrobial jjsptide Defl-1 [Nasonia SFGGVVGDSACAANCLSMGKA 389 peptide Defi-l vitripennisj GGSCNGGICECR

antimicrobial antimicrobial peptide Defl-2 [Nasonia V K i i HAM S W! W S XA l S! J'! . 390 pepiide Defi-2 vitripennisl DELEDLVDVODWEEAWDDN

AGIRORRVTCDLLSFGGKVGHS

ACAANCLSMGKAGGRCNGGV COCRKTTFGDLWNKRFG

antimicrobial antimicrobial peptide Defl-2 [Nasonia SFGGKVGHSACAANCLSMGKA 391 peptide Defi-2 vitripennisj GGRCNGGVCOCR

antimicrobial antimicrobial peptide defensin 1-1 JNasonia MKLLLVVAFIAVAVTAGLSIPL 392 pepiide defensin 1- Yitripennisj, NEFEDLVDFODWDEAAVDEDA

GVRORRVTCDLLSFGGVVGDS ACAANCLSMGKAGGSCNGGIC ECRKTTFKELWDORFG antimicrobial antimicrobial peptide defensin i -2 [Nasonia MKFL.iIAVFSAMWSAAI.SLPL 393 peptide defeosin 1- vitripennis] DELEDL\ VODWEEA.WDD

AGI ORRVTCDLLSFGGKVGHS ACAANCLSMG AGGRCNGGV COCRKTTFGDLWNKRFG

Antimicrobial Antimicrobial peptide hirobricin- i FSKYEROKDKRPYSERXNOYT 394 peptide lumbricin- i GPOFLYPPERIPPOKVIKWNEEG

LPIYEIPGEGGHAEPAAA

Antimicrobial gii 126793 lspjP28794|MBPi MAIZE RSGRGECRRQCLRRHEGQPWE 395 peptide MBP-1 Antimicrobial peptide MBP-1 TQECMRRCRRRG

antimicrobial antimicrobial peptide MGD2b MKAVFVLLVVGLCIMMMDVA 396 peptide MGD2b TAGFGCPNNYACHOHCKSIRGY

CGGYCASWFRLRCTCYRCGGR RDDVEDIFDIYD VAVERF

Antimicrobial Antimicrobial peptide NK-lysin GIACWSCRKILOKLEDLVGEOP 397 peptide NK-rysin E ΑΉΝΈΑΑ SRVCRNLGLL GA

CKKIMRTCLRLiSRDILAGKKPO EVCVDIKLCKH

antimicrobial antimicrobial peptide odorranain BI MFTLKKSLLVLFFLGIVSLSVCD 398 peptide odorranain IOdorrana grahami] OKRDADEEDGGEVTGEEV RA Bi ALKGC WTKSIPPKPCFGKR antimicrobial antimicrobial peptide odorranain B4 MFTLKKSLFVLFFLGIVSLSVCE 399 peptide odorranain. IOdorrana grahami] HNRDADEEDGGEAIGGEVRRA B4 ALKGC WTK SiPPKPC SGKR antimicrobial antimicrobial peptide odorranain B5 MFTLKKSLLVLFFLG1VSLSVCE 400 peptide odorranain IOdorrana grahami^'j HNRDADEEDGGEVTGEEVKRA B5 I Odorrana ALKGCWTNSIPPKPCSGKR grahamij

antimicrobial antimicrobial peptide odorranain B6 AALRGCWTKSIPPKPCSGKR 401 peptide odorranain precursor iRana graharoi]

B6

antimicrobial antimicrobial peptide odorranain-03 AVPL1YNRPG1YAPKRPKGK 402 peptide odorranain- precursor I Rana grahami]

03

antimicrobial antimicrobial peptide OGC l precursor [Rana AIGNELKTLG LAO ILGKOPK 403 peptide OGCl graharci] MLKL WKWN WK S SDVE YHLAK

C

antimicrobial antimicrobial peptide 0GC2 precursor [Rana AIG ILKTLGNLAOKILGK 404 peptide 0GC2

Antimicrobial gi!236997lsb!AAB20020. l!!bbmi 1.55718!bbsi GVLS VIGYL KLGTGALNAVL 405 peptide PGQ 59194i236997]PGO^an.timiciObial peptide KQ

iXenopus iaevis. Peptide, 24 aa]

Antimicrobial Antimicrobial peptide 1 F SGS VNOAC SGFGWK 406 peptide!

Antimicrobial Antimicrobial protein Ace-AMPl ONICPR-VNR-IVTPCVAYGLGRA 407 protein Ace-AMPl PIAPCCRAL DLRF TRNLRR

AACRCLVGWNRNPGLRR PR FONIPRDCR TFVRPFWWRPRI OCGRIN

Antimicrobial Antimicrobial protein pip MKWTAAFLVLVIWLMAOPGE 408 protein pip CFLGLIFHGLVHAGKLIHGLl Bacteneciti-7 Ba.ctenecin-7 RRLRPRRPRLPRPRPRPRPRPRS 430

LPLPRPOPRRIPRPILLPWRPPRP IPRPOPOPIPRWL

Bactericcia Bacteriocin MNNLYRDLAPISAAAWAQIEEE 431

VARTFKRSVAGRRWDVKDPG GFGLAAVGTGHLRGIAAPQKG VDA LREVKALVELTVPFELQR

DEIDAVERGANDADWQPAKDA

ATELAYAEDRAIFDGYKAAGIV

GIREGSSNSRLELPTDAADYPA

AVGRALEOLRLAGVDGPYSVL

LGADAYTALSEGSDDGYPTIDH

IKRTVSGDIIWAPALNGGCVLST

RGGDFELHLGODLSIGYOSHTD VVRLYLRETLTFLMLTSEA

Bacteriocin Bacteriocin MNNLYRDLAPISAAAWAQIEEE 432

VARTFKRSVAGRRWDVKDPG

GFGLAAVGTGHLRGIAAPQKG

VDAKLREVKALVELTVPFELQR

DEIDAVERGA DADWQPAKDA

ATELAYAEDRAIFDGYKAAGIV

GIREGSSNSRLELPTDAADYPA

AVGRALEQLRLAGVDGPYSVL

LGADAYTALSEGSDDGYPTiDH

IKRTVSGDIIWAPALNGGCVLST

RGGDFELHLGODLSIGYOSHTD

KVVRLYLRETLTFLMLTSEA

Bacteriocin Bacteriocin bavarian- ^~N TKYYGNGVYCNSKI CWVDWG 433 bavaricin-MN OAAGGIGOTWXGWLGGAIPG

K

Bacteriocia Bacteriocin microcin B17 VGIGGGGGGGGGGSCGGOGGG 434 microcin B17 CGGCSNGCSGGNGGSGGSGSHi

Bacteriocia protein Bacteriocin protein MNNLHRELAPISEAAWAOIEEE 435

ASRTLKRYLAARRWDVPEAK

GFGF S AVGTGHVERID APGSDIR

AVRRNVLPLVELRWFTLARDA

IDDVERGAGDSDWOPLKDAAK

KIAFAEDRAVFDGYAAAGILGL

REGTSNPKLALPSSASDYPAAIA

AALNOLRLAGVNGPYAVVLGA

GVYTALSGGDDEGYPVFRHIES

LIDGKIVWAPAIEGGFVLSTRGG

DFELDIGODFSIGYSSHSADSVE

LYLOESFTFOLLTTEA b-defeiisin2-like b-defensin2-like protein 1 NPVTCLRSGAICHPGFCPRRYK 436 protein. 1 HIGiCGVSAIKCCK

b-defensin2-like b-defeosiii2-like protein 2 NPVTCIRSGAICHPGFCPGRYKH 437 rotein 2 IGVCGVPLTKCCK b-defensi«2-iike b-defensin2-like protein 4 PVTCLRSGATCHPGFCPRRYK 438 rotein 4 fflGVCGVSAIKCCK

Beta - defeasm Beia - defensin 105 A ( Beta - defensin 105B) GLDF SOPFP SGEF AVCE SCKLG 439 iOSA i Beta - RGKCRKECLE E PDG C^'RL F defensin 105B) LCCRQRI

beta defensin beta defensin NHRSCHRIKGVCAPDRCPRNM 440

ROIGTCFGPPVKCCR

beta defensin I beta defensin 1 DHY CVSSGGOCLYSACPTFTKI 441

OGTCYGGKAKCCK

beta defensin 103 beta defensin 103 O YYCRVRGGRCAVLSCLPKE 442

EOIGKCSTRGRKCCR

Beta defensin 2 Beta defensin 2 AVGSLKSIGYEAELDHCHTNGG 443

YCVRA1CPPS ARRPGSCFPEKNP

CCKYMK

Beta defensin 2 Beta defensin 2 NPISCARNRGVCIP1GCLPGMKO 444

1GTCGLPGTKCCR

beta defensin 2 beta defensin 2 PVTCLRSGAICHPGFCPRRYK 445

HIGTCGLSVIKCCK

Beta defensin 3 Beia defensin 3 NSVTCS NGGFCISPKCLPGS 446

OiGTCSLPGSKCCK

beta defensin 39 beta defensin 39 DDSIOCFOKNNTCHTNOCPYFO 447

DEIGTCYDKRGKCCOKRLLHIR

VPRKK V

Beta defensin-2 Beta defensin-2 HRSCYR KGVCAPARCPRNM 448

ROIGTCHGPPVKCCRKK

beta defensin-6-like beta defensin-6-like antimicrobial peptide DTLACROSHGSCSFVACRAPSV 449 antimicrobial DIGTCRGGKLKCCK

peptide

Beta-basrubm a!26391709!sp!P83187!BRB BASAL Beta- KIMAKPSKFYEOLRGR 450 basrabin

Beta-defensin 1 Beta-defensin 1 DHY CVRSGGOCLYSACP1YTR 451 iOGTCYHGKAKCCK

Beta-defensin 1 Beta-defensin 1 DOYIC AR GGTC F SPCPLFTRl 452

DGTCYRGKAKCC

Beta-defensin 1 Beia-defensin 1 NSVTCS NGGFCISPKCPPGMK 453

OIGTCGLPGSKCCR

beta-defensin 1 beta-defensin 1 POSCHRNKGVCVPiRCPRSMRO 454

IGTCLGAPVKCCR

Beta-defensin 10 Beia-defensin 10 DLKHLILKAQLTRCYKFGGFCH 455

YNICPGNSRF SNCHPE LRCC

KNIKOF

beta-defensin 102 beta-defensin 102 LSGRVLFPLSCIGSSGFCFPFRCP 456

HNREEIGRCFFPIO

beta-defensin 103 beta-defensin 103 O YY CRVRGGRCA VLTCLPKE 457

EOIGKCSTRGRKCCR

Beta-defensin Beta-defensin 104 A precursor EFELDRICGYGTARCRKKCRSO 458

104 precursor EYRIGRCPNTYACCLRKWDESL

LNRTKP Beta-defensin Beta-defensin 105A GLDFSOPFPSGEFAVCESCKLG 459 105 A RGKCRKECLENEKPDGNCRLNF

LCCRORI

Beta-defensin Beta-defensin 106A FFDEKC KLKGTCKNNCGKNE 460 106A ELlALCOKSL CCRTlOPCGSnD beta-defensin 11 beta-defensin 11 DLKHLILKAOLARCYKFGGFCY 461

NSMCPPHTKFKiNCHPDHLHCC INMKELEGST

beta-defensin 124 beta-defensin 124 LALGHMOPGR .SEFKRCWKGOG 462

ACRTYCTROETYLHMCPD A SL CCLPYGSRPL

beta-defensin 127 beta-defensin 127 VTEOLKRCWGEYIRGYCRKIC 463

RISEIREVLCENGRYCCL VEL EARR ITKPPPPE

beta-defensin 14 beta-defensin 14 FLP TLRKFFCRIRGGRCAVLN 464

CLGKEEOIGRCS SGRKCCR K

K

beta-defensin 2 beta-defensin 2 DHYICAK GGTC FSPCPLFNRI 465

EGTCYSG AKCCI

Beta-defensin 34 Beta-defensin 34 FFFFDE CSRTNGRCTASCLKNE 466

ELVALCW NLKCCVTVQSCGR SKGNQSDEC SGHMGTRG

beta-defensin 37 beta-defensin 37 DTLA CIENKDTCRLKN^'CPRLHN 467

VVGTCYEGKGKCCH

beta-defensin 4 beta-defensin 4 [Pan troglodytes] DPVTCLKSGAICHPVFCPRRYK 468 [Pan troglodytes] OIGTCGLPGTKCCK

Beta-defensin 5 Beta-defensin 5 TiNNPVSCCMlGGiCRYLCKG 469

NiLO G CGVTSL CC R

Beta-defensin- 1 Beta-defensin- ! SFSCSONGGFCISPKCLPGSKOI 470

GTCTLPGSKCCR

Beta-defensin].04A Beta-defensinl 04 A EFELDRICGYGTARCRKKCRSO 471

EYR1GRCPNTFACCLRKWDESL LNRTKP

Beta-defensinl04A Bela-defensinl04A EFELDRICGYGTARCRKKCRSO 472

EYRIGRCPNTYACCLRKWDESL LNRTKP

Beta-defensin 104 A Beta-defensinl 04A EFEWDRiCGYGTARCRNKCRSO 473

EYRIGRCPNTFACCLRKWDESL

LNSTKP

Beta-defensini05A Beta-defensin! 05A GLDFSOPFPSDEFAVCESCKLG 474

RGKCRKECLENEKPDGNCRLNF LCCRERI

Beta-defensinl 05 A Beta-defensinl 05A GLDFSOPFPSGEFAVCESCKLG 475

RGKCRKECLENEKPDGNCRLNF

LC^'CRORi

Beta-defensinl 05A Beta-defensinl 05 A GLDF SOPFP SGEF A VFES CKF SR 476

GKCRKECLENEKPDGNCRLNFL CCROSI Bet.a-defensinlO.5A Beta-defen.sin.105A GLEFSEPFPSGRFAVCESCKI.GR 477

GKCRKECLENEKPDGSCRLNFL

CCRPRM

Beta-defesisinl 06A Beta-defensinl 06 A FFDDKCDKLRGTCKNSCEKNEE 478

LTSFCO SLKCCRTIOTCGNTTD

Beta-defensinl06A Beta-defensinl 06A FFDEKCG LKGTCK NCGKNE 479

ELIALCQKSLKCCRTK)PCGSIID

Beta-defensinl 06A Beta-defensinl 06 A FFDEKC KLKGTCKNNCGKNE 480

ELlALCO SLKCCRTlOPCGSliD

Borabinin Bombinin G1GALSAKGA LKGLAKGL. AZHF 481

AN

Bombinin H-like Bombinin H-like peptide 1 ITGPVLGLVGKPLESLLE 482 peptide 1

Bombinin-like rii l 8202396jspiP82286.1 !BMNL2 BOMVAj GIGASILSAGKSALKGFAKGLA 483 peptide 2 18202396]Bombinin-like pepiides 2 EHFAN

precursor [Contains: Acidic peptide 2-1 ;

Bombinin-like peptide 2 (BLP-2);

Octapeptide 2; Acidic peptide 2-2;

Bombinin-H2j

Bombini.n-1ik.e gil l 15057lsp|P29003 |BMNL2 BOMOR GiGSAlLSAGK.SALKGLAK.GLA 484 peptide 2 (BLP-2 ) Bombinin-like peptide 2 (BLP-2 ) EHFAN

Bone marrow Bone marrow proteoglycan LHLR SET8TFETPLG AKTLPEBE 485 proteoglycan ETPEOEMEETPCRELEEEEEWG

SGSEDAS KDGAVESiSVPD V

DKNLTCPEEEDTVKVVGIPGCO

TCRYLLVRSLOTFSOAWFTCRR

CYRGNLVSIHNFNINYRiOCSVS

AI.NOGOVWIGGR1TGSGRCRR F

OWVDGSR\\^rNFAYWAAHOPWS

RGGHCVALCTRGGY RRAHCL

RRLPFICSY

Bone marrow Bone marrow proteoglycan. TCRYLLVRRAECFDKAOSVCRR 486 proteoglycan. CYRGTLASIHSFSVNFGIOSAW

GINOGOVWKKJRIKGWGRCKR FRWVDGSSWNFAYWAAGOPC

PGGGRCVTLCTOGGHWRLSHC VKRRPFICSY

Bone marrow Bone marrow proteoglycan TGRYLLVRRPECFNKAOLVCRS 487 proteoglycan CYRGTLASIHSFSVNFMOSFVR

GINOGOVWIGGRiVGWGRCKR FRWnXJSSW FAYWAAGOPRR GGGRCVTLCTRGGHWRRSGCG KRRPFICAY

Brevinin-iBb gi|4I0i6806ispiP82834jBRlBB RANBE FLPAIAGMAAKFLPKIFCAISKK 488

Brevinin-IBb C

Brevinin-lBd ei!41016808!spjP82836jBRlBD RANBE FLPAlAGVAAKFLPKiFCAISKK. 489

Brevinin-lBd C

brevinin- ICHb brevinin-ICHb FLPV1AGLAAKVLPKLFCAITKK 490

C

brevmin- l E-OGl brevinin-l.E-OGl antimicrobial peptide FLPLLA.GLAANFLPKLFCKTTKK 491 antimicrobial precursor IRana grahami] C peptide

brevinin- 1 E-OG3 brevinin- 1E-OG3 antimicrobial peptide FLPLLAGLAA FLP LFCXITKK 492 antimicrobial precursor [Rana rahami] C

peptide

brevinin- 1E-QG4 brevinin- 1E-OG4 antimicrobial peptide FLPFLAGLAA FLPKLFCKITR 493 antimicrobial precursor Rana grahami] c

peptide

breviniri-lE-OG5 brevinin- 1 E-OG5 antimicrobial peptide FLPLLAGLAANFLPKLFCKITRK 494 antimicrobial precursor [Rana grahamii c

peptide

brevinin- lE-RTa brevinin- ΙΕ-RTa antimicrobial r>er>tide MFTFKKSMLLLFFLGTINLSLCE 495 antimicrobial precursor [Amolops ricketti] OERNADEEERRDDPDETNVEVE peptide KRFLPLLAGVVANFLPOilCKIA

RKC

Brevinin-lP Brevinin-lP FLPALTGIAAKALPSLLCKIT K 496

Brevinin- 1 R Brevinin- 1R FFPAIFRLVAKVVPSnCSVTKKC 497

Brevinin-lRa Brevinin-lRa \ ! Pl^;\ .\ SV -\.\ H\! \101 l \ V( \ \S 498

RRC

brevinin- 1-RAA 10 brevinin- 1-RAAlO antimicrobial peptide FLPAVIRVAANVLPTAFCAISKK 499 antimicrobial precursor [Rana andersonii] c

peptide

brevinin-l-RAA5 brevinin- 1 -RAA5 antimicrobial peptide FLPAViRVAA VLPTVFCAISKK 500 antimicrobial c

peptide

brevinin- 1-RAB2 brevinin- 1-RAB2 antimicrobial peptide FLPLLAGLAANFLPKLFCKITKK 501 antimicrobial precursor [Rana andersoniij c

peptide

brevinin- 1 -RAB2 brevinin- 1-RAB2 antimicrobial peptide FLPLIAGLAANFLPKLFCKITKK 502 antimicrobial precursor Rana andersonii] c

peptide

brevinin- 1 -RAB2 brevinin- 1-RAB2 antimicrobial peptide FLPLIAGLAANFLPKLFCKITKK 503 antimicrobial precursor [Rana andersonii^"!

peptide

brevinin- IRTa brevinin- IRTa antimicrobial peptide MFTFKKSMLLLFFLGTINLSLCE 504 antimicrobial precursor f Amolops rickettij OERNADEEERRDDEDKRDVEV peptide EKRFLGSLLGLVGKIVPTLICK1S

KKC

brevinin- lRTb brevinin- IRTb antimicrobial peptide MFTSKKSMLLLFFLGTINLSLCE 505 antimicrobial precursor [Amolops rickettij OERNADEEERRDDEDKRDVEV peptide EKRFLGSLLGLVGKWPTLFCKI

SKKC

Brevinin- 1 S Brevinin- I S FFP AILR V AAK VGP A VLC ΑΪΤΚ 506

KC

Brevinin- IV Brevinin -IV FLPLI A SVAANLVPKiFCKlTKK 507

c

Brevinin- lVb Bre inin- 1 Vb FLPLIAGLAANFLPKIFCAITKKC 508

Brevinin-2CDYb Brevinin-2CDYb GLFS WTGVLKAV GKNVAG SL 509

LEOLKCKISGGC

brevinin-2E-OGl brevinin-2E-OG 1 antimicrobial peptide GLLDTFKN ALNAAKSAGVSV 510 antimicrobial precursor [Rana grahami] LNALSCKLSKTC

peptide brevinin-2E-OG2 brevinin-2E-OG2 antimicrobial peptide GLLDTFKNEAI. APKSAGVSVL 511 antimicrobial precursor [Rana graharni] SLSCKLSKTC

peptide

brevinin-2E-OG4 brevinin-2E-OG4 antimicrobial peptide GLLDTF NLALNAA SAGVSV 512 antimicrobial LN SLSCKLFKTC

peptide

brevinin-2E-OG6 bi'evii]iii-2E-OG6 antimicrobial peptide GLLDTFKNLALNAAKSAGVSV 513 antimicrobial precursor [Ran graharni] LNSLSCKLSKTC

peptide

brevmin-2E-QG7 brevinin-2E-OG7 antimicrobial peptide GLLDTFKNMALNAAKSAGVSV 514 antimicrobial precursor [ Rana graharni]. LNSLSCKLSKTC brevinm-2LTc brevinin-2LTc antimicrobial peptide [Rana GVLDTFKDVAIGVAKGAGTGV 515 antimicrobial latouchii] LKALLCKLDK s c

peptide

Brevinin-2Ra Brevinin-2Ra GILDSL NFAKDAAGILLKKAS 516

CKLSGOC

brevmm-2-RA13 brevinin-2-RA 13 antimicrobial peptide SFLTSFKDMAIKVAKDAGVN'IL 517 antimicrobial precursor [ Rana andersonii | N^'l^'ISCKlFKTC

Begtide

breviinn-2-RA14 brevinin-2-RA i 4 antimicrobial peptide SFLTSFKDMAIKVAKDAGVNIL 518 antimicrobial precursor [Rama andersonii] NTISCKiSKTC

peptide precursor

[Rana andersonii]

brevmin-2-RA20 brevinm-2-RA20 antimicrobial peptide GLLDTLKNMAINAAKDAG V S V 519 antimicrobial precursor [Rana andersonii]. L TLSCKLSKTC

peptide

brevinirt-2-RA21 brevinm-2-RA23 antimicrobial peptide GFLDTL-KNMALNAAKGAGGSV 520 antimicrobial LKALFCKLFKTC

peptide

brevinin-2-RA22 brevinin-2-RA22 antimicrobial peptide GLLDTLKNMATNAAKGAGVSV 521 antimicrobial LKALSCKLFKTC

peptide

brevmin-2-RA6 brevinin-2-RA6 antimicrobial peptide GLLDTLKNMAJNAAKGAGVSV 522 antimicrobial LNALSCKLSKTC

peptide

Brevinin-2Rb Brevmin-2Rb GLMSTLKGAATNAAVTLLNKL 523

OCKLTGTC

Brevinin-2Rc Brevinin-2Rc GLMSTLKGAATNVAVTLLNKL 524

QCKLTGTC

Brevinin-2Rd Brevinin-2Rd ( i i l .DSLK N I \ \.\ \0! 1.1.\K VS 525

CKLSGOC

brevinin~2RTa brevinin-2RTa antimicrobial peptide MFTTKKSLLVLFFLGTISLSFCE 526 antimicrobial precursor [Amolops ricketti] EERNADEDDGEMTEEEKRGLM peptide STLKDFGKTAAKEIAOSLLSTAS

CKLA TC

brevinin-2RTb bre viiiiii-2RTb antimicrobial peptide MFTSKKSLLVLFFLGTISLSFCE 527 antimicrobial precursor [Amolops ricketti} EERNADEDDGEMTEEVKRGILD peptide TLKEFGKTAAKGIAOSLLSTAS

CKLAKTC

Casbene synthase Casbene synthase STTHOEVMPLAYFPPTVWG RF 537

ASLTFNP SEFE SYDERVTA'XKKK

VKDILISSTSDSVETV!LTDLLCR

LGVSYHFENDIEELLSKIF SOP

DLVDEKECDLYTAAIWRVFRO

HGF MSSDVFSKF DSDG EKE

SLRGDAKGMLSLFEASHLSVHG

EDILEEAFAFTKDYLOSSAVELF

PNLKRHTT ALEOPFHSGVPRLE

ARKFIDLYEADIECRNETLLEFA

KLDYNRVOLLFIOOELCOFSKW

WKDL LASDiPYARDRMAEIFF

WAVAMYFEPDYAHTRMIIAKV

VLL!SLiDDT!DAYAT EETHlL

AEAVARWDMSCLEKLPDYMK

VIYKLLLNTFSEFEKELTAEGKS

YSVKYGRE A FGELVRGYYLEA

VWRDEGKIPSFDDYLYNGSMT

TGLPLVSTASFMGVOEITGLNEF

OWLET PKLSYASGAFIRLVND

LT SH VTEOOR GHV AS C1DC YM

NOHGVSKDEAVKILOKMATDC

WKEI EEC ROSOVSVGHLMR

iVNLARLTD V SYKYGDG YTDSO

OLKOFVKGLFVDPISi catiielicidiri catiielicidin RLKEUTTGGGKiGEKlRRiGGRi 538

DFFKNLQPREEKS

Catiielicidin Catiielicidiri SLWLLLLGLVLPS A SAO ALSYR 539

EAVLRAVDRINDGSSEANLYRL LELDPPPKDVEDRG ARKP A SFR VKETVCPRTSOOPLEOCDF EN GLV

catiielicidiri catiielicidin antimicrobial peptide precursor GDFFRKSKEKIGKEFKRJVORIK 540 antimicrobial [Pan troglodytes! DFLRN

peptide

catiielicidin caihelicidin antimicrobial peptide [ a!tus MQPFi RDVP SL WRSLSLLLLLG L 541 antimicrobial norvegicusl. GLPLAVSOTLSYREAVLRAVDD peptide FNOOSLDTNLYRLLDLDSEPOG

DEDPDTPKYVRFRVKETVCSKA

SOOLPEOCAFKEOG COCMG TLNOAAESFDISCDAPGIOPF

RFKKISRLAGLLRKGGEKFGEK

ERKIGOKiKDFFO EAPE!EO caihelicidin catiielicidin antimicrobial peptide \TSYKEAVLRAIDGINQRSSDA 542 antimicrobial NLYRLLDLDPRPTMDGDPDTPK peptide PVSFTVKETVCPRTTOOSPEDC

D

caihelicidin-4 cathelicidin-4 IBubaius bubalisj NEDLGTRKPVSFTVKETVCPRT 543

THOPAEOCGFKERGR

Catheiicidin-5 , Caihelicidin- 5 , Antibacterial peptide GGLRSLGR lLRAWK YGPilVP 544 Antibacterial BMAP-28 , Myeloid antibacterial peptide 28 IIRIG peptide BMAP-28 .

Myeloid

antibacterial

peptide 28

cathelicidin-BF cathelicidin-BF KFFRKLKKS VKKRAKEFFK PR 545

ViGVSIPF

cathelicidin-BF- 15 cathelicidin-BF- 15 KFFRKLKKSVKKRAK 546

Catheiiii Cathelin QLRYREAVLRAVDRLNEQSSEA 547

LYRLLELDQPPKADEDPGTPK

PVSFTVKETVCPRPTRQPPELCD

FKEKOCVGTVTLNPSIHSLDISC

NEiOSV

caiiomc cationic antimicrobial protein { acaca GDFFR SKEKIGKEFKRTVORIK 548 antimicrobial mulattii] DFLRN

protein

cationic cationic antimicrobial protein VLSYKEAVLRAIDGTNORSSDA 549 antimicrobial LYRLLDLDPRPTMDGDPDTPK

[protein. PVSFTVKETVCPRTTOOSPEDC

D

Cecropin ui!25Q89S47!sp|P83420|CEC ΟΪ Ε WKPFKKIEKAVRRVRDGVAKA 550

Cecropin GPAVAVVGOAT cecropin 3 cecropin 3 MNFTKLF1MVA1AVLLLAGIQPV 551

EAAPRMEIGKRREKLGRNVFKA AKKALPVIAGYKALG

cecropin A cecropin A M FKKILFFWACLVFTVTAAP 552

EPRWKFF JEKVGONIRDGITK AGPAVAWGOAAAISGK

cecropin E cecropin E [Bombvx mori] MNF SR ALF YVF A VFLVC A S VM 553

[Bombvx mori] AAPEPRWKIFKKJEKVGO RD

GnKAGPAVAWGOAATLAHGK

Cecropin-A Cecropin-A GGLKKLGKKLEGAGKRVFNAA 554

EKALPVVAGAKAL

Cecropin-A «i|2508 858isp|P834i3|CECA HELVi R WKVFKJ iE VG RMRDG ViKA 555

Cecropin-A APAiE VLGQAKAL

Cecropin-A Ki!46395677ispiP82290iCECA ANOGA GRLK LGKKIEGAGKRVFKAA 556 precursor Cecropin-A precursor 1 Contains: Cecropin- EKALPVVAGVKALG

A; Cecropin-A amidated isoform]

Cecropin -B ei!25089860|sp|P83414!CECB HELVi KW VFKKIE VGRNIRDGiVKA ^"'

Ceeropin-B GPAiAVLGOA

Cecropin-C ril25089862lsp|P83415iCECC HELVi RW VFKKIEKMGRMRDGVIKA 558

Cecropin-C APAIEVLGOAK

cecropin-D cecropin-D preciirsor [Asriiis convotvuii] PFKELERAGORVRDAIIS 559

Cecropin -D gil l 16092|sp!P01510!CECD HYACE W PF ELEKVGORVRD ViSA 560

Cecropin-D precursor GPAVATVAOATALAK

Cecropin-D-like ail l 56630481lsp|P85210!CECD GALME ENFFKEIERAGORIRDAIISAAPA 561 peptide Cecropin-D-like peptide VETLAOAOKIIKGGD

CGA 41-60 CGA 41-60 TLRGDERILSILRHONLLKE 562

CGA 41 -70 CGA. 41-70 TLRGDERILSILRHONLLKELOD 563

LALOGAK

CGA 47-60 CGA 47-60 RILSILRHONLLKE 564

CGA 47-70 CGA 47-70 RILSILRHONLLKELODLALOGA 565 K

Chain A, Solution Chain A, Solution Structure Of FOWORNIRKVRX 566 Structure Of Antimicrobial And Endotoxin- Neutralizing

Antimicrobial And Peptide Lfl 1 In Dpc Micelles.

Endotoxin- Neutralizing

Peptide Lf! ί in

Dpc Micelles.

Chain A, Solution Kii 159162437 !pdb 11 HU6 ! Ai 159162437 ] Chai XNLRRliRKGIHIiK YG 567 Structure Of G10 11 A, Solution Structure Of G 10 Novispirin

Novispirin

Chain A, Solution gi| 159162436lodb| lHU5|Ari591624361Chai XNLRRIIRK1IHIIKKYG 568

Structure Of n A, Solution Structure Of Ovispirin-1

Ovispirin-1

Chain Solution ri! i 59162438jpdb!lHU7iAl!59162438]Chai XNLRRITRKIIIillKKYG 569 Structure ΟΓΓ7 n A. Solution Structure Of T7 NovisDirm

Novispirin

Chain A, Structure Chain A, Structure Of The Antimicrobial RRWFWR 570 Of The Peptide CyclofRrwfwr ) Bound To Dpc

Antimicrobial Micelles

Peptide

CyciofRrwfwr )

Bound To Dpc

Micelles

Chain A, Structure Chain A, Structure Of The Caniionic, RRWWFR 571 Of The Cantionic, Antimicrobial Hexapeptide Cvclo(Rrwwfr j

Antimicrobial Bound To Dpc-Micelles

Hexapeptide

CycloCRrwwfr )

Bound To Dpc- Micelies

Chain A. The m\ 157872589|pdbjm6X|Af ί 5787258⁽i]Chai KFPWWAVPFLR 572

Structure Of The n A The Structure Of The Antimicrobial

Antimicrobial Peptide Triirpticin Bound To Micelles-A

Peptide Tritrpticin Distinct Membrane-Bound Peptide Fold

Bound To .( .e j e3}

Micelles-A Distinct

Membrane-Bound

Peptide Fold

(peptide3)

Cicadin gi|26392 \ 76|sp|P83282|ClCD C1CFL NEYHGFVDKANNENKRKKOO 573

Cicadin GRDDF KPNNFANRRRKDDY

NENYYDDVDAADW

Cicerarin gi!68053347!spjP83986.1 iCARI CiCAR[680 VKSTGRADDDLAVKT YLPP 574

53347] Cic erarii!

Cicerin gi|68053357|spiP83987iC j cICAR ARCENFADSYROPPISSSOT 575

Cicerin

Circuliti-A ί CIRA gil l7433719lsplP56871 ICIRA CHAPA GIPCGESCVWiPCiSAALGCSCK 576

Ciiculin-A fCIRA. NKVCYRN

ciaRL-37 ciaRL-37 RLGDII.OKAREKIEGGLKKI.VO 577

KIKDFFG FAPRTES

Class Π sec- Class ΪΙ sec-dependent bacierioein YYGNGLYCNi E CWVD OA 578 dependent KOEIGKIIV GWV

bacierioein Clavanm-E Clavanin-E LFKLLGKilHIIVGNFVPIGFSI VF 579

Coccinin Coccinin KOTENLADTY 580

Colutellin-A Colutellin-A VISIIPV 581

Cortico statin 1 Corticostatin 1 GICACRRRFCPNSERFSGYCRV 582

NGARYVRCCSRR

Corticosiatin-3 gi! U84l9|sp!P01376!DEF3 RABIT VVCACRRALCLPRERRAGFCRI 583 precursor Corticostatin- 3 precursor (Corticostatin ill) RGRIHPLCCRR

(Corticostatin III) (CS-iil) (Macrophage antibiotic peptide

(CS-IIi) MCP-1) (NP-1 ) (Antiadrenocorticotropin

(Macrophage peptide 111)

antibiotic peptide

MCP-1 ) ( P-1)

(Antiadrenocorticot

ropin _.¾tidejll)

Corticostat.m-4 ci; I 184221 sp !PO 1377 , 2|DEF4 ABITil i 842 WCACRRALCL.PLERRAGFCRI 584 precursor 2]Corttcostatia-4 Drecursor (Corticostatin IV) RGRIHPLCCRR

(Corticostatin TV) (CS-TV^") (Macrophage antibiotic peptide

(CS-TV) MCP-2) (NP-2) (Antiadrenocorticotropin

(^"Macrophage peptide IV)

antibiotic peptide

MCP-2) (NP-2)

(Antiadrenocorticot

ropin peptide TV)

Corticostatin-6 cii416897|sp!P80223!DEF7 RABIT GICACRRRFCLNFEOFSGYCRV 585 (Corticcstaiin VI} Coriicostatin-6 (Corticostaim VI) (CS-VD NGARYVRCCSRR

I CS- V I ) (Neutrophil antibiotic peptide NP-6)

(Neutrophil

antibiotic

peptideNP-6}

Corticostatit!- Corticostatin-related peptide LCRP CPCGRRRCCVRGLNVYCCF 586 reiated peptide

LCRP

crustin 1 crustin 1 [Procambarus clarkii] MWMATGAVMAA PPCLSL P 587

KVDIPRCT SCOAEDKPGLFFC CDNKGTNAGKCPRVHLOODER EVLCDKNOL YPNHLNCKOD S DCHLWEKC CFLPDNNOLICRS S EV

crastin 2 crustin 2 i Proeambarus clarkii] MLRVLVLSMLVVAALGHLPRP 588

KPPQPGCNYYCT PEGPNKGA

KYCCGPOFLPLIREEKHN^'GFCPP

PLKDCTRILPPOVCPHDGHCPIN

O CCFDTCLDLHTC PAHFYIN

crustin-iike crustin-iike antimicrobial peptide MLKFVVLSVVAVAVVOSOEDT 589 antimicrobial IFenneropenaeus indicus] RFLGVSGGVAGGGFVPGVPGH peptide GGIAPGFECNYCRTRYGYVCCK

PGRCIWRDTCPGillNRPPICRO DTECFGSDKCCYDTCLNDTVC KPIVLGSEG

crustin-iike crustin-iike antimicrobial peptide type 1 PWRSIECNYCRTRYGYVCCKPG 590 antimicrobial j ^"Penaeus monodon] RCPOIRETCPGLRKGVPICRODT pefi e.ixpe.1 DCFGSDKCCFDTCLNDTVCKPI

VAGSOG crustin-like crustin-like antimicrobial peptide type 2 LKFWLSWAVAWHAODK 591 antimicrobial jTenaeus monodonj GNADT FLGGYGVPGGGVPGV peptide tvoe 2 GVPGVGGGFLPGVPGHGGWP

GGGGLLPGGOFECNYCRTRYG YVCCKPGRCPOIRETCPGLRKGT

PICRODTDCFGSDKCCFDTCLN DTVCKPIVLGSEG

cryptdin related cryptdin related sequence peptide LODAALGWGRRCPRCPPCPRCS 592 sequence peptide WCPRCPTCPGCNCNPK

cryptdiit related cryptdin related sequence peptide LODAAVGWGRRCPOCPRCPSC 593 sequence peptide PSCPRCPRCPRCKCNPK

cryptdin related cryptdin related sequence peptide LODAAVGWGRRCPOCPRCPSC 594 sequence peptide PSCPRCPRCPRCKCNPK

cryptdin related cryptdin related sequence peptide LODAAVGWGRRCPOCPRCPSC 595 sequence peptide PSCPRCPRCPRCKCNPK

cryptdin related cryptdin related sequence peptide [Mus LODAALGWGRRCPRCPPCPRCS 596 sequence peptide miisciilus] WCPRCPTCPRCNCNPK

[Mus musculus]

Cryptonin Cryptonin GLLNGLALRLGKRALKKiiKRL 597

CR

C-terminal C-terminal fragment, LL-3703-37) IGKEFKR ORIKDFLRNLVPRT 598 fragment, LL- ES

Cucurmoschin rii52782770isp|P84158.1 ICUCN CUCMAfS PORGEGGRAG LLREEOEI 599

2782770jCucurmoschin

Cyclopeptide E Cvclopeptide E PGLGFY 600

Cvclopeptide F Cyclopeptide F PGMGIYLPM 601

Cyclotide vibi-E Cyclotide vibi-E G1PCAESCV 1PCTVTAL1GCGC 602

S^'N VCYN

Cydotide vi i-G Cyclotide vibi-G GTFPCGESCVFIPCLTSA1GCSC 603

KSKVCYKN

Cyclotide vibi-H Cyclotide vibi-H GLLPCAESCVYIPCLTTViGCSC 604

KSKVCYKN

Cyclovio!acin-02 Cycloviolacin-02 GTPCGESCVWTPCISSA1GCSCKS 605

KVCYRN

Cysteine-ricb Cysteine -rich antifungal protein 1 OKLCERPSGTW SG VCGNNN A C 606 antifungal protein 1 KNOCINLEKARHGSCNYVFPAH

KCiCYFPC

Cysteine-ricb Cysieine-rich antifungal protein 1 OKLCERPSGTWSGVCG SNAC 607 antifungal protein I XOC! M HK \ H( iS( \V \TP \ H

KCiCYFPC

Cysteine -rich gi!46l47 |spiP30227.2|AFPi BRA Ai4614 OKLCERPSGTWSGVCGNNNAC 608 antifungal protein 1 78] Cysteine-ricb antifungal protein 1 KNOCIN

iAFPl) (AFP1)

Cysteine -rich Cvsteine-rich antifungal protein 1 precursor OKLCERPSGTWSGVCG NNAC 609 antifungal protein i i^'AFP l ) KNOCFNLEKARHGSCNYV'FPAH precursor iAFPl) KCiCYFPC

Cysteine -rich C steine-rich antifungal protein 1 precursor OKLCERPSGTWSGVCGNNNAC 610 antifungal protein i (AFPl) KNOCiNLEKARHGSCNYVFPAH precursor ί AFP 11 KCiCYFPC Cytoiasectotoxin- C γίο is ectotoxin^■■ I b GFFGNTWKKI GKADKIML K 625 ib AVKL VKKEGiSKEEAOA VD

AMSKKOI LYI KYYGKKALO KASEKL

Cytoinsectotoxin- Cytoinsectotoxin- 1 c GFFGNTWKKIKGKADKIMLKK 626 j_c AVKTMVKKEGISKEEAOAKVD

AMSKKOIRLYA'LKYYGKKALC) KASEKL

Cytomsectotoxin- Cy to ins ectotoxin - 1 d GFFGNTWKKIKGKADKIMLKK 627 l d AVKIMVKKEG1TKEEAOAKVD

AMSKXOIItLYLLKY YGKKALO KASEKL

Cvtoinsectotoxiti- Cytoinsectoto in- 1 e GFFGNTWKKIKGKADKIMLKK 628 ie AA'KIMVKKEGISKEEAOAKVD

A SKKQIRLYLTJCYYGKKALO KASEKL

Decoralin Decorai in SLLSLIRKLIT 629

DEFBl-like protein DEFB 3 -like protein DHYNCVRSGGQCLYSACPIYTK 630

IOGTCYHGKAKCCK

DEFBl-like protein DEFBl-like protein , Beta-defensin 1 DHYNCVRSGGOCLYSACPIYTK 631 . Beta-defensin 1 IOGTCYHGKAKCCK

Defensin Defensin GFGVGDSACAAHCIARRNRGG 632

YCNAKTVCVC

defensin defensin GYGCPFNOYOCHSHCSGIRGYK 633

GGYCKGTFKOTCKCY

Defensin Defensin HSACAANCLSMGKA.GGRCENG 634

VCLCR

Defensin Defensin MEKKSL A .GLCFLFLVLF VAOEI 635

WTEAKTCENLADKY^'RGPCFSG CDTHCTTKENAVSGRCRDDFR CWCTKRC

Defensin Defensin M VLAVSLAFLLIAGLISTSLAO 636

NEEGGEKELVRVRRGGYYCPFF ODKCHRHCRSFGRKAG YCGGF LKKTCICVMK

Defensin Defensin SKWFTFNHAACAAHCILLGNR 637

GGHCVGTVCHCR

Defensin beta 1 Defensin beia 1 PLSCRLNRGICVPIRCPGNLRO 638

IGTCFTPSVKCCR

defensin [Dresssena defensin [Dreissena polymorpha] MSKLVVFSLLIAAAV SVSA 639 polvmoTpha] APOKRITCDLLGGVWILGADTA

CAGHCYTLNHPGGHCEGGYCY CRPGTFSEILG

defensin [Zea defensin Zea mays] MPSYKKLVrVGFALTLLLVSFG 640 ma s] MDASAKLCSTT DLLICGGAIP

G AVNO A CDDTCRNKGYTGGGF

CNMKIORCVCRKPCALEEOTEA RAGDEAAGGAGDMMSRTPGR

WOIE defensin ί defensin 1 precursor FTCDVLSVEAKGVKL f-LAA CGI 641 precursor HCLFRERTGGYCNKKRVCICR

Defensin 2 Defensin 2 MKVLAVSLAFLLIAGLISTSLAE 642

NDEGGEKELVRVRRGGYYCPF RODKCMRHCRSFGRKAGYCGG FLKKTCICV

Defensin D Defensin D GFGVGDSACAAHCiARG RGG 643

YC SKKVCVC

Defensin J 1 -2 Defensin Jl-2 RTCESOSHRFKGLCFSKSNCGS 644

VCHTEGF GGHCRGFRRRCFCT RHC

Defensin protein 1 Defensin protein 1 ATVRNSRPEAAGEPSGVSSTE 645

GD WRHIEKRDVSYOGEGNTRR FDNPFGCPADEGKCFDFiCNN AYDIGYCGGSYRATCVCYRK

Defensin protein 2 Defensin protein 2 MATORREISWTFGPLYTWRTTK 646

GYGTTLETTNATSTSSKPSRRYE

NPYGCPTDEGKCFDRCNDSEFE GGYCGGSYRATCVCYRT

defensin related defensin related cryptdin CYREGGECLQRCIGLFHKIKCC 647 cryptdin K

Defensin Tk-AMP- Defensin Tk-AMP-Dl RTCOSOSHKFKGACFSDTNCDS 648 DI VCRTENFPRGOCNOHHVERKC

YCERDC

Defensin Tk-AMP- Defensin Tk-AMP-D L 3 RDCESDSH FHGACF^'SDTNCAN 649 Dl . l VCOTEGFTAGKCVG VQRHCHC

T DC

Defensin Tk-AMP- Defensin Tk-AMP-D2 RTCESOSHKFKGPCFSDS CAT 650 D2 VCRTENFPRGOCNOHHVERKC

YCERSC

Defensin Tk-AMP- Defensin Tk-AMP-D3 RDCKSDSHKFHGACFSDTNC^'A 651 D3 NYCOTEGFTRGKCDGIHCHC!

D

Defensin Tk-AMP- Defensin Tk-AMP-D4 RDCTSOSHKFVGLCLSDRNCAS 652 D4 VCLTEYFTGGKCDHRRCVCTK

GC

Defensin TJk-AMP- Defensin Tk-AMP-D5 RECRSESKKFVGLCYSDTNCAS 653 Ώ2 VCLTERFPGGKCDGYRRCFCTK

DC

Defensin Tk-AMP- Defensin Tk-AMP-D6 RDCRSOSKTFVGLCVSDTNCAS 654 D6 VCLTEHFPGGKCDGYRRCFCTK

DC

Defensin Tk-AMP- Defensin T¾-AMP-D6.3 RECRSOSKOFVGLCVSDT CAS 655 D6.1 VCLTEHFPGGKCDGYRRCFCTK

Ώ£.

Defensin Tm- Defensin Tm-AMP-DL2 RTCOSOSHKFKGACFSDT CAS 656 AMP-D1.2 VCRTENFPRGOCNOHHVERKC

YCERDC

Defensin, alpha 6 Defensin, alpha 6 DCYCRiPAClAGERRYGTCIYOG 657

RLWAFCC Defensin, bete Defensin, beta 103B OKYYCRVRGGRCAVLSCLPKE 658 i 03B EOIG CSTRGRKCCR

Defensin, beta Defensin, bete 106B ( Beta-defensk 6 ) FFDEKCNKLKGTCKNNCGKNE 659 106B f Beta- ELIALC KSLKCCRTIOPCGSIiD defensiii 6 !

Defensin, bete Defensin, beta 107 A AIHRALISKRMEGHCEAECLTFE 660 107A VKIGGCRAELAPFCCKNRKKH defensin, beta 107B defensin, beta 107B AiHRALiSKRMEGHCEAECLTFE 661

VKIGGCRAELAPFCCKNRKKH

DefensinS DefensinS LRDLKCFCRRKSCNWGEGIMG1 662

CKKRYGSPILCCR

Defensin-5 Defensin-5 precursor E SLOERADEATTOKO SGEDNO 663 precursor DLAISFAGNGLSALRTSGSOAR

ATCYCRIGHCTTLESLSGVCE1S GRLYRLCCR

Defensin-7 Defensin-7 EPLOARADEMPAO OPPADDO 664

DVV1YFSGDDSSSLOVPGSTKG

L1CHCRVLY CLFGEHLGGT SFiH GERYPiCCY

Defensin-Al Defensin-Al DTTFCRCRVSCNILEKYSGKCE 665

LSGRTARICC

Defensin- A2 Defensin-A2 STITCYCRSRCRMLEKNSGTCR 666

SSNCTYTLCC

Defensin- A3 Defensin-A3 RIITCSCRTFCFLGERISGRCYOS 667

VFIYRLCCRG

Defensin-A4 Defensin-A4 HSCVCRRICAA.RO VRKGRCSR 668

RRICCLY

Defensin-Bi Defensin-Bl GMKEKCVTMGGYCRKOCRVO 669

DALSG Y CRNE PCC V

Defensin-B2 Defensin-B2 GL NKCAYFRGOCRRKCPORDI 670

FFGFCRNHDOCCLSSLHTRH

Defensin-B3 Defensin-B3 GTSRVRICREKGGHCDADCHLE 671

ERHLGGCRAAYLTFCC

Defensin-B4 Defensin-B4 CKGKLGYCRSKCOSKOVELGK 672

C STKA iCCGi STGTS S SOGSHE V

PVINSEPALESKPEPODTOEEEA

TMVSE

Defensin-B5 Defensin-B5 KKCRERGGOCHSGVCSWNE F 673

IGFCSFARPCC

Defensin-B6 Defensin-B6 MEILLGS^'NGGARCDINKKSFD 674

CYHRNGRCRFNCRKREYN^'NGD CSOYOSCCLPTRNL

Defensin-BvL Defensin-BvL EVRRRRRRPPCEDVNGOCOPR 675

GNPCLRLRGACPRGSRCCMPTV

AAH

Defensin-iike Defensin-iike protein 123 MRPRSRAGDKFMSOGOELCHE 676 protein 123 YFOLTAPCEKOPCroMCSSKYK

TGKGVCGPAVHOCFCTFSCTV Defensin-iike Defensin-iike protein 292 LLETDASRNKPSSYIPLCGSD 677 protein 292 SCGGLWCPRKGGKYSCISMT

CDIOEDCPKLVRCKDSPGPYCM

EGFCTC

Defensin-related Defensin-related cryptdin- 1 1 LRDLVCYCRSRGCKGRERMNG 678 cryptdin- 1 1 TCRKGHLLYMLCCR

Defensin-related Defensin-related cryptdin- i 3 LRDLVCYCRKRGC .RREHMNG 679 cryptdin- 13 TCRRGHLMYTLCCR

Defensin-related Defensin-related cryptdin- 14 LRDLVCYCRTRGCKRRERMNG 680 cryptdin- 14 TCRKGHLMHTLCCR

Defensin-related Defensin-related cryptdin- i 5 LRDLVCYCRKRGCKRREHTNGT 681 cryptdin- 15 CRKGHLLYMLCCR

Defensin-related Defensin-related cryptdin- 17 LRDEVCYCRKRGC RREH!ViNG 682 cryptdin- 17 TCRKGHLLYTLCCR

Defensin-related Defensin-related cryptdin-20 8RDLICYCRKGGCNRGEQVYGT 683 cryptdin-20 CSGRLLYCCPRR

Defensin-related Defensin-related cryptdin-2i SRDLiCLCRNRRCNRGELFYGT 684 crvptdin-21 CAGPFLRCCRRRR

Defensin-related Defensin-related cryptdin-22 SRDLICLC^'RKRRCNRGELFYGT 685 cr ptdin-22 CAGPFLRCCRRRR

Defensin-related Defensin-related cryptdin-23 LRDLVCYCRTRGCKRRERMNG 686 cryptdin-23 TCRKGHLIYTLCC

Defensin-related Defensin-related cryptdin-24 LRDLVC Y CRARGC GRERMNG 687 cryptdiii-24 TCS GHLLYMLCC

Defensin-related Defensin-related cryptdin-25 CEDLICYCRTRGCKRRERLNGT 688 cryptdin-25 CR GHLMYMLWCC

Defensin-related Defensin-related cryptdin-26 LRDLGCYCRKRGCTRRERI GT 689 cryptdin-26 CRKGHLMYTLCCL

Defensin-related Defensin-related cryptdin-5 SKKLICYCR1RGC RRERVFGTC 690 cryptdin-5 R LFLTFVFCCS

Defensin-related Defensin-related cryptdin-7 LRDLVCYCRTRGC RREHMNG 691 cryptdin-7 TCRKGHLMYTLCCR

Defensin-related Def ens in- re la ted cryptdi n - 8 LRDLVCYCRKR.GCKJ R.EHMNG 692 cryptdin- 8 TCRKGHLMYTLCCR

Defensin-related Defensin-related cryptdin- 9 LRDLVCYCRKRGC RREi-EviNG 693 cryptdin -9 TCRKGHLLYMLCCR

Defensin-related Defensin-related cryptdin-related sequence I RFPWCRKCRVCOKCOVCOKCP 694 cryptdin- related VCPTCPOCPK.OPLCEERONKTA sequence 1 iTTOAP TOHKGC

Defensin-related Defensin-related cryptdin-related sequence PPCPSCLSCPWCPRCLRCPMCK 695 cryptdin-related 12 CNPK

sequence 12

Defensin-related Defensin-related cryptdin-related sequence 2 LGWGRRCP CPRCPSCPSCPRC 696 cryptdin -related PRCPRCKCNPK

sequence 2

Defensin-related Defensin-related cryptdin-related sequence 7 PRCPPCPRCSWCPRCPTCPRCN 697 cryptdin-related CNPK

sequence 7

Defensin- Defensin-relatedcryptditi- 10 LRDLVCYCRKRGC GRERMNG 698 relatedcryptdin-10 TCRKGHLLYTMCCR Demidefensin-3 Detnidefensin-3 RCICVLGIC 699

Dermadi stinctin-L gi!41016985ispjP83639iDD8L PHYDS ALWKTLLKNVG AAGKAALN 700 (DD L) Dermadistinctin-L (DD L) AVTD VNO

dermaseptin Bl dermaseptin B 1 DVLKKIGTVALHAGKAALGAV 701

ADTISO

Dermaseptin B2 gii i706455!s-)iP80282!DMSl PHYBI AMWKDVLKKIGTVALHAGKA 702

(^"Dermaseptin B2) Dermaseptin B2 precursor (DermaseDtin B2^'s ALGAVADTISO

Dermasepiiii DRG 1 Dermaseptin DRG1 GLWSNIKTAGKEAAKAALKAA 703

GKAALGAVTDAV

Dermaseptin DRG2 Demiaseptin DRG2 RGLWSKIKEAGKAALTAAGKA 704

ALGAVSDAV

demiaseptin S 10 dermaseptin S10 EEEKREGE EKEOEDDNOSEE 705

RGLVSDLLSTVTGLLGNLGGGG LKKi

dermaseptin S 1 1 dermaseptin S 1 1 EEEKRENEDEEEOEDDEOSEEK 706

RALWKTLLKGAGKVFGHVAK

OFLGSOGOPES

dermaseptin S 12 d rmaseptin Si 2 EEEKRENEDEENOEDDEQSEMR 707

RGLWSKI EAAKTAGKMAMGF VNDMVGEO

dermaseptin S 13 dermaseptin Si 3 DEEKRENEDEENOEDDEOSEM 708

RRGLRSKIKEAAKTAGKMALG FVNDMAGEO

dermaseptin S9 dermaseptin S9 DEEKRENEDEENOEDDEOSEM 709

RRGLRSKiWLWVLLMiWOES KFKKM

Dermaseptm-2 Dermaseptin-2 GLWKSLLK VGVAAGKAALN 710

AVTDMVNO

Dermaseptin-3 Dermaseptin-3 ALWKDVLKKIGTVALHAGKAA 711

FGAAADTISOGGS

Dennasepiin-4 Dermaseptin-4 GL S iSKO GKLAAiAAAK A 712

GKAVLNAASEAL

Derniaseptin-5 Dermaseptin-5 GLWSTIKQKGKEAAIAAAKAA 713

GQAALGAL

Dermaseptin-6 Dermaseptin-6 GLWSTIKQKG EAAIAAAKAA 714

GQAVLNSASEAL

Dermaseptin-? Dermaseptin-7 GLWSTIKOKGKEAAIA AKAA 715

GQAALNAASEAL

Dermaseptin-like gii29123254!gb|AAO62950.1 ![29123254]der GLLSGILNTAGGLLGNLIGSLS 716 precursor DRP- maseptin-like precursor DRP-AC-1 GES

AC-1 [Agalychnis I Agalychnis eallidryas]

callidryas]

Derma septin-like gi!29123256!sbjAA06295 ! .1 |[29123256]der GLLSGiENSAGGLLGNIJGSLSN 111 precursor DRP- maseptin-like precursor DRP-AC-2 GES

AC-2 [Agalychnis [A gal ve mis cal 1 dry as]

callidrvas]

Derniaseptin-like κϊ|29Ϊ23258|8Γ}|ΑΑ062952 ||^'29Ϊ23258 |άβτ ' SVLSTITDMAKAAGRAALNAIT 718 precursor DRP- maseptin-like precursor DRP-AC-3 GLVNOGEO

AC-3 j Agalyehnis [Agaivehnis cailidryasj

cailidryasj Diapause-specific Diarjaiise-soecific peptide DSP) AVRIGPCDOVCPR1VPERHECCR 219 peptide ί Dsp AHGRSGYAYCSGGG YCN

Diceniracin Dicentracin precursor f Dicensracine ) FFHHIFRGiVHVG SIHKLVTG 720 precursor

ί Diceritracin )

Disease resistance Disease resistance response protei n 39 TCEHLADTYRGVCFT ASCD 721 response protein 39 DHCKNKAHLISGTCHDWKCFC

TQNC

Distinct in-like Dis tin ctiii- like ΐ) epti de LVSAIIEGR YL VLKKE R 722 peptide LKEKNKAKNSKEN

Dclabeiianin-B2 ei!24636789!sp!P83376!DBB2 DOLAU SHODCYE ALHKCM ASH SKPF S 723

Dola.bellanin-B2 CSMKFHMCLOOO drosoirivcm-like A drosoriivciii-like A MiOIKF^'LCLFLAlMTIVYLDSNV 724

AEARDCLSGTFKGPCWAWSGE CRRLCIEEGRVSGHCSGGSKC WCEGC

Dybowskin-2CDYa Dybowskin-2CDYa RS A VGRHGR RFGLRKHRKH 725

Dybowskin- Dybowskin-2CDYb RSAVGRHSRRFGLRKHRKH 726 2CDYb

Dvbo'*skit!--4 Dybowskin-4 VWPLGLViCKALKIC 727

Dvbo skin-6 Dvbowskin-6 FLPLLLAGLPLKLCFLF KC 728

Enteric beta Enteric beta defeiisin. POSCHR KGICVPIRCPGNMR 729 defensin OIGTCLGPPVK.CCR

EP2R protein EP2B protein KVFFLFAVLFCLVRRNSVHIS 730

HQEARGP

Epinecidin- l gi!34101 171 ieb|AA057624. i ΙΓ3410 i 1711epi FIFHI1KGLFHAGKMIHGLVTRR 731 necidin-1 prepropeptide i Epinepherus M

coioides]

Eryngin gi!66773950!sp|P84525IEiYGN PLEER ATRVVYCNRRSGSVYGGDDTV 732

Ervngin YYEG

Escidentin-l Esciilentin-1 GiFSKF^'GRKKl NLLISGLKls'VG 733

KEVGMDWRTG1DIAGC 1KGE

C

Esculenti n-1 gi|416969lsp|P32414|ESl RANES G1FS LGRKKIKNLLISGLK VG 734

Esculentin-1 KEVGMDWRTG1DIAGCKI GE

C

Esculentiii-1B Esculentin- IB GiFSKLAGKKLKNLLiSGL NV 735

GKEVGMDVVRTGIDIAGCKIKG

EC

Esculentin- l.Vb Esculeiitin-lVb GIFTKI KKKAKTGVFNIIKTIG 736

EAGMDVIRAG1DTISCKIKGEC

Esculentin-2B gij4 i 016981 jspjP82839jES2B RA BE GLFSiLRGAAKEAS GLGKDLT 737

Esculentin-2B KLGVDLVACKJSKOC

Esculentin-2L ei!41016980!spjP82827jES2L RANLU GILSLFTGGIKALGKTLFKMAG 738

Escuientin-2L AGAEHLAC ATNOC

Esculentin-2-OGl 1 Esculentm-2-OGl 1 antimicrobial peptide FTLKKSLLVLFFLGTiSLSLCOEE 3 antimicrobial RAADEEDNGEVEE

peptide

esculentin-2-OG3 esculentin-2-OG3 antimicrobial peptide IKDAAKLIGK^'FVAKEAGKTGLE 740 antimicrobial precursor fRana grahami^'i LMACKITNOC

peptide esculentiti-2-OG5 esculentin- 2-OG5 antimic rob ial peptid e GLFTL1KGAAKLIGRTVAKEAG 741 antimicrobial precursor [Rana grahami] KTGLELMACKITNOC

peptide

Esculentin-2R Escuieiitin-2R GILSLVKVAKIAGKTFAKEGGK 742

FGLEFIACKVTNOC

Esculentin-2Ra Esculentm-2Ra GILSLVKGAAKLLGKGLAKEGG 743

KVGLEFIACKVTNOC

Esculentin-2Rb Esculeiitin-2Rb GiFSLVKGVAKLAGKTLAKEGG 744

KFGLELAMCKIAKQC

Esculentrn-2Vb Esculentin-2Vb GLFSILKGVGKIAIKGLGKNLGK 745

MGLDLVSCKISKEC

Esculentin-IGra Esculentin-IGra GLFSKFAGKGIK LIFKGVKHIG 746

KEVGMDVIRTGIDVAGCKIKGE

c

ETDI30 ETD130 142

CER

ETD131 ETD131 DKLIGSCVWGAVNTTSNCNAE 748

CKRRGYKGGHCGSFANVNCW COT

ETD 132 ETD132 DKIJGSCVWOAVNYTSNCNAE 749

CXRRGYKGGHCGSFINYNCWC FT

ETD133 ETD133 DKLIGSCVWGAVNYTSNCNAE 250

CKRRGYKGGHCGSF ANIN C W C ET

ETD134 ETD134 DKLiGSCVWGAVNYTSNCNAE 751

CKRRGYKGGHCGSFLNINCWC

ET

ETD135 ETD135 DKLIGSCVWGAVNYTSNCNAE 752

Γ Η Ri ; YKGGHCG SFLNVNCWC ET

ETD140 ETD140 NKLIGSCVWGAVNYTSNCNAE 253

CKRRG YKGGHCG SF AN VNC W GET

ETD 150 ETD150 DKLIGSCVWGA\T\^TYTRNCNAE 754

CKRRGYKGGHCGSF A \¾^TCW CET

ETD151 ETDiSi DKLIGSCVWOAVNYTSNCRAE 755

CKRRGYKGGHCGSFANVNCW^" CET

ETD152 ETD152 DKLIGSCVWGAVNYTSRCNAE 756

CKRRGYKGGHCGSFANVNCW CET

ETD154 ETD i 54 DKLIGSCVWLAVNYTSNCNAE 757

CKRRG YK.GGHCG SFLNVNCWC ET

ETDI56 ETD156 DKLIGSCVWLAVNYTSNCNAE 758

CKRRG YKGGHCG SF AN VNC W CET ETD 179 ETD179 DKTJGSCVWGAVNYTSNCRAE 25

C J RGYKGGHCGSFLNVNCWC

ET

Flower-specific flower- speci fie gamma-thionin NEMGGPLVVEARTCESQSHKF 760 gamma-thionin KGTCLSDTNCANVCHSERFSGG

KCRGFRRRCFCTTHC

Flower-specific Flower-specific gamma-thionin RECKTESNTFPGTCTTK PPCRK A 761 gamnia-thionin CISEKFTDGHCSKLLRRCLCTKP

CVFDEKMIKTGAETLVEEAKTL AAALLEEEIMDN

Frenatin-1 fresiatia-l GLLDALSGILGL 762

Frenalin-2 Frenatin-2 GLLGTLGNLLNGLGL 763

Frenatm-3 gi!3023785!si)iP56249!FRE3 LITIN GLMSVLGHAVGNVLGGLFKPK 764

Frenatin- 3 s

Frenatin-4 Frenatin-4 GFLDKLKKGASDFANALVNS1K 765

GT

Gaegurin-1 gi! 1 1698 i3|si)!P80395!GGN l RA RU SLFSLIKAGAKFLG NLLKOGA 766

Gaegurin-1 CYAACKAS OC

Gaegurin-2 gii ! 169814!spiP80396!GGN2 RANRU GTMSIVKDVAKNAAKEA AKGA 767

Gaegurin-2 LSTLSCKLAKTC

Gaeguriii-3 gi! l l 69815|sDiP80397|GGN3 RANRU GIMS1VKDVAKTAAKEAAKGA 768

Gaeguiin-3 LSTLSCKLAKTC

Gaeeurin-4 gii2506236lsrjiP80398IGGN4 RANRU GILDTLKOFA GVGKDLVKGA 769

Gaegurin-4 precursor AOGVLSTVSCKLAKTC

Gaegurin-5 «l2506237is»IP80399iGGN5 RANRU FLGALFKVASKVLPSVFCAITK 770

Gae aurin- 5 precursor KC

Gaegurm-6 gii i l698 ! 8|spiP80400|GGN6 RANRU FLPLLAGLAANFLFmCKISYKC 771

Gae urin-6

Gaeguriii-6-RN Gaegurin-6-RN antimicrobial peptide FPMKKSLLLIFFLGTINLSFCEEE 772 antimicrobial RNAEEEKRDGDDEMDVEVO R peptide

Gaegurin-6-RN Gaeaurin-6-RN antimicrobial peptide; FTMKKSLLLIFFLGTINLSLCEEE antimicrobial RNAEEEKRDGDDEMDVEVOK peptide

Gaegurin-6-RN Gaegiirin-6-RN antimicrobial peptide FTMKKSLLLLFFLGTINLSLCEK 774 antimicrobial ERNAEEEKRDGDDETDVEVOK peptide

Gal 3 Gal 3 TOCR1RGGFCRVGSCRFPHIA1G 775

KCATFISCC

Gal 9 Gal 9 DTLACROSHGSCSFVACRAPSV 776

DIGTCRGGKLKCCK Hepcidin Hepcidin PHOTGOLTDLRAODTAGAEAG 812

LOPTLOLRRLRR DTHFPICiFC CGCCKTPKCGFCCKT

Hepcidin Hepcidin PHOTGOLTDLRAODTAGAEAG 813

LOPTLOLR LR RDTHFPIC1PC CGCCKTPKCGLCCIT

Hepcidin Hepcidin PHOTGOLTDLRAODTAGAEAG 814

LOPTLOLRRLRRRDTHFPICIFC CGCC TP CGLCCKT

Hepcidin Hepcidin PPOTROLTDLOTKDTAGAAAG 815

LTPVLORRRRDTHFPICiFCC^'GC CRKGTC^'GMCCRT

Hepcidin Hepcidin OSHLSLCRFCC CCRN GCGY 816

CCKF

hepcidin 2 hepcidin 2 KTFSVAVAVAVVLTFiCLOES 817

SAVSFTEVOELEEP SNGSPVA AYEE SEESWKMPYASRRWRC RFCCRCCPR RGCGLCCQRR

hepcidin heacidin antimicrobial Deptide [Equus MALNT IRAACLLLLLLASLTS 818 antimicrobial caballus] GSVLPHOTROLADLOTODAAG peptide MAGAAAGLMPGLHOLRRRDT

HFPICTLCCGCC KOKCGWCC KT

hepcidin hepcidin antimicrobial peptide [Equus ALNTNIRAACLLLLLLASLTS 819 antimicrobial caballus Ϊ GSVLPHOTROLADLOTODAAG peptide MAGAAAGLMPGLHOLRRRDT

HFPICTLCCGCCNKOKCGWCC KT

hepcidin heccidin antimicrobial peptide 1 LCRFCCKCCR KGCGYCCKF 820 antimicrobial

peptide 1

Hepcidin Hepcidin antimicrobial peptide 2 OMROTTELOPLHGEESRADiAlP 821 antimicrobial M K.RRK R!⁾i X rnCRi^;CCOCCN peptide 2 KPSCG1CCE

Hepcidin- 1 Hepcidin- 1 OIHLSLCGLCCNCa-INlGCGFC 822

CKT

Hepcidin-2 Hepcidin-2 DINFFICRFCCOCCNKPSCGICC 823

EE

Hepcidin-20 gii i0863973!reflNP 066998.1! hepcidin ICIFCCG CCHRSKCGMCCKT 824 aniiniicrobiaj peptide Homo sapiens]

Hepcidin-25 / Hepcidin-25 / LEAP DTHFPICIFCCGCCHRSKCGMC 825

LEAP CKT

Hepcidin-like Hepcidin-like peptide DCRFCCGCCTDVSGCGVCCRF 826 peptide

[synthetic construct hy asirt [Hvas hvasin [Hvas araneus] MRLLWI.LV AMVVTVI.AAATPT 839 araneus] AAWORPLTRP PFSRPRPYRPN

YG

Hylaseptin-Pl gi|56748934|sp|P84292|HLPf HYLPIJ GILDA1KA1AKAAG 840 (HSP1) Hvlaseptin-Pl (HSP1 )

Hvlin-bi i^'Hy-b l ) Hvlin-b i (Ήν-bl i FiGAILPAIAGLVHGLlNR 841

Hvlin-b2 fHv-b2 ) Hylin-b2 (Hv-b2 ) FTGAILPATAGLVGGLINR 842

Hyposin-HA3 Hyposin-HA3 LRPAV iVRTKG 843

I-Ivposin-HA4 Hvrx>sin-HA4 FRPALiVRT GTRL 844 hypothetical hypothetical protein KRSFTEYTOViETVSK KVFLE 845 protein OLLLA PKLYDVMOKYNAGLL

K RV LFESLYK T RSYLR

s

hypothetical hypothetical protein PDFMIAASDADAWRGEFTPVL 846jOtein GELHLGVNSLDY AYFARLHPH

RDDLLREVDLDFPRPRLLVMAP

MEAGANLVPRTQRALVRPQDH

LV ALT SRVPFPTRGRPLNG ADL

TVAEOPDGWE1RVPGGERFDL

MEIFAQPLKTALMARVSFFRDE

HLPRISFGRLVVVREOWRIAAD

ELAFAAVRDTRDRYVHARRW

WRRRDLPTRVFVKSPLERKPFH

VDAD SPALVELLC AAVRR hvDotlietical hypothetical protein PSVVDOIAKVEDILKRLNLIKRE 847 protein RiOVL DLKEKILiLNKKSiANY'

EOOLFOOELEKYRGFONRLVO

ATHKOAALMRELTVAFNGLLO

I)KRVRAE08KYESFORORGAVi

GRYKRAYOEFLDLEAGLOSAK

TWYKENdKETVESLEKNVETFV hypothetical hypothetical protein RiVDCKRSEGFCOEYCNYLETO 848 protein VGYCSKKKDACC

hypothetical hypothetical protein BC 5124 NNVFQNKEKNYYEAFYTEEKF 849 protein BC 5124 KK ALKVTTPE AYK SL VDLNTQK

DSL RARYGYIORATVKTSPLS

YFGKTTYYSLNKKDSEETLOLN

'NA'V YLiLTAAMNDVEVMNLL RI 1NPVFK 1N

hypothetical hypothetical protein BC5■ 24 NT>FVTQNKEKNYYTAFYTEEKF 850 protein BC5124 K AL VTTPE A YKSLVDL i

DSLNRARYGYIORATVKTSPLS

YFGKTTYYSLNKKDSEETLOLN

N ^^rKYLILTAAMNDVEV fNLL

RiKINPVFKKiNN hypothetical hypothetical protein Saci 0231 RSDLP RTL TfflRAGVKYSL 857 protein Saci 0231 MEDELLLSKHPLSTiERGRKEKA

SDWDTPG STAND VTRGTOiLETN

GYTDPVmSPELYTRLFRVYDK

SGTYET I.VKHATETTVSPL1 GI.

AWSKKGFYVME TPAKVEFL

GREGINSDYTIWGKIAPYLTDTN

A

hypothetical hypothetical protein Sente 271 12 HPDVVSYFMiHHDW FDFFHY 858 protein Sente EKDGD1KG S YFLCNGKQIGIMA 27112 RRSYPLSSDEVLIPFSPHARCFFP

DKTNKLSIINKQ II ATW IAR

KKONCI1KE SF SPKFE TRRNEI

ORFIRNGGET CTSOL SDKEIS S S

YISLFHSRFGGTLPCYEYDNLL

MFISHLRELMFGHVLFWD PC

ATDIVLKSESSCNVYYDVPNGA

VLNDENCMKLSPGSVLMWLN hypothetical hypothetical protein ST0993 NlIKWDOOAlPFYETKVODNA.il 859 protein ST0993 SDKOVPYPLST.INTLFKVMPDL

PKEETOPVFMKAYLTHSRKEDL

LTYREHPLSiLORSKKMNRSDW IPGNIVNDIVRAYEOVLSSGYS

DVNLnPPYVHALLYRWDRTG

TMEIELLRHLGNIYV SPNVDT1V

VISKOVLYVYEKKSTTLENLGR

DGV YE V YMLS SEL APY VTDPE

Ib-AMPl Tb-AMPl OWGRRCCGWGPGRRYCVRWC 860 ib-AMP2 lb-AMP2 OYGRRCCNWGPG RRYCKRWC 861

Tb-AMP3 Ib-A P3 OYRHRCCAWGPGRKYCKRWC 862

Ib-AMP4 ib-AMP4 OWGRRCCGWGPGRRYCRRWC 863

Ixo sin Ki| ί 10279027!sp|O2LKX9!TXOSN IXOSi GLH VMREVLGYERN S YKKFF 864 ixosi LR

lxosin-B lxosin-B OLKVDLWGTRSGIOPEOHSSGK 865

SDVRRWRSRY

.Telle in- 1 Jellein-1 PFKISIHL 866

Jelleii -2 Jellein-2 TPFK1SIHL 867

Kalata-Bl gi| 174337ii|sp|P56254.3iKABi ^'OLDAFj 37 VCGETCVGGTCNTPGCTCSWP 868 precursor 433718 JKalata-B i precursor VCTRNGLP kallikrein-reiated kallikrein-reiated peptidase 5 ilNGSDCDMHTOPWOAALLLRP 869 peptidase 5 OI YCGAVLVHPOWLLTAAHC

RKK RWLGHYSLSPVYESGO

OMFOGVKSIPHPGYSHPGHS D

i^lLIKL RRlRPT DVRPI VSS

HCPSAGTKCLVSGWGTT SPO

VHFPKVLOCLMSVLSOKRCED

AYPROK⁾DTMFCAGD AGRDS

COGDSGGPWCNGSLOGLVSW

GDYPCARPNRPGVYTNLCKFTK

WIOETIOANS

Kassinatuerin-1 gi|67460722|sp|P0C010|KASl KAS8E GFMKYIGPL1PHAVKATSDL1 870

Kassinatuerin- 1

iacoferricin Iacoferricin lEGRFKCRRWOWRMKKLGAPS 871

1TCVRRAF

lactoferricin lactoferricin MFKCRRWOWRMKKLGAPSITC 872

VRRAF

lactoferricin b 15 lactoferricin b 15 PMFKCWRWOWRWKKLGAM 873 iaciofenin lactoferrin [Bubalus bubalisj WOWRMKKLGAPCiSCLRRAFA 874

LESIRAIPEKKADAVTLDDAMV FEAGRGCLRLRPVAAEMYGTK ECIQS

L-amino- L-amino-acidoxidase ADDKNPLEEFRET YEVFLETA 875 acidoxidase KNGLKATSNPKRVV1VGAGMA

GLSAAY

L-arnino- L-amiao-acidoxidase ADDRNPLEOCFRETDYEEFLEIA 876 acidoxidase RNNLELATSNPKH\^rVIVGAGMA

GLSAAYVLSGGGHOVTV

Larsthionme Lantliionine biosynthesis protein KOIAS 1TIYOGKELOLFRKLVE 877 biosynthesis LKLLROCITlPNNRGilTSliOFLE

EYEVGKEHPLLEELHAALHSFE

KSSSFERINDWNEIKRILSLLQK

GDKKVGSEIIYEDVIFKDVR D

TITPK1R SFLEGLADFILLFDVN

VRVQYEIAQLFYEKYGKSTEKL

S^'N ^'SNLLNEVFFREIHQFYPYYQ

NOKYRYKEAKAKEiOOLDELR

DOFLI EFESLILNVDOSVEVIDI

ELLIEKYTSLIPEYIKKDSNiSYT

LFLOETTDENR^LNNVYDGOEK

FISRFKDFFMPHYETKEYSNY1E

RVLNEDNCYEVDELFGFNGGiH

ERKSFINIVNLDVGYORFNHKD

AKOVROFKVRYNTERJ aEFLD

D YKICNLVYKSSLVPMFLPGIL

SVMLYLFOSGRLNFDrrSLVKE

ENYVPRITFGNVVLSRKKWKVI

MEDLKDILESKLE

Lantibiotic mutacin Lantibiotic mutacin B-Ny266 FKS SFCTPG CAKTG SFN S YCC 878 B-Mv266

Lantibiotics Lantibiotics Mersacidin CXFXLPGGGG VCXLXXECIX 879 Lingual _gl;2494049!ss)iO28880!LAP BOVI Lingual VRNSOSCRR KGICVP1RCPGS 898 antimicrobial antimicrobial peptide precursor MR.OIGTCLGAOVK.CCRR

peptide ί LAP- related

prepropeptide )

LINOCIN Ml 8 LlNOCIN ΜΪ8 MDlLRRENAQFPASiW SAIE EA 899

GLVFGKHLTGRKWDFKGGLGI

GFSSLPTGRViSS E LGEASVG

VRMNTPVIELK1PFSFPESEVEA1

LREANAFD1SS1E AAKK.VCVA

ENELVFYGL KEG1EGLIPS1PH

KPIKAKGDE1LPAVAEG1KELVN

SEIEGPYALLIOPOYFGKLFGVA

GN8GYPLTLKLAELLOGNNIIV

APALKSGALLV SLRGGDYELYS

GMDIGVG YSEKKSTNHELFFFE

TLTFRINTPEA

Linocin MI 8 Linocin Ml 8 bacteriocin protein MNDLMRDLAPISAKAWAEIETE 900 bacteriocin protein A GTLT VTLAARK WDFKGPL

GWDASSVSLGRTEALAEEPKA

AGSAAVVTVR RAVQPLIELCV

PFTLKRAELEAIARGASDADLD

PVIEAAllAiAIAEDRAVFHGFAA

GGiTGlGEASAEHALDLPADLA

DFPGVLVRALAVLRDRGVDGP

YALVLGRTVYOOLMETTTPGG

YPVLOHVRRLFEGPLIWAPGVD

GA LISORGGDFELTVGRDFSI

GYHDI-IDAOSVHLYLOESMTFR

CLGPEA

Linocin M18 Linocin Mi 8 bacteriocin protein MNNLHRELAPISAAAWAOIEEE 901 bacteriocin protein VARTFKRSVAGRRWDVEEPC

GVELSGVGTGHLHTIAAPRERV

GA LREVKALVEFTVPFELRRD

AIDAVERGARDADWOPAKDAA

ORLAFVEDSAiFDGYPAAGIVGi

REATSNRKIALPSDVGAYPGAI GDAVEALRLAGVDGPYSVLLG ADAYTALAEAREHGYPVLDHI

KRIVSGErv'WAPALSGGCVLST

RGGDFALHI..GEDVSIGYRSHND

EWHLYLRETFTFLMLTSEA

Linocin Ml 8 Linocin Mi 8 bacteriocin protein PODEWAELREAAROAADSIRVF 902 bacteriocin protein RRYIPTTRVGRGVEYVPVEREG

VR D W K i \ !'!S \ ! !S W i D

YA RTGOPLDAGDALRAAAEL

ALEEDRLVAHTLLNLSNALKM

AATSWDEPGKAVAEVSKAVAE

LIKAGAPGPYILFVDPARFA LV

S EKTGVMELTRi AIV FJW

PTPWPPSAALLISASPOTLDLVI

GADTEVEYLGPEDGKFILFRLW

ETIAVRV Linocin Ml 8 Linocin Ml 8 bacteriocin rsroiein MDNLHR L APiSDAAWAOiEDE 903 bacteriociti protein AARTLKRYLGARRWDVHGPE

GFGLSAVGTGHLRPATALAEGV

ESHRREV PLLELRVPFTLTRA

AIDDVARGSNDSDWOPL DAA

R IALAEDRLVFLGHGDAGIRGI

LPETSNPIVA1PANVADYPEAV

ASAVSELRLAGV GPYALILGT

TAFTAA GGAEDGYPVL HLE

RLVDVPV SOALEGGAWTT

RGGDFDLWLGODISIGYLSHDA

ASVTLYLOESLTFOMOTSEA

Linocin Ml 8 Linocin Ml 8 bacteriocin rarotein NNLHRELAPIA SSAWAOIEEE 904 bacteriociti protein VARTFKRSVAGRRWDVEGPA

GPGLSAVGTGHLRDVTAPREO

VSARLREVRN ^⁷ELTVPFELSR DAIDSVERGARDADWOPAKDA AORLAFAEDGAIFDGYLAADIV GIREGTSNRKLILPTDVSAYPDA ISDALEALRLAGVDGPYTVVLG SD AYT ALSE A RDOGYPVLGHIK RIVSGEIVWAPAISGGCVLSTRG GDYELHLGEDVSIGYTSHTDKV VRLYLRETFTFLMLTSEA

Linocin Ml 8 Linocin Ml 8 bacteriocin rarotein MNNLHRELAPIA SSAWAOIEEE 90S bacteriociti protein VARTFKRSVAGRRWDVEGPA

GPGLSAVGTGHLRDVTAPREO

VSARLREVRNWELTVPFELSR

DAIDSVERGARDADWOPAKDA

AORLAFAEDGAIFDGYLAADIV

GIREGTS RKLTLPTDVSAYPD

AISDA LEA LRLAGVDGPYTV VL

GSDAYTALSEARDOGYPVLGHI

KRIVSGEIVWAPAISGGCVLSTR

GGDYELHLGEDVSIGYTSHTDK

WRLYLRETFTFLMLTSEA

Linocin Ml 8 Linocin Ml 8 bacteriocin protein MNNLHRELAPISSAAWEOIE.EE 906 bacteriocin protei VARTFKRSVAGRRWDVEGPA

GPELSAVGTGHLLDVAAPRELV ARLREVRTIVELTVPFEL8RDA

IDSVERGARDADWQPA EAAO

RLAFAEDNAIFDGYPAAGIVGI

EGTSNRRLTLPADVGAYPDAIS

DALEALRLAGVDGPYSWLGS

DAYTALSEARDOGYPVLGHIKR

IVSGENWAPAISGGCVLSTRGG

DYELHLGEDVSIGYTSHTD GV

RLYLRETFTFLMLTSEA Linocin Ml 8 Linocin Ml 8 bacteriocin rsroiein MNNLHRELAPISSAAWEOIE.EE 907 bacteriociti protein VARTFKRSVAGRRVVDVEGPA

GPELSAVGTGHLLDVAAPRELV

NARLREVR1TVELTVPFELSRDA

IDSVERGARDADWOPAKEAAO

RLAFAEE3NA1FDGYPAAGIVG1R

EGTSNRRLTLPADVGAYPDAIS

DALEALRLAGVDGPYS LGS

DAYTALSEARDOGYPVLGHIKR

IVSGEITWAPAISGGCVLSTRGG

DYELHLGEDVSIGYTSHTDK.GV

RLYLRETFTFLMLTSEA

Linocin Ml 8 Linocin Ml 8 bacteriocin rarotein MNNLHRELAPISSEAWSOIE.EE 908 bacteriociti protein VARTFKRSVAGRRWDVKGPG

GVDLSGVGTGHOSTIAAPHHGV

I A L SEVKALVOL TVPFELSRD

AIDAVERGANDSDWOAAKDAA

KELAYAEDRAIFE⁾GY AAGIVG

IREGSSNTSLALPADVADYPNAI

GGALOOLRLAGVDGPYSVLLG

ADAYTALGEASDOGYPVIEHIK

RIVNGEITWAPALEGGSVLSMR

GGDYELHLGODVSIGYOSHTDS

TVRLYLRETLTFLMLTSEA

Linocin Ml 8 Linocin Ml 8 bacteriocin rarotein MNNLHRELAPISSSAWEOIE.EE 909 bacteriociti protein VARTFKRSVAGRRVVDVDGPE

GPELSAVGTGHLVEVAAPREOV

NARLREVRTIVELTVPFELSRDA

IDSVERGARDADWOPAKDAAO

RLAFAEDGAIFDGYAAASRVGIR

EGTS NKLTLPADVSAYPDAIS

DALEALRLAGVDGPYS LGS

DAYTALSEARDOGYPVLGHIK

IVSGFJIWAPAISGGCVLSTRGG

DYELHLGEDVS!GYTSHTDKW

RLYLRETFTFLMLTSEA

Linocin Ml 8 Linocin Ml 8 bacteriocin protein MNNLHRELAPVSASAWOQIEEE 910 bacteriocin protei VARTFKRSVAGRRVVDVEGPA

GPALSAVGTGHLCDVAAPREL

VSARLREVRT.TVELTVPFELSRD

AiDSVERGARDADWOPAKDA

ORLA FAEDG AiFDGY AA AGi VG

IREGTSNRKLALPADVSAYPDAT

SDALEALRLAGVDGPYSVVLGS

DAYTALSEARDOGYPVLGHIKR

rVSGEnWAPAISGGCVLSTRGG

DYELHLGEDVSIGYTSHTDKVV

RLYLRETLTFLMLTGEA Linocin Ml 8 Linocin Ml 8 bacteriocin »roiein ARTFKRSVAGRRVVDVEGPGG 911 bacteriocin protein TEL-SGVGTGHOTAIAAPOOGW

ARLAEVKRLVEFTVPFELOREAI DSVLR GA DADWOPAKD AAK ELAYAEDRAIFDGYOAAGIGGI REG S SNAPLALP ADIGD YPH AIG ALEELRLAGVDGPYSVLLGA DAYTA.LSEA.RDOGYPV1EHIKRI VNGDIiWA PALTGGSVLSTRGG DFELHLGEDLSIGYLSHTDSW RLYLRETLTFLMLTSEA

Linocin Ml 8 il24879768]Linocin Ml 8 bacteriocin MNNLHREL APISS AAWEOIEEE 912 bacteriocin protein protein [Burkholderia cenocepaeia PC 184] VARTFKRSVAGRRWDVEGPA 1 Birrkbolderia GPELSAVGTGHLLDVAAPRELV cenocepaeia ARLREVRTIVELTVPFELSRDA PCI 841 IDSVERGARDADWOPAKEAAO

RLAFAEDNA1FDGYPAAGIVGIR

EGTSNRRLTL ADVGAYPDAIS

DALEALRLAGVDGPYSVVLGS

DAYTALSEARDOGYPVLGHIKR

IVSGE1IWAPA1SGGCVLSTRGG

DYELHLGEDVSIGYTSHTDKGV

RLYLRETFTFLML liver expressed liver expressed antimicrobial peptide 2 LAAWCLViMVLSOOVASSPVPV 913 antimicrobial fPelteobagrus fulvidraeo] MEILSGSVOGVORSLRRMARM peptide 2 ( LEAP- TPLWRIVGT PHGAYCO NYE

21 CSTG1CR GHCSFS

liver expressed liver expressed antimicrobial peptide 2 RLKRMTPFWRGVSLRPVGASC 914 antimicrobial [Gallus eallus] RDNSECITMLCR RCFLRTAS peptide 2 [Galliis E

eallus]

liver-expressed liver-expressed antimicrobial peptide 2 LLAWCLVFLViVOOVTSSPVPO 915 antimicrobial f Ctenopharyngodon idell a] SDTPLTSVOEVORSL RTARMT peptide 2 PLWRIMGT PHGAYCQNHYEC

STGICRKGHCSYS

liver-expressed liver-expressed antimicrobial peptide 2 LYLMVLAOOVAPSPVREIEAAL 916 antimicrobial [Ictalurus punctatus] G SLOG V ORSLRRMARMTPL W R peptide 2 IMGT PHGAYCONNYECSTGIC

R GHCSFS

liver-expressed liver-expressed antimicrobial peptide 2 RRVARMTPLWR.1MSS PFGAY 917 antimicrobial [Paralicb.tb.Ys olivaceus] CONNYECSTGLCRAGHCSTS peptide 2

Liver-expressed Liver-expressed antimicrobial peptide 2 ( MTPFWRAVSLRPIGASCRDDSE 918 antimicrobial LEAP - 2 ) CITRLCRKRRC SL S V AQE

peptide 2 ( LEAP -

Liver-expressed Liver-expressed antimicrobial peotide 2 ί MTPFWRAVSLRPIGASCRDDSE 919 antimicrobial LEAP - 2 ) CLTRLCR RRCSLSVAOE peptide 2 ( LEAP - Ώ Long palate, lung Long palate, lung and nasal epithelium COELLETVGTLARID DELG A 933 and nasal carcinoma-associated protein 3 IONSLVGEPILONVIXJSVTAVN epithelium RGLLGSGGLLGGGGLLGHGGV carcinoma- FG-WEELSGLKIEELTLPKVLL associated orotein 3 LLPGFGVOLSLHTKVGMHCSGP

LGGLLOLAAFA TSRVALAV

SSRGTPILILKR.CSTLLGHISLFS

GLLPTPLFGVVEOMLFKVLPGL

LCPVVDSVLGVVNELLGAVLG

LVSLGALGSVEFSLATLPLIS O

YIELDINPrVKSVAGDIIDFPKSR

APAKVPPKKDHTSOVMVPLYL

FNTTFGLLOTNGALDMDITPEL

VPSDVPLTTTDLAALLPE ALGK

LPLHOOLLLFLRVREAPTVTLH KKALVSLPANIHVLFYVPKGT

PESLFELNSVMTVRAOLAPSAT

KLfflSLSLERLSVKVASSFTHAF

DGSRLEEWLSHWGAVYAPKL VALDVGIPLP VLNI FSNSVL

E.TVEN AV VLT VA S

Long palate, lung Long palate, lung and nasal epithelium MLOOSDALHSALREVPLGVGDI 934 and nasal carcinoma-associated protein 4 (Lisand- PYNDFHVRGPPPVYTNGKKLD epithelium buiding protein RY2G5 ) GIYOYGH1ETNDNTAOLGGKYR carcinoma- YGEILESEGSIRDLR SGYRSAE associated rjrotein 4 NAYGGHRGLGRYRAAPVGRLIi fLigaiid-binding RRELOPGEIPPG VATG A VGPGG protein RY2G5 ) LLGTGGMLAADGILAGOGGLL

GGGGLLGDGGLLGGGGVLGVL

GEGGlLSTVOGiTGLRIVELTLP

RVSVRLLPGVGVYLSLYTRVAI

NGKSLTGFLDIAvEV TAKVRL TMDRTGYPRLVIERCDTLLGGI

KV LLRGLLP LVD LWRYL

ADYLPDLLCPlVDWLGLWriO

LGLVDSLIPLGILGSVOYTFSSLP

LYTGEFLELDL TLVGEAGGGL

IDYPLGWPAV8PKPMPELPPMG

DNTKSOLAMSANFLGSVLTLLO

KOHALDLDITNGMFEELPPLTT

ATLGALIPKVFOOYPESCPLIIRI

OVLNPPSVMLOKD ALVKVLA

TAEV VSOPKDLETTICLIDVD

TEFLASFSTEGDKL TDAKLEK

TSLNLRTSNVG FDIGLMEVLV

EKIFDLAFMPAMNAVLGSGVPL

PKIL iDFS ADlDVLEDLLVLS

A

Low-molecular Low-molecular cysteine-rich antifungal QKLCEKPSGTWSGVCGNSNAC 935 cysteine-rich protein LCR77 , cysteine-rich antifungal KNOCINLEGAKHGSCrsTVA'FPAH antifungal protein protein At2g26020 KCiCYVPC

LCR77 , cvsteme- rieh antifungal protein At.2g26020

Lumbrican Lumbrican RO D RPYSERKNQYTGPOFL 936

YPPERIPP

Lycocitin-1 gil 14632498i|sp!P0C2ij6.1 ILYCl LYCSIi 1 GKLOAFLAKMKEIAAOTL 937

4632498 HLycocitin-1

Lvcocitin-2 gil 146324982!spiP0C2U7.1 1.YC2 LYCSIH GRLOAFLAKMKEIAAOTL 938

463249821Lvcocitin-2

Lvcocitin-3 Lycocitin-3 IKWF TMKSLA FLAKEOMK 939

HLGE

Lycotoxin-1 gi|47605786|sp|P61507|LYTl i ll K it Λ IWLTALKFLGKHAAKHLAKOO 940

(Lycotoxin Γ) Lycotoxin- i (^"Lycotoxin i) LSKL

Lycotoxin-2 »i476G5787|sp|P6l 508ILYT2 HOGCA KIKWF TMKSIAKFIA EOMK 941

(Lycotoxin 11) Lycotoxin-2 (Lycotoxin 11) HLGGE

Lysozyme Lysozyme iSDACLTCiCKOESYGCTOIGCR 942

MDGRSLSCGYFOT KSYWIDCG

RLGSSWEACADDYNCAVRCVR

A YMKKYIGKSGCT AN CKN YA R

LH GGPKGCTKPSTLTYWNAV

KNOGCS NS

lysozyme lysozyme RWK.FFKKIEKVGQNIRDGIIKA 943

GPAVAWGOAAAIS

Lysozyme Lysozyme TISSACLRCICNVESGCRPIGCH 944

YDWSYSCGYFOIKENYWEDC

G PGTSF A.CANDYTCASNCV

RAYM RYIGSSGCPANCESYAR

IliNGGPRGCRHPSTLRYWEKVH

OQGCNVNS

Magamm 2 d! i26683jsp!P11006!MAGA XENLA GIGKFLHSAK FGKAFVGEIMN 945

Magaimns precursor [Contains: Small acidic s

peptide: Magainin- 1 (Magaimn 1); Magainin- 2 (Magainin ID]

Magainin 2 Magainin 2 GIG YLHSAKKFGKAWVGEIM 946

NS

MAP34-A protein MAP34-A protein (MAP34-B protein) SYREAVLRAVDOFNERSAEANL 947

(MAP34-B protein) YRLLELDPPPEOD AEDOGARKP

VSFRVKETVCPRTSOOPVEOCD

Mastoparan-like ri! 110279044isp|P0ClM4|MASTA VESMG i WY Gi VWi \ i .= . 948 peptide 12 a Mastoparan-like peotide 12a

Mastoparan-like gil 1 10279046|sp|POClM5|MASTB VESMG 1NWKGIAA.MKKLL 949 peptide 12b Mastoparan-like peptide 12b

Mastoparan-like gil 158705868isp| AOSPIO. l!MASTC VESM IMXAIAALAKKLLG 950 peptide 12c Gr 1587058681Mastoparan-like peptide 12c

precursor precursor

Mastoparan-like gil 15870586 |sp|P0C5G7.1|MASTD VESM INLKAIAAMAKKLL 951 peptide 12d G[158705869]Mastoparan-like peptide 12d

Maximin 1 gil24637996lsplP83080IM lHl BOM M X GIGTKILGGVKTAL GALKELA 952

Max.imi.ns ! /H l precursor [Contains; STYA

Maximin- 1 ; Maximin-Hl iMaxiniin-6 ]

Maximin 2 gi|24637997 j spiP8308 Ϊ|Μ2Η1 BOMMX GIGTKILGGVKTALKGALKELA 953

Maximins 2/H1 precursor [Contains: STYVT Maximin-2; Maximin-H! (Maximin-6)]

Maximin 3 ril24637998lspiP83082iM3H2 BOMMX OIGGKIL.SGLKTALKOAAKELA 954

Maximins 3 H2 precursor [Contains; STYLH

Maximin-3 ; Maximin-H2 ]

Maximin 4 gi|24637999lsp|P83083|M4H31 BOMMX GIGGVLLSAGKAALKGLAKVL 955

Maximins 4/H3 type 1 precursor [ Contains: AEKYAN

Maximin-4; Maximin-H31

Maximin 5 gii24638000!sp!P83084!M5H41 BOMMX SiG AKILGGVKTFFKG ALKELA S 956

Maximins 5/Ή4 tvpe 1 precursor [^"Contains: TYLO

Maximin- 5 ; Maxirnin-H4]

Maximin HI Ki|24637996|sp|P83080!MlHl BOMMX 1LGPV1ST1GGVLGGLLK L 957

Maximins 1/Hl precursor [Contains:

Maximin- 1 ; Maximin-H 1 (Maximisi-6 [

Maximin H12 Ma imin H 32 T.IGPVT..GT..VSNALGGT..LKNT 958

Maximin H2 gi!24637998!sp!P83082!M3H2 BOMMX ILGPVLSMVGSALGGLIKKl 959

Maximins 3/H2 precursor [Contains:

Maximin-3 ; Maximin-H2 j

Maximin H3 ri!24637999!spiP83083!M4H3 i BOMMX ILGPVLGLVGNALGGLIKKI 960

Maximins 4/H3 type 1 precursor {Contains:

Maximin-4 ; Maximin-H 3 ]

Maximin H4 Maximin H4 !LGPVTSKICJGVLGGLLKNL 961

Maximin v type 2 Maximin y ty e 2 precursor G1GGALLSAGKAALKGLAKGF 962 precursor A hl i i

Maximin- 10 Maximin- 10 GIGGALLSAGKSALKGLAKGLA 963

EHFAS

Maximin- 1 1 Maximin- 11 GIGTKT1GGLKT A V KGALKEL A S 964

TYVN

Maximin-6 Maximin-6 GiGGALLSAGKSALKGLAKGLA 965

EHFAN

Maximin-7 Maximin-7 G1GAK1LGGVKTALKGALKELA 966

STYV

Maximin- 8 Ma imin-8 GiGTKiLGGLKTAVKGALKELA 967

STYVN

Maximin-9 Maximin-9 GIGRKFLGGV TTFRCGVKDFA 968

SKHLY

Maximin-H 10 Max imin-H 10 ILGPVLGLVS ALGGLLKNL 969

Maximin-H 3 1 Maximin-H 1 1 iLGPVLGLVGSALGGLiKKI 970

Maximin-H 33 Maximi -HI 3 iLGPVlKTiGGVLGGLLKNL 971

Maximin-H 14 Maximin-H 14 1LGP VLGL VGEPLGGLIKK1 972

Maximin-H 15 Maximin-H 15 LGPVLGLVG ALGGLLKNL 973

Maximin-H 16 Maximin-H 16 1LGPVLSLVG ALGGLIKKI 974

Maximin-Ηό Maximin-H6 ILGPViGTIGN\'LGGLLKNL 975

Maximin-H7 Maximin-H7 ILGPVIKTiGGViGGLLKNL 976

Maximin-H8 Maximin-H8 ILGPVLGLVSNALGGLLK i 9_.77

Maximin-H9 Maximin-H9 ILGPVLGLVSNALGGLiKKI 978

Maximin-Hv Maximin-Hv 1LGPVLSLV GSALGGLIKKI 979

Maximin-Hw Max imin-Hw ILGPVLGLVSNAIGGLIKKI 980

Maximin-y Maximin-y GTC.iGALLSAGKSALKGLA.KGF A 981

EHF Maximin-z Maximin-z GIGGALLSAGKSALKGLAKGLV 982

EHFA

MBP-1 MBP- 1 TRGYVMVGSARTFNEAOWVC 983

QRCY^'RG LASiHSFAFNYOVQC

TSAGLNVAOVWIGGOLRG GR

CRRFVWVDRTVW FAYWARG

OPWGGRORGRCVTLCARGGH

WRRSHCGKRRPFVCTY

Megourin- 1 Megourin- 1 YLDV QLANYLLCiGNGQVFN 984

GRKTCOIGCRAVCQOPGCSGY

KECEOIPNiRLHKYRCFlCNEA

Megourin-2 Megourin-2 YLDVNOIASYLLCLGOGAVFNG 985

RKTCOIGCRAACOOPGCGGYK ECEOIPNIRLHK YR CHCNSG

Meeourin-3 Mesourin-3 YLDVNOIASYLLCLGEGAVFNG 986

RKTCOIGCRAACOOPGCGGYK ECEOIPNIRLHKYR CFICi SG

Melitiiti Melittin (Allergen Aps m ΠΙ) (allergen Api m GIGAVLKVLTTGLPALIS W1KRK 987

3} RQQ

eiittin-like Melittin-like peptide (MLP } FIGSALKVLAGVLPSIVSWYKO 988 peptide (MLP }

meucin- 13 meucin- 13 IFGAIAGLLKNTF 989 meuciii- 1.8 meucin- 18 FFGHLFKLATKIIPSLFQ 990

Microcin V Microcin V ASGRDIAMAIGTLSGOFVAGGI 991

GAAAGGVAGGATYDYASTHKP NPAMSPSGLGGTIKOKPEGIPSE AWNYAAGRLCNWSPN LSDV

CL

Microciti-24 Microcin-24 AGDPLADPNSOIVROIMSNAAW 992

GPPLVPERFRGMAVGAAGGVT

OTWXJAAAHMPVNVPIPKVP

MGP8WNGSKG

Microolusin A Chain A, Nmr Structure Of Microplusin A HHOELCTKGDDALVTELECiRL 993 Antimicrobial Antimicrobial Peptide From Rhipicephalus RISPETNAAFDNAVOOLNCLNR

Peptide (Boophitus) Microplus ACAYRKMCATNNLEOAMSVYF

TNEQ1KEIHDAATACDPEAHHE

HDH

milk lysozyme milk lysozyme GCVWPDGKAITTI-IKLOTTMLE 994

TKALIMGYFKSIATGGAMMAK POEOLTPVIYPAV

milk lysozyme milk lysozyme GCVWPDGKAITTHKLOTTMLE 995

TKALIMGYF SIATGGAMMAT ODGAVTPVIYPAV

milk Iysozvme milk lysozyme MKALLILGLLLFSVAVOGKVFE 996

RCELARSLKRFGMD FRGTSLA

N

milk lysozyme milk lysozyme GCVWPDG AITTHKLOTTMOE 997

TKALIMGYFKSLATGGAMMAK POEOLTPVTYPAV

milk lysozyme milk lysozyme MKALLILGLLLFSVAVOGKVFE 998

RCELARSLKRFGMDNFRGITLA Mytilin B Μγίίϋί! B antimicrobial peptide KA A VII. ATALVAIL AVHEAE A 1020 antimicrobial SCASRCKGHCRARRCGYYVSV peptide LYRGRCYCKCLRCSSEHS KFP

ENEGSSPSDMMPOMNENENTE FGODMPTGETEOGETGI

Mviilin -B gil 6225741 IsolPS 1613 !MYTB YTED SCASRCKGHCRARRCGYYVSV 102.1

Mytilin- B LYRGRCYCKCLRC

Mytin yjyn ei! 6225739!s»iP81614IMYMY MYTED DCCRKPFRKHCWDCTAGTPYY 1022

My si m vein GYSTR FGCTC

Nadl Nadl RECKTESNTFPG1C1TKPPCRKA 1023

CISEKFTDGHCSKILRRCLCTKP

c

Neocarzinostatin Neocarzinostatin AAPTATVTPSSGLSDGTVVKVA 1 24

GAGLQAGTAYDVGQCAWVDT

GVL ACNP ADF S S V TADANGSAS

TSLTVRRSFEGFLFDGTRWGTV

DCTTAACQVGLSDAAGNGPEG

VAISFN

Neuropeptide-like Neuropeptide-like protein 33 OWGYGGPYGGYGGGYGGGPW 1025 protein 33 GYGGGWRRRHWGGYGGGPW

GGYGGGPWGGYY

Neutrophil Neutrophil antibiotic peptide NP-3B GRCVCRKOLLCSYRE.RRIGDCK 1026 antibiotic peptide IRGVRFPFCCPR

NP-3B

Neutrophil Neutrophil antibiotic peptide NP-4 VSCTCRRFSCGFGERASGSCTV 1027 antibiotic peptide NGVRHTLCCRR

NP-4

Neutrophil Neutrophil antibiotic neptide NP-5 VFCTCRGFLCGSGERASGSCTFN 1028 antibiotic peptide GVRHTLCCRR

NP-5

neutrophil beta neutrophil beta defensin 10 | ^"Bubalus bubalis j LLLLLWLSSGSGFTOGVGSNL 1029 defensin 10 TCWRNRGICOLKOGPVRMNOI

GTCFG

neutrophil beta neutrophil beta defensin ί 1 [Bubalus bubalis^"! IJ..AI FLVLSAGSGFTOGVGNP 1030 defensin i l VSCARNKGTCVPSRCPGNMRO

MICHDY

neutrophil beta neutrophil beta defensin 12 [Bubalus bubalis] LLALLFLVLSAGSGFTOGVGNP 1031 defensin 12 VSCARN GICVPSR

neutrophil beta neutrophil beta defensin 5 [Bubalus bubalis] LLVLLFLVLSAGSGFTOGVG P 1032 defensin 5 VAVLGIKASVCRAGALET

Neutrophil beta- Neutrophil beta-defensin 4 SPLSCRGNRG VCLPIRCPGRLRO 1033 defensin 4 IGTCFGPRVPCCR

Neutrophil cationic Neutrophil cationic peptide 1 ( GNCP-1 ) RRCICTTRTCRFPYRRLGTC1FO 1034 peptide 1 ( GNCP- NRVYTFCC

Neutrophil cationic gii l352227!s-)iP491 12IDEF2 CAVPO RRCTCTTRTCRFPYRRLGTCLFO 1035 peptide 2 precursor Neutrophil cationic peptide 2 precursor iCP- NRVYTFCC

fCP-2.) ί GNCP-2.) 2) fGNCP-2)

Neutrophil defensin Neutrophil defensin 4 VCSCRLVFCRRTELRVGNCL1G 1036 4 GVSFTYCCTRVD pepide NisB NisB K SFTEYTOVIETVSKNKVFLE 1056

OLLLANPKLYDVMOKYNAGLL

K RVK LFESIY T RSYLR

STPFGLF SET SIG VF SKS SOYKL GKTTKGIRLDTOWLIRLVHK

MEVDFSKKLSFTK.N ANYKFG

DRVFOVYT

Non-specific lipid- Non-specific lipid-transfer protein 1TCGLVASKLAPC1GYLQGAPGP 1057 transfer protein SAACCGG1 SLNSAAASPADRK

TACTCLKSAATS1KG1NYGKAA

SLPRQCGVSVPYAISPNTNCNAI

H

Nonspecific lipid - gi!2509082 l!sp|P83434!NLTP i PHAAIJ MTCGOVOGNLAOCIGFI.O GG 1058 transfer protein 1 Nonspecific lipid-transfer protein 1 CLTP 1)

fLTP 1.) ( S-LTPtt INS-LTPl !

Non-specific lipid- Non-specific lipid-transfer protein 3 AVSCGDVTSSIAPCLSYVMGRE 1059 transfer protem 3 SSPSSSCCSGVRTLNGKASSSAD

RRTACSCLKNMASSF^'RNLNMG NAASiPSKCGVS V AFPISTS VDC SKI

Non-specific lipid- Non-specific lipid-transfer protein 4, 1 AiSCGQVSSALSPCISYARGNGA 1060 trarjsfer protein 4, 1 KPPAACCSGVKRLAGAAQSTA

DKOAACKCIKSAAGGLNAGKA AGiPSMCG VSVPYAi SAS VDC S KIR

Non-SDCcific lipid- on-specific lipid-transfer protein Cwl 8 AITCGOVSSALGPCAAYAKGSG 1061 transfer protein precursor TSPSAGCCSGVKRLAGLARSTA Cwl 8 precursor DKOATCRCLKSVAGAYNAGRA

AGiPSRCGVSVPYTISASVDCS IH

OaBacl l OaBacl l RRLRPRRPRLPRPRPRPRPRPRS 1062

LPLPRPKPRPIPRPLPLPRPRPKPI

PRPLPLPRPRPRRIPRPLPLPRPR PRPlPRPLPLPOPOPSPiPRPL

OaBac5 OaBacS RFRPPIRRPPIRPPFRPPFRPPVRP 1063

PIRPPFRPPFRPPIGPFP

OaBac7,5 OaBac7.5 RRLRPRRPRLPRPRPRPRPRPRS 1064

LPLPRPOPRRIPRPiLLPWRPPRP iPRPOiOPiPRWL

OdDl OdDl GFLDTFKNLALNAAKSAGVSVL 1065

NSLSCKLF^'KTC

OdE l OdEl GLGGAKKNF1IAAN TAPOSVK 1066

TFSCKLYNG

OdGl OdGl FMPILSCSRFKRC 1067

OdMl OdMl ATAWDFGPHGLLP1RP1RIRPLC 1068

GKDKS

odorranain-Bl odorranain-Bl antimicrobial peptide AALKGCWTKSIPPKPCFGKR 1069 antimicrobial

peptide Opiscorpine-2 Opiscorpine-2 KWL E SION IDEKIG FLG 1092

GMAKAVVHKLAKNEFMCMAN DPTGSCETHCOKASGEKGYC

HGTKCKCG LSY

Qpiseorpine-3 Opiscorpine-3 KWL E SIONKIDEKIG NTLG 1093

GMAKAVVHKLAKNEFMCVAN VDMTKSCDTHCQKASGEKGYC HGTKCKCGWLSY

Opiscorpine-4 piscoipine-4 KWLNEKSIQNKIDEKIGKNFLG 1094

GMAKAVVHKLAKNEFMCVANI DMTKSCDTHCOKASGEKGYCH GTKCKCGVPLSY

Ooistoporin- 1 ei!28201847!spjP833 i .3.1 lOPOl OPICA1282 GKVWDW1KSTAKKLWNSEPVK 1095

01847]Opistoporin- 1 ELKNTALNAAKNLVAEKIGATP

s

Opistoporin-2 gi!2820i 84 !sp|P83314.1 |OP02 OP CA[282 GKVWDW1KSTAKKLWNSEPVK 1096

01848 jOpistoporin-2 ELK TALNAAKNFVAEKIGATP

s

Opistoporkt3 Opistoporiti3 GKVWDWIKSTAXKLWNSEPVK 1097

ELKNTALNAAKNLVAEKIGATP E

Opistoporm4 Opistoporiii4 GKVWL WIKKTAKDVLNSDVA 1098

KOLKNKALNAAKNFVAEKIGA TPS

Osmot in-like Osmotin-iike protein TPM- 3 ATFEVRNNCPYTVWAASTPIGG 1099 protein TPM- 1 GRRLDRGOTWVINAPRGTKMA

RIWGRTNCNFDGDGRGSCOTG

DCGGVLOCTGWGKPPNTLAEY

ALDOFSNLDFWDISLVDGFNIP

MTFAPTNPSGGKCHAIHCTANI

NGECPGSLRWGGCNNPCTTFG

GOOYCCTOGPCGPTDLSRFFKO

RCPDAYSYPQDDPTSTFTCPSGS

TNYRWFCPNGVTSPNFPLEMP

SSDEEAK

Ostricacin-2 Ostricacin-2 APGNKAECEREKGYCGFLKCSF 1100

PFWSGKCSRFFFCCKNIW

P14a I 4a ONSPQDYLAVH DARAOVGVG 1101

PMSWDANLASRAONYANSRAG

DCNLIHSGAGENLAKGGGDFTG

RAAVOLWVSERPSYNYATNOC

VGGKKCRHYTOVVWRls'SVRL

GCGRARCrsTsiGWWFiSCNYDPV

GNWIGORPY

PI 8 P18 KWKLFKKIPKFLHLAKKF 1 102

Palustrin- ] c Palustrin- lc AL SILRGLEKLA KMGIALTNCK 1 103

ATKKC

Paiiistrin-3b Palustrin-3b GIFPKIIGKGIKTGIVNGIKSLVK 1 104

GVGMKVFKAGLSNIGNTGCNE

DEC pali!strin-OGl palustrin-OGl antimicrobial peotide GIAVDTIKOAGKKFFLNVLDKIR i 105 antimicrobial CKVAGGCRT

peptide

palustrin-RA2 palustrin-RA2 antimicrobial peptide IGTISLSLCEOERDADEDEGETL 1106 antimicrobial precursor [Rana andersoiiii] RE

peptide

Parabutoporin ei!26397622!spjP83312|PBPO PARSC FKLGSFLKK AWK SKLAKKLR A 1 107

Parabutoporiii GKEML DYAKGI.EEGGSEEV

PGO

Pardaxin Pa4 Pardaxin Pa4 GFFALIPKIISSPLFKTLLSAVGS 1108

ALSSSGGOE

Pathogenesis- Pathogenesis-related protein PR-5d SGVFEVH NCPYTVWAAATPV 1109 related protein PR- GGGR LERGOSWWFWAPPGTK

5d MARI WGRTNCN FDG AGRGW C

QTGDCGGVLECKGWG PP TL

AEYALNQFSNLDFWD1SVIDGF

NiPMSFGPTKPGPGKCHGlQCTA

NINGECPGSLRVPGGC: NPCTT

FGGQQYCCTQGPCGPTELSRWF

KQRCPDAYSYPQDDPTSTFTCT

SWTTDYKVMFCPYGSAHNETT NFPLEMPTSTFIEVAK penaeidin 3i penaeidin 3j MRLWCLVFLASFALVCOGOV 1 110

YKGGYTRPVPRPPFVRPLPGGPI GPYNGCPVSCRGISFSOARSCCS RLGRCCHVGKG

Penaeidrn-2b Penaeidin-2b YRGGYTGPIPRPPPIGRPPLRPV 111 1

CNACYRLSVSDARNCCIKFGSC CHLVK

Penaeidin -2il Penaeidin-2d QRGGFTGPIPRPPPHGRPPLGPTC 1112

NACYRLSFSDVRICCNFLGKCC

HI.VK

Penaeidin-3b (Pen- Penaeidin-3b (Pen-3b ) (P3-b ) QVYKGGYTRPVPRPPPFVRPLP 1113 3b ) fP3-b ) GGPIGPYNGCPVSCRGISFSQAR

SCCSRLGRCCHVGKGYS

Penaeidin-3c fPen- Penaeidrxi-3c (Pen-3c ) fP3-c ) OVYKGGYTRPIPRPPFVRPVPG 1 114

3 c ! iP3-c ) GPIGPYNGCPVSCRGISFSOARS

CCSRLGRCCHVGKGYS

Psnaeidin-3d , Penaeidin-3d Penaeidin-3f QVYKGGYTRPIPRPPPFVRPLPG 1115

Penaeidin-3f GPIGPYNGCPISCRGiSFSOARSC

CSRLGRCCHVGKGYS

Penaeidin-3g Penaeidin-3g QVYKGGYTRPIPRPPPFVRPLPG 1116

GPISPYNGCPVSCRGiSFSQARS

CCSRLGRCCHVGKGYS

Penaeidin-3h Penaeidin- h OWKGGYTRPIPRPPPFVRPLPG 1 117

GPIGPYNGCPISCRGISFSOARSY

CSRLGRCCHVGKGYS

Penaeidm-3i Penaeidin-3i OVYKGGYTRPIPRPPPFVRPLPG 1118

GPIGPYNGRPVSCRGISFSQARS CCSRLGRCCHVGKGYS Perforin Perforin. PCYTATRSECKOKHKFVPGVW

MAGEGMDVTTLRRSGSFPVNT

ORFLRPDRTCTLC NSLMRDAT

ORLPVAITHWRPHSSHCOR VA

AA VI-iSTEGVAREAAANIN D

WRVGLDVNPRPEANMRASVAG

SFISKYANFAAEKTYODOYNFN

SDTVECRMYSFRLVOKPPLHLD

FKKALRALPR FNSSTEHAYHR

LISSYGTHFITAVDLGGRiSVLT

ALRTCOLTLNGLTADEVGDCL VEAQVSIGAQASVSSEYKACE

EKKKQHKMATSFHQTYRERHV

EVLGGPLDSTHDLLFGNQATPE

QFSTWTASLPSNPGLVDYSLEP

LHTLLEEQ P REALROAISHYi

MSRARWQNCSRPCRSGQHKSS

HDSCQCECODSKVTNQDCCPR

QRGLAHLWSNFRAEHLWGDY

TTATDAYLKVFFGGQEFRTGW

WN NNPRWTD MDFENVLLST

GGPLRVQVWDADYGWDDDLL

GSCDRSPHSGFHEVTCELNHGR

VKFSYHAKCLPHLTGGTCLEYA

PQGLLGDPPGNRSGAVW

Perforin Perforin PCYTATR5ECKQNHKFVPGVW

AA GEGVD VTTLR RS S SFP V TG FLRPDRTCTLC NALM DGiQ RLPVA1AHWRPHGSHCQRNVA TTKV S STEGVARE AAANINND WRAGLDVNPKPEANVHVSVAG SHSKIANFAAEKAHQDOYNFNT DTVECRMYSFRLAQKPPLHPDF RKALKNLPHNf N S STEHA YRRL ISSYGTHFITAVDLGGRVSVLTA LRTCQLTLDGLTADEVGDCLSV

'SIGAQAS V S SE YKACEEK

KKQHKIATSFHQTYRERHVEVL

FrYQA CLJmTGE CLEYAl Q

GLLG^^GN SGA Ponericin-W3 gil l 8202408lsp|P82425|PCW3 PACGO GiWGTLAKIGIKAVPRViSMLK i 166

Ponericin-W3 KKKO

Ponericin-W4 ri! 18202409!spjP82426jPCW4 PACGO GIWGTALKWGVKLLPKLVG A 1167

Ponericin-W4 OTKKO

Ponericin-W5 ei| 18202410!sp|P82427|PCW5 PACGO FWGALIKGAAKLIPSWGLFKK 1168

Ponericin-W5 l

PREDICTED: PREDiCTED: defensin. beta 103A OKYYCRVRGGRCAVLSCLPKE 1169 defensin,. beia EOIGKCSTRGRKCCR

103 A

PREDICTED: PREDICTED: sperm associated antigen 1 1 A VDCRR SEGFCOE YCNYMETOV 1 170 sperm associated GYCSKKKDACC

antigen 1 1A

prepromelittin- gi! l54347366ldbi|BAF74740.i|fl54347366]p VIGSILGALASGLPTLISWIKNR 1171 related peptide repromelittin-related peptide [Rana

[Rana sakuraiij/Peptide VR-23

sakuraiij/Peptide

VR-23

prepromelittin- gii 154347368|dbilBAF74741.1IF1543473681p AIGSILGALAKGLPTLISWI NR 1 172 reiated peptide repromelittin-related peptide [Rana tagoi]

1 Rana tagoij

preprotemporin- rii i l9852237ldbi|BAP42773.1 |ri l98522371p FLPVILPViGKLLNGiLGK 1173

I SKa iRana reproternporin- 1 SKa [Rana sakuraii]

sakuraii]

Probable cysteine- Probabie cysteine-rich antifungal protein O LCE PSGTWSGVCGNSNAC 1 174 rich antifungal NOCiNLEGAKMGSCNYVFPAH

ETO-Sin KCiCYFPC

probactenecin. 7 probactenecin 7 (Cathelicidin [Bubalus ALSYREAVLRAVDRINDGSSEA 1 175

(Caihelicidm) bubalis] LYRLEELDPPP DVEDRGARK

PASFRVKETVCPRTSOOPLEOC

Praline-rich gi! i56633553!spjP85214.1 iPROPi GALMEf D101PG1KKPTHRDIIIPNWNPNV 1 176 antimicrobial 156633553 j Proline-rich antimicrobial RTOPWORFGGNKS

peptide 1 peptide 1

p roline-rich prote in proline-rich protein LKLTYVLGVLLVLFTVDSSCO 1 177

RiiLPTYRPPRORPVIIRTVREAD EPLWLYKGDNIERAPTTADHPI LP SHDDVKLDPNRR YAR SLDSP S AKRGGGSH STS SG SHDAG A.TH PGYNRRNAfiEIRLPEPFRFPSPT VPKPIDIDPILPHPWSPROTYPIY ARSTRDIOIPGIKKPTHRDIIiPN WNP VRTOPWORFGG KS

Prophenin-2 Prophenin-2 AFPPPNVPGPRFPPPNVPGPRFP 1 178

PPNFPGPRFPPP FPGPRFPPPNF PGPPFPPPIFPGPWFPPPPPFRPPP FGPPRFP

Protegrin-4 Protegrin-4 RGGRLCYCRGWICFCVGR 1 179

Protegrin-5 Protegrin-5 RGGRLCYCRPRFCVCVGR 1180 Protein 5d i Pr-Sd ) Protein 5d ( Pr-5d ) SG-VFEVHNNCPYTVW/VAATPV 1 18 1

GGGRRLERGOSWWFWAPPGTK

MARIWGRTNCNFDGAGRGWC

OTGDCGGVLECKGWG PPNTL

AEYAL OFS LDFWDISVIDGF

NIPMSFGPTKPGPGKCHGIOCTA

NINGECPGSLR GGCNNPCTT

FGGOOYCCTOGPCGPTELSRWF

KORCPDAYSYPODDPTSTFTCT

SWTTDYKVMFCPYG

Protein NP24 Protein NP24 A^'T^'IE VR CP Υ^'Γ V AASTPIGG 1 182

GRRLNRGQT\¥VINAPRGTKMA

RIWGRTGCNFNAAGRGTCQTG

DCGGVLQCTGWGKPPNTLAEY

ALDOFSNLDFWDiSLVDGFNIP

MTFAPTKPSGGKCIIAIHCTANI

NGECPRALKVPGGCNNPCTTFG

GOOYCCTOGPCGPTELSKFFKK

RCPDAYSYPODDPTSTFTCPGG

STNYRVVFCP GVADPNFPLEM

PASTDEVAK

Protein synthesis Protein synthesis inhibitor ί AAKMAKNVDKPLFTATFNVOA 1 183 inhibitor I SSADYATFIAGIRNKLRNPAHFS

HNRPVLPPVEPNWPSRWFHVV

LKASPTSAGLTLAIRADNTYLEG

FKSSDGTWWELTPGIJPGATYV

GFGGTYRDLIXjDTDKLTNVAL

GROOLADAVTALHGRTKADKP

SGPKOOOAREAVTTLLLMVNE

ATRFOTVSGF VA GLLHPK AVEK

KSGKIGNEMKAOVNGWODLSA

ALLKTDVKPPPGKSP A KF ΑΡΪΕΚ

MGVRTAVOAANTLGILLFVEVP

GGLTVAKALELFHASGGK

Protein synthesis Protein synthesis inhibitor II AAKMAKNVDKTLFTATFNVQA 1184 inhibitor II SSADYATFIAGIRNKLRNPAHFS

HNEPVLPPVEPNVPPSRWFHVV

LKASPTSAGLTLAIRADNTYLEG

FKSSDGTWWELTPGLIPGATYV

GFGGTYRDLLGDTDKLTNVAL

GROOLEDAVTALHGRTKADKA

SGPKOOOAREAVTTLLLMVNE

ATRFOTVSGFVAGLLHPKAVEK

KSGKIGISTEMKAOVNGWODLSA

ALLKTDVKPPPGK SPAKFTPIEK

MGVRTAEOAAATLGILLFVEVP

GGLTVAKALELFHASGGK

Psalmopeotoxin- 1 Psalmopeotoxin- 1 ACGILHDNCVWPAONPCCRGL 1185

OCRYGKCLVOV Psa.lmopeotoxin-2 Psalmopeotoxiit-2 RCLPAGKTCVRGPM VPCCGS 1186

CSO KCT

Pseudin-1 ri!21542188!5piP83188iPSl PSEPD GLNTLK VFOGLHEAIKLIN 1 1187

Pseiiditt-1 VQ

Pseudin-2 eij21542189lspiP83189iPS2 PSEPD GLNALK VFOGiHEAiKErNNH 1188

Pseudin-2 YQ

Pseuditi-3 gi!21542 i 90|sp|P83190IP83 PSEPD G1NTLKKVTOGLHEVIKLVSNHE 1189

Pseudin-3

Pseudin-4 _ril21542191lsplP83191IPS4 PSEPD GiNTLK VlOGLHEVlKLVSMi 1190

Pseudin-4 A

Pseudo-hevein Pseudo-hevein EOCGROAGGKLCPNNLCCSOY 1191

GWCGSSDDYCSPSKNCOSNCK

GGG

Psoriasiti [Equus Pscriasin FEquus caballus] MSETEAEASVIGIIELFHKYTGR 1192 caballus] DDMID PGLL MLODNFP FL

AACD GTDYLANVFEKKD N

RDKKIDFSEFLSLLGDIATDYHK

OSHGAPACSEGDO

PsYchimicin. PsYcliimicin INN RVPPCDOVCSRTNPEKD 1193

ECCRAHGHAFHATCSGG OCY RR

Puroindoline-B Puroindoline-B EVGGGGGSOOCPOERPKLSSCK 1194

DYYMERC^'FTMKDFPVTWPTK

WW GGCEHEYREKCCKOLSOI

APOCRCDSIRRViOGRLGGFLGl

WRGEVF OLORAOSLPSKC M

GADCKFPSGYYW

Putative antifungal Putative antifungal protein LCKRE SET W SGRC VN D YQCRD 1195

HCLNDRGNDGYCAGGYPWYR

SCFCFFSC

putative putative antimicrobiai peptide precursor GFWS IKDFAKKAWNSPLANE 1196 antimicrobial Orj isthacanthus cavaporam] LKS AI.NAA NFVSEKIGATPS peptide

putative gi|157841288|refiNP 00ΪΪ03367.Ϊ!ίΪ5^:784Ϊ2 ' AALRGALRAVARVGKAILPHV 1197 antimicrobial 8]putative antimicrobial peptide A Northern AIANPYVRTPYVHJSINP

peptide A Northern Europe Heligoland variant [Ciona

Europe Heligoland intestinaiis]

variant FCkma

intestinalis]

putative putative antimicrobial protein [ synthetic MEYWCYRK PYRKCR 11.98 antimicrobial construct]

■protein putative bacteriocia putative bacieriocin family orotein IvlNNLHRELAPITSEAWAAlEEE 1 199 family protein AGRTFKRHIAGRRVVDVAGPH

GVDFSAVGLGRTTGIAAPDEGV

OARORWAPLVELRVPFTLSRE

ELDNVERGAKDTDLDA\⁷KEAA

RRIAFAEDRA1FEGYPAAGITGI

RAAGSNAPITVPDDARLVPEAIT

OALTALRL AGVDGPYSVLLSAE

LYTEVSETSDHGYPIRTHIERLIP

DGEI1WAPAIDGAFVLTTR.GGD

YELTLGODVSTGYLSHDADTVR

LYFOOTMOFLVHTAEA putative putative transcriptional regulator HPDIVDYFMKRH WFIFKFFHY 1200 transcriptional EEDDKIKGAYFICNDONIGH.TR regulator RTFPLSSDE1LIPMAPDLRCFLPD

RTNRLSALHOPOIRNAIWKI.TR

KKONCLVKEAFSSKFEKTRRNE

YORFLKKGGSVKSVADCSSDEL

THIFIELFRSRFG TSSCYPADNL

ANFFSOLHHLLFGHILYTEGIPC

AFDTVLKSESOMNVYFDVSNGA

3KNECRPLSPGS1LMWLN putative putative transcriptional regulator HPDiVDYF KR_HNWHFKl⁷F}iY 1201 transcriptional EDDKIKGAYFICNDONIGILTR regiilator RTFPLSSDEILIPMAPDLRCFLPD

RTNRLSALHOPOIRNAIWKLTR

KKONCL VKETF S SKFEKRRRNE

YOOFLKKGGSVKSVADCSSDEL

THIFIELFOSRFGNTLSCYPADN

LATFFSOLHI-ILLFGHILYIEGIPC

AFD1VLKSESOMNVYFDVSNGA

1KNEFRPLSPGSILMWLN

Pw2 Pw2 HPLKOYWWRPSI 1202

PYLa'PGLa gi!730432|sp|O99134|PYLA XENLA GMASKAGAiAGKiAKVALKAL 1203 precursor PYLa'PGLa precursor f Contains: PYLa;

1 Contains: PYLa; PGLaj

PGLaj

Rana.cyclin-E gi!41688618!spjP83663jRACYE RANES SAPRGCWTKSYPPKPC 1204

R.aaacvclm-E

Ranacyciin-T d!47117i2 i!spjP837i9]RACYT RANTE GALRGCWTKSYPPKPCK 1205

Ranacyclin-T precursor

Ranalexin gi!730^*587isD!P39084!RLX RA CA FLGGLIKIVPAMICAVTKKC 1206

Ranalexin precursor

Ranalexin- ICa gi!4i0i76i?!spiP82876!RLCA RA CL FLGGLMKAFPALICAVTKKC^' 1207

Ranalexin- ICa

Ranalexin- lCb gi|41017618|sp|P82877|RLCB RANCL FLGGLMKAFPAIICAVTKKC 1208

Ranalexin- I Cb

Ranatuerin 2SKa Ranatuerin 2S a [Rana sakuraii] GLLDAIKDTAONLFANVLDKIK 1209

[Rana sakiiraii] CKFTKC

Ranatuerin- 1 gi!4Iu 7604 !P8274i |RANl RANCA SMLSVL NLGKVGLGFVACKIN 1210

Ranatuerin- 1 KQC peptide salivary giand salivary gland antimicrobial peptide 1 MRMSI CFAVIFVAFAFFLGOIS 1232 antimicrobial [synthetic construct! . RAEACIPDGGRCHESDPGPGCC peptide 1 [synthetic SGFCYRERNW DGDCR RP construct! .

Scarabaeein Scarabaeein ELPKLPDD VL1RS SNCPKGK 1233

V WNGFDCKSPF AF S

seminalplasmin ri!27806807|refj P 77638Ϊ. l|f 278068071se SDEKASPDKHHRFSLSRYA LA 1234

[Bos taurus] minalplasmin [Bos taurus] NRLANPKLLETFXS WiGDRGN

RSVK

Sequence 1 from pat !US ! 5221732 i H344255751 S equ ersce 1 GiGKFLHSA KFGKAFVGFJM 1235 patent US 5221732 from patent US 5221732 SK

Sequence I from pat!US!56079 i4| 11209678 l lSequence 1 from KKIEK ΑίΚΗίΡ ΚΪΚΑ GPG VTIGI 1236 patent US 5607914 patent US 5607914 AHAKSOLW

Sequence 1 from [3941161]Sequence 1 from patent US GFFKKAXRKVKIIAGRRVLDTA 1237 patent US 5734015 5734015 KGVGRHY VNI XLNRYR

Sequence 1 from [4001461] Sequence 1 from patent US IIGGR 1238 paten! US 5798336 5798336

Sequence 1 from pat|US|5856127| l [5938880]Sequence 1 from M ASR A AGL AARL A RL ALR 1239 patent US 5856127 patent US 5856127

Sequence 1 from patlUSi5905187| l [72242841Sequence 1 from RSGRGECRROCLRR11EGOPWE 1240 patent US 5905187 patent US 5905187 TOECMRRCRRRGG

Sequence 1 from Sequence 1 from patent US 6127336 RSVCRQIKICRRRGGCYYLCTN 1241 paten! US 6127336 RPY

Sequence 1 from patiUS!62 ϊ Ϊ Ϊ48[ΊΪΪ5 Ϊ 08327]Seqxience Ϊ DFASCHTNGGICLPNRCPGHMI 1242 patent US 6211148 from patent US 6211148 OiGlCFRPRVLC^'CRSW

Sequence 1 from Sequence 1 from patent US 6329504 RTCENLADKYRGPCFSGCD^'T^'HC 1243 patent US 6329504 TTKENA V ^'SGRCRDDFRCXXTK

Sequence 1 from Sequence 1 from patent US 6476189 LTCDLLSFEAKGFAA 1244 patent US 6476189

Sequence 1 from pa!!US!6492328j 112969521 llSequence 1 .,RRXXRKXXH11KKYG 12.45 oaten! US 6492328 from patent US 6492328

Sequence 1 from Sequence 1 from patent US 6605698 CKNOCIRLEKARHGS 1246 patent US 6605698

Sequence 1 from pat!US!6624140j 1 [40151049]Sequence 1 GRLRKKWKAF KFLKILAC 1247 patent US 6624140 from patent US 6624140

Sequence 1 from Sequence 1 from patent US 6653280 RLCERPSGTXSGVCGNNNACR 1248 patent US 6653280 NQCRNLERAEHGSCNYVFPAH

KXXXYFP

Sequence 1 from pat!US!6696238i U47232905]Seqnence 1 MRLHHLLLALLFLVLSAGSGFT 1249 patent US 6696238 from patent US 6696238 OGVRNSOSCRRNKGICVPIRCP

GSMROIGTCLGAOV CCRRK

Sequence 1 from pa!!US!6696559i 1 [47235321 [Sequence 1 YXXiOXWXHYR 1250 paten! US 6696559 from patent US 6696559

Sequence 1 from pat!US!6730659i 1 [539233691Sequence 1 NOGRHFCGGALTHARFVMTAA 1251 patent US 6730659 from patent US 6730659 SCFO

Sequence 1 from Sequence 1 from patent US 6743598 XEDXXXXXXXRGXGXGXXXX 1252 patent US 6743598

Sequence 1 from pai!USi6743769i l [53934458jSequence 1 SDDPKESEGDLHCVCV TTSLV 1253 paten! US 6743769 from patent US 6743769 RPRHITNLELI AGGHCPTANLI

ATKKNGRKLCLDLOAALYKKK

ilKKLLES Sequence 10 from patlUSI6730659| 101539231781Sequence 10 OGRHFCGGA1THARFVMTAA 1278 patent US 6730659 from patent US 6730659 RCFO

Sequence 10 from Sequence 10 from patent US 6743598 EPSi FY RRGA 1279 paten! US 6743598

Sequence 1 0 from pat!US!6743769i 101539344671Sequence 10 KL YKKWKNKLKR SLKRLG 1280 patent US 6743769 from patent US 6743769

Sequence 10 from patiUS!6747007| 10[539376351Sequence 10 RRWCRRVCYAGFCYRKCR 1281 patent US 6747007 from patent US 6747007

Sequence 10 from Sequence 30 from patent US 6790833 LAHOKPFI 1282 patent US 6790833

Sequence 10 from pa!|US!681 8407| 10[56646449]Sequence 10 WKSFIKKLTSAAKKVTTAA P 1283 paten! US 6818407 from patent US 6818407 LTK

Sequence 10 from pat!US!6835536j 10[59753992]Sequence 10 ILKKYPYYPYRRK 1284 patent US 6835536 from p _x atent US 6835536

Sequence 1 from pat!US!6887847j l 0j 67584688iSequence 10 RRWVRRVRRVWRRWRWRR 1285 patent US 6887847 from patent US 6887847 WVRR

Sequence 1 0 from pat!US!6906035| 10174472293 [Sequence 10 KWKSF1KNLTKVL KVVTTALP 1286 patent US 6906035 from patent US 6906035 AL1S

Sequence 1 from ioatlUSi 7091 18 ! 1.01 1 157941911 Sequence 10 RFARRFARRFARRFARRFARRF 1287 patent US 7091 185 from: patent US 7091 185 ARRFAR

Sequence 1 0 from ipatlUSi7244710l l0ri557164571SequeQce 10 VPKCX PV 1288 patent US 724471 from patent US 7244710

Sequence 10 from ipat|USi7314858110f 167246737^'|Sequence Ϊ6 ' RGCICRCIGRGCICRCIG 1289 patent US 7314858 from patent US 7314858

Sequence 1 0 from [340761 1 jSequence 100 from patent US LRRGGRWILATPRAIL 1290 patent US 5714577 5714577

Sequence 100 from Sequence 100 from patent US 6605698 GSCNYVFPAHKCICYF 1291 paten! US 6605698

Sequence 1 00 from ^'pai!US!6835536i l00[597541 71 iSeauence WRWWKVAWRWVKW 3292 patent US 6835536 100 from patent US 6835536

Sequence 100 from Sequence 100 from patent US 7001924 FRXT KNADFKAIFRVGLSVSK 1293 patent US 7001924 LG AVTRNOiKRRIRHNF VHK

SHLDFWIAROPAKDMTTLEME K LL

Sequence 1 00 from lpatlUSI7314858l l00ri672468231Sequence RCLCRRRVC 1294 patent US 7314858 100 from patent US 73 14858

Sequence 101 from i3407612]Sequence 101 from patent US LWETLRRGGRW1LA1PREIL 1295 patent US 5714577 5714577

Sequence 1 1 from Sequence 101 from patent US 6605698 IRLEKARHGSC YVFPA 1296 paten! US 6605698

Sequence 101 from Sequence 101 from patent US 7001924 YR! K ADFQRlYRLGiSVS KL 1297 paten! US 7001924 GNAVLR KIKRAIRENFKWIKS

H1DII\TARQPAKDMTTLQIQNS

LE

Sequence 1 01 from ipat!lJS!7314858! 101 Π67246824 ISequence RCLCRRRFC 3298 patent US 7314858 101 from patent US 7334858

Sequence 102 from [3407613]Sequence 102 from patent US LRRGGRWILAIPREIL 1299 patent US 5714577 5714577

Sequence 102 from Sequence 102 from patent US 6605698 RLEKARHGSCNYVFPAH 1300 patent US 6605698

Sequence 102 from Sequence 102 from patent US 7001924 YRiKKDSDFORlYRLGiSVSKKE 1301 paten! US 7001924 GNAVLRNKIKRAIREAYRLNID

EK1D1I VIARV S SKD1DKOI ONSL E

Sequence 103 from i3407614]Sequence Ϊ 03 from patent US WILAIPR 1RGGRLWETL 1302 patent US 5714577 5714577

Sequence 103 from Sequence 103 from patent US 6605698 LEK ARHG S CNYVFP AHK 1303 paten! US 6605698

Sequence 103 from patjU S |6835536] 103(59754177 ]S equence WXWWXVAWXWVXW 1304 patent US 6835536 103 from patent US 6835536

Sequence 103 from Sequence 103 from patent US 700 924 KGLK SEDFR WRVGISVSK 1305 patent US 7001924 VG AITRNRVRRLIKE WIA MK

DOIDIVFVRAIPPAATASYESIK

LV

Sequence 103 from jpat!U Si 73 Ϊ4858 ! ί 03 [ 167246826 ISequence RCLCGRRVC 1306 patent US 7314858 103 from patent US 7314858

Sequence 1 04 from [340761 ]Sequence 104 from patent US WETLPRRIRGGRLWILAI 1307 patent US 5714577 5714577

Sequence 104 from Sequence 104 from patent US 6605698 EKARHGSCNYVFPAHKC 1308 patent US 6605698

Sequence 1 4 from Sequence 104 from patent US 7001924 LRLKHWODFOTVYRFG ITVSOK 1309 paten! US 7001 924 VSKKATVRNREKROTR WINHF

0P0iDWnVLPv9GiGC]NrVT.RFL REEF.

Sequence 1 4 from patiUSi7334858! 104f 167246827]Seqiienee RCLCTRRFC 13 10 patent US 7314858 104 from patent US 7314858

Sequence 1 5 from [3407616]Sequence 105 from patent US RIRRPIALIWRGGRRLTEWI, 131 1 paten! US 5714577 5714577

Sequence 105 from Sequence 105 from patent US 6605698 KARHGSC YVFPAHKCI 1312 patent US 6605698

Sequence 1 05 from pat!US!6835536| 105Γ5975418 ^Sequence WXWWXPXWXWPXW 1313 patent US 6835536 105 from patent US 6835536

Sequence 105 from Sequence 105 from patent US 7001924 NRLRRREDFAKVYRIGIWSKK 1314 patent US 7001924 VSKLAVTRNRFKROLRAIFRQL

\ S( ⁾I X)\ \ \ΊΛΊ ! V XS PWOHL GDDLK

Sequence 106 from [3407617]Sequence 106 from patent US DLWETLKKGGRWILAIPRRIKO 1315 patent US 5714577 5714577 GLELTL

Sequence 106 from Sequence 106 from patent US 6605698 ARHGSCNYVFPAUKCIC 1316 paten! US 6605698

Sequence 106 from Sequence 106 from patent US 7001924 ISLKSKIEIOKIFRTLVTFSKGFRG 1317 patent US 7001924 SVKR RiRRLFKEAFRKRLELL

D1IFWSYGKLTLTYFSIESLMK

Sequence 106 from pat!USi7314858| 106N 672468291Sequence RCLCVRRVC 1318 patent US 7314858 106 from patent US 73 14858

Sequence 107 from 13407618 ISequence 107 from patent US LWETLGRVGRWVLAIPRRIROG 1319 patent US 5714577 5714577 LELAL

Sequence 1 07 from Sequence 107 from patent US 6605698 RHGSCNYVFPAFfKCICY 1320 patent US 6605698

Sequence 107 from Sequence 107 from patent US 7001924 ERLRGSCRVRAVFRFLATFRRG 1321 patent US 7001924 YGKAVAR RARRLSKEAYRAL

KS SLDLVLLVS WEDSLAAYOR

LLCVLC Sequence 107 from patlUSI7314858| 107r i672468301Sequence RCICGRRIC 1322 patent US 7314858 107 from patent US 73 14858

Sequence 108 from f3407619]Sequence 108 from patent US YHRLRRLLLIVTRIVELLGRR 1323 patent US 5714577 5714577

Sequence 108 from Sequence 308 from patent US 6605698 HGSC YVFPAHKCICYF 1324 paten! US 6605698

Sequence 108 from Sequence 108 from patent US 7001924 ARLL KO VTV^'OKVGiTVSK 1325 patent US 7001924 K GKAHORN^'RFKRIVREAP^'RHV

RPNLGVViSPRGNSQPDFLKLSE ELLORIP

Sequence 108 from pat!USI7314858| 108[1672468311Sequence RCICRLRVC 1326 patent US 7314858 108 from patent US 7314858

Sequence 109 from [3407620]Sequence 109 from patent US YHRLRDLLRTVTRTVELLGRR 1327 patent US 5714577 5714577

Sequence 109 from Sequence 109 from patent US 6605698 I K ! \:K \ R! IGS( \ Y V! P.\ i l 1328 patent US 6605698

Sequence 109 from pat|USi6835536| 109f 597541891Sequence KWWRRALOALKNGLPALIS 1329 patent US 6835536 109 from patent US 6835536

Sequence 1 9 from Sequence 109 from patent US 7001924 AmJCRKQFWVOKVGVTVSK 1330 patent US 7001 924 EGKAHORNRFKRIVREAFRHV

RPNLO A'A^'SPKGGTLP FG I.S ADLLKHIP

Sequence 1 9 from !Pat|US!7334858! 109E 1672468321Sequence RCICRLRFC 1331 patent US 7314858 109 from patent US 7314858

Sequence 11 from patiUSi55191 I5| l lf l6102371Sequence 11 XXXIXX AKXXXXAXXXXKG 1332 patent US 5519115 from patent US 5519115 IG

Sequence 11 from patiUS|5607914111 ί 2096791 ISequetice 1 1 GWLRRIGRRTERVGOH LKKAL 3333 patent US 5607914 from patent US 5607914 RALARHW

Sequence 1 1 from i^"4001471 jSequence 1 1 from patent US HAOY OR 1334 patent US 5798336 5798336

Sequence 11 from pat!US!5856127| l l[5938890]Sequence 11 AARAAGLAARLAALALR 1335 patent US 5856127 from patent US 5856127

Sequence 11 from pat|US|5998374| 1 1 [ 1006631 SlSequence 11 MKTITLTLLTLGLGIDAKSLEESK 3336 patent US 5998374 from patent US 5998374 ADEEKFLRFIGSVIHGIGHLVHH

IGVALGDDOODNG FYGYYAE DNGKHWYDTGDO

Sequence 11 from patjij S!619 Ϊ254! 1 H Ϊ41 199591 Sequence 11 1LPW WPWWPWWPWRR 3337 patent US 6191254 from patent US 6191254

Sequence 11 f m: pat!US!6492328i l 1J2969522 HSequence U KNLRRITRXilHllKKYG 3338 patent US 6492328 from patent US 6492328

Sequence 11 from Sequence 11 from patent US 6605698 RHGSC YVF 1339 patent US 6605698

Sequence 1 1 from pat|US|6638531 j 1 1 [401638571Sequence 1 1 KRLFKELLFSLRKY 1340 patent US 6638531 from patent US 663853 1

Sequence 11 from pat!USi6730659j 11 [53923179]Sequence 11 NQGRHFCGGALiHARFVMTAA 1341 patent US 6730659 from patent US 6730659 QFQ

Sequence 11 from Sequence 1 1 from patent US 6743598 YSTGMVHLLLOVTIDGR Yl 1342 patent US 6743598

Sequence 1 1 from patiUS!6743769l 11 [53934468 jSequence 11 ALY LFK LLKR 1343 patent US 6743769 from patent US 6743769

Sequence 11 from pat!US!6747007j l l [53937636]Sequence 11 RRWCFRVCYRGRFCYRKCR 1344 patent US 6747007 from patent US 6747007

Sequence 1 1 from Sequence 11 from patent US 6790833 A AS YK CLHKRCR 3345 patent US 6790833

Sequence 11 from pat!US|6818407| 11 [56646450jSequence 1 i KW KFIKKiGiGAVLKVLTTGL 1346 patent US 6 18407 from patent US 68 18407 PAL LTKK

Sequence 11 from pallUSI6835536| 11 [597539941Sequei.ee 11 H KWPWPWR K 1347 paten! US 6835536 from patent US 6835536

Sequence 11 from pat! S 168878471 i U67584689]Sequence 11 V V RVVRVVR WV RVR 1348 patent US 6887847 from patent US 6887847 RVWRRVVRVVRRWVRR

Sequence 11 from pai|US|6906035| Π i^'744722 4 jSequence 11 WKLFKKKGTGAVLTVLTTGL 1349 patent US 6906035 from patent US 6906035 PALIS

Sequence 1 1 from Sequence 11 from patent US 7078380 VGALAVWWLWLWLW 1350 patent US 7078380

Sequence 1 1 from ipat!U8!7091.185111 Π 157941921Sequeace 1 1 RFARRFARRFARRFARRFARRF 135 1 patent US 7091185 from patent US 7091 1 85 ARRFARRFAR

Sequence 11 from !pat!US!7244710! l l f l55716458]Seqiience 11 VPKCCKPV 1352 patent US 7244710 from patent US 7244710

Sequence 110 from | 3407621]Sequence 1 10 from patent US YHRLRDLLL1VRRTVELLGRR 1353 patent US 5714577 5714577

Sequence 110 from Sequence 110 from patent US 6605698 RLE3L' RHGSCNYVFPAFI 1354 patent US 6605698

Sequence 1 10 from Sequence 1 10 from patent US 7001924 SRVLKRK0FLY1TRMG1TVSKK 1355 patent US 7001924 FG AHERNSFKR^'WREVFRHV

RHQLQIVWPKGHKQRPVFSKL LQDFINQIP

Sequence 110 from pat!US!7314858j 110[ 167246833]Sequence RCiC^'TLRVC 1356 patent US 7314858 110 from patent US 7314858

Sequence 1 102 Sequence 3 102 from patent US 6573361 MAKIFR1TGTMSK GKDPLYFR 1357 from patent US EYKALKPEDALEILYSEFGGR 6573361 YKVKRSRTKILNIEEIKPEDVTDP

VLK LVTA

Sequence 1103 Sequence 1103 from patent US 6573361 MKMKT iFRVKGKFLMGDKLQ 1358 from patent U S PFTKELN AIREEE1YERLYSEFGS 6573361 KHRVPRSKVKIEEIEEISPEEVO

DPVV ALVOR

Sequence 1104 Sequence 1104 from patent US 6573361 AEVKIFMVRGTAIFSASRFPTSO 1359 from patent US KFT WRAE EKOAIEYiYSOE 6573361 GG Mil RY IHIOETKEYKEDE

ITDKTIRDLA LDKIIM

Sequence 1 105 Sequence 1105 from patent US 6573361 AEVKiFMVRGTAiFSASRFPTSO 1360 from patent US KYVRALNEKOAffiYIYSOLGGK 6573361 KINDTT YT YKR SKKLRKMKS

QTRQ

Sequence 111 from [3407622jSequei.ee H i from patent US YHRLRDLLLIVTRiVRLLGRR 1361 patent US 5714577 5714577

Sequence 11 1 from Sequence 111 fr m: patent US 6605698 LEKARHGSCNYVFPAHKC 1362 patent US 6605698

Sequence 111 from Sequence Π Ϊ from patent US 7001924 ERLRLRRDFLLIFRLGIVVKRKF 1363 patent US 7001924 GKATRR KLKIIN ^YREIFRR K

GVIDIVVIPIi KLSEEFERVDFW TYREKLL

Sequence 111 from !patlUS!7 14858! 11 i ll 67246834]8eq«ence RCICTLRFC 1364 patent US 7314858 1 1 1 from patent US 73 14858 Sequence 1119 Sequence 1119 from patent US 6573361 VFYKVTLSRSLIGVPHTTKSrVK 1365 from patent US SLGLGKRGSt KKVNPAi A GS 6573361 LAKVKELVKVEVTEHELTPSOO

RELR SNPCFiVEKETiD

Sequence 112 from | 3407623]Sequcnce 1 12 from patent US YHRLRDLLL1VTR IVCLLGR 1366 patent US 5714577 5714577

Sequence 112 from Sequence 112 from patent US 6605698 EKARHGSC YVFPAHKCi 1367 patent US 6605698

Sequence 1 12 from pat|US!68355361 12159754195^'iSequence KWKLFKKIGIGAVLKVLTTGLP 1368 patent US 6835536 1 12 from patent US 6835536 AL LT

Sequence 112 from Sequence 112 from patent US 6936432 VRGS1PLOASAAFP AARLLKT 1369 patent US 6936432 DEFSSVFRLRPWRRTAHFVTYG

KPTGRDARLGLVIGKKYAARA

VTRNLVKRLAREAFRTRRAEFA

GWDILLRLHA

Sequence 1 12 from Sequence 1 12 from patent US 7001924 ERLYLRDEINTVFSMLVSVAKK 1370 patent US 7001 924 RFRR AV RNRVRRLVREA YRL

HLLDVLOEROIYATIAFMW

SDELPDFRTVERA

Sequence 112 from ipatiUSi73 i4858l l i2 i67246835iSequ RCICVLRVC 1371 patent US 7314858 112 from patent US 7314858

Sequence 1 122 Sequence 3 122 from patent US 6573361 VKVKSKNSVIKLLSTAASGYSR 1372 from patent US YTS1KKGAPLVTOVRYDPWKR 657336 ? HVLFKEAKKRKVAERKPLDFLR

TAK

Sequence 113 from f3407624]Sequenee 1 13 from patent US YHRLRDLLLIVRR1VCLLGRR 1373 patent US 5714577 5714577

Sequence 113 from Sequence 1 13 from patent US 6605698 ARHGSC YVFPAHKCIC 1374 paten! US 6605698

Sequence 113 from Sequence 113 from patent US 7001924 LRGEREFR VRRIGLVYSKKTL 1375 patent US 7001924 KHAVKRNRARRRVREALRTMP

PELRAILMLNPGVLTVPFPELQA ALAOALORGAG

Sequence 113 from !pa!iUS!73 14858! 113ri672468361Sequence RCICVLRFC 1376 paien! US 7314858 1 13 from patent US 7314858

Sequence 114 from j 3407625 [Sequence 114 from patent US YHRLLRDLLIVTRIVELLGRR 1377 patent US 5714577 5714577

Sequence 114 from Sequence 114 from patent US 6605698 AREfGSC YVFPAHKCICY 1378 patent US 6605698

Sequence 114 from Sequence 114 from patent US 7001924 ARL GGFLLLiR VLFT VGKKL V 1379 patent US 7001924 PRAVDRMRI RLMREAYRLEK

ILDHQVMLAf LYRARADAiPS LERFRAIRHM

Sequence 114 from pat!US!7314858j 114[ 1672468371Sequence RCLCGLRVC 1380 patent US 7314858 114 from patent US 7314858

Sequence 1 15 from 3407626jSequence 1 15 from patent US YHRLRRLLLlVTRiVELL 1381 patent US 5714577 5734577

Sequence 115 from pa!!US!6835536j l l5i^"597542011Sequence WKSFIKKLTSAAKKVLTTGLP 1382 paten! US 6835536 1 15 from patent US 6835536 AI.1S

Sequence 115 from patlUSI7314858| 115[167246838]Sequence RCLCGLRIC 1383 patent US 7314858 115 from patent US 7314858

Sequence 1 16 from [3407627jSequenee 1 16 from patent US YHRLRDLLRIVTRIVELL 1384 patent US 5714577 5714577

Sequence 116 from Sequence 116 from patent US 6605698 ! R i .HK A R}-K ; S( W VH'A H K 1385 patent US 6605698

Sequence 116 from pat|USj68355 6[Ti6[59754203|Sequence WKLFIKKLTPAV KVLLTGLP 1386 patent US 6835536 116 from patent US 6835536 ALiS

Sequence 116 from pat|TJS|7314858| ί i6|^"f67246839 |Sequence CLCTLRVC 1387 patent US 7314858 116 from patent US 7314858

Sequence 117 from [3407628]Seq«ence 1 17 from patent US YHRLRDLLL3V RTVELL 1388 patent US 5714577 5714577

Sequence 117 from Sequence 117 from patent US 6605698 RLEKARHGSCNYVFPAHKC 1389 patent US 6605698

Sequence 117 from pat!USi6835536j 1 7L597542051Sequence GKPRPYSPIPTSPRPIRY 1390 patent US 6835536 1 17 from paten US 6835536

Sequence 117 from paii Si7314L58j i nir67246840^"]Sequence RCLCTLRIC 1391 patent US 7314858 117 from patent US 7314858

Sequence 118 from | 3407629]Sequence 1 i 8 from patent US YHRLRDLLLiVTR JVRLL 1392 patent US 5714577 5714577

Sequence 118 from Sequence 118 from patent US 6605698 LE ARHGSCNYVFPAH CI 1393 patent US 6605698

Sequence 1 18 from pa!jUSi6835536i 1 18[597542071Sequence RLARTWIRVAR 1394 patent US 6835536 1 18 from patent US 6835536

Sequence 118 from !pat|US!7314858| 118|^"1672468411Sequence RCLCVLRVC 1395 patent US 7314858 118 from patent US 7314858

Sequence 1184 Sequence 1 1.84 from patent US 6573361 MLKIRL RCGRK OTSF 1WM 1396 from patent US NLDKRDGOAIEELGFMNPRTK 6573361 EKYL INKINHYLRLGA PTKT

VFDLLNKAKII

Sequence 1185 Sequence 1185 from patent US 6573361 VKLRLKRYGRKGOVTYRIVA 1397 from patent US MNNLSRRDGKAIEELGF YN PRT 6573361 NE8SLMANIKRRIEOGAQPTNT

VRYILAKANIL

Sequence 1186 Sequence 1 186 from patens US 657336 i MVKLRL J CGR OOAVYRIVA 1398 from patent US 1DVRSRREGRDLR VGFYDPIK 6573361 NOTCL VPAILYFLEKGAOPTR

TVYDILR AEFFKEKERTI. S

Sequence 1 187 Sequence 1 187 from patent US 657336 i MVKLRLKRCGRKOOAIYRIVAI 1399 from patent US DVRSRREGRDLRKVGFYDPIKN 657336 S OTCLNVPATLYFLE GAOPTRT

VYDILRKAEFFKDKERTLS

Sequence 1188 Sequence 1188 from patent US 6573361 MLKLRL RSGRK OPSYRLW 1400 from patent: US MENTTRRDGRPVEOVGYY TIT 6573361 KESYFDVIKIKKWL YGAKPTO

TVLNLLKKAKIIDO

Sequence 1189 Sequence 1189 from patent US 6573361 LKLRLKRCGRKORFYDPIKN 1401 from patent US OTCI.WPAIEYFFE GAOPTRT 6573361 VSDTLR AEFFKEKERTLS

Sequence 119 from [3407630]Sequence 119 from patent US YHRLRDLLLiVTRIVCLL 1402 patent US 5714577 5714577

Sequence 1 19 from Sequence 1 19 from patent US 6605698 EKARHGSC YVFPAHKCiC 1403 patent US 6605698

Sequence 119 from pat!US!6835536j 119[59754209]Sequence 1LRWPWWPWRR 1404 patent US 6835536 119 from patent US 6835536 Sequence 119 from pat!USi73148581119N 672468421Sequence RCLCVLRIC 1405 patent US 7314858 1 19 from patent US 73 14858

Sequence 1190 Sequence 1 190 from patent US 6573361 MV LRLKRYGRKQQPSYRTVA 1406 from patent U S MDSRSKRDGKAIEELGFYNP1T

6573361 NETRIDIAKILKRLKQGAQTTRT

VKNILNEAQILAKENS

Sequence 1191 Sequence 1191 from oatent US 6573361 M VKLRLKRCG RKQRAV YRIVA 1407 from patent US ID SRREORDLRKVGFYDPiT 6573361 NOTYLNLPAILDFLKKGAQPTR

TVHDISKKAGIFTELNLNKTKL

Sequence 1 192 Sequence 1 192 from patent US 65733 1 MVKLRLKRCXJRKORAVYEJVA 1408 from patent US IDVRSRREGKDLOKVGFYDPIK

6573361 NOTYLNVPAILYFLEKGAOPTE

TVQD1LKKAEVFKELRLNQPKF

Sequence 1193 Sequence 1 193 from patent US 6573361 MVKLRI.KRCGR ORAVYR1VA 1409 fro patent US IDWSRREGKDLRKVGFYDPIK

6573361 NQTYL WAILYTIJEKGAOPTG

TVODILKKAEVFKELRP OS

Sequence 1 195 Sequence 3 195 from patent US 65733 1 MA SKERVG iRNPOEKT ViV A 1410 from patent US VNNRVRHNKYS illRTKKYOV 6573361 HDHSHTC LGDEvKiSEVKPiSK

TKRWIISEVLSSTVNPEKFGD

Sequence 1196 Sequence 1196 from patent US 6573361 \ U^>\ K l K VU V VSN MOK n v v 1411 from patent US KVE SRY SHPiY SKTMTKTRKYL 6573361 AHDEMGEC GDOVLVOECRP

LSKR RWTLSKVLSKSSLVS

Sequence 1197 Sequence 11 97 from oatent US 6573361 MPEKETTGKWSDKMN TIW 1412 from patent US AVENRlSHRKYA TMTRTKKY 6573361 KAHDE ECA.VGDIVTIOETRP

LSRTKCWTIvIVNlLSKSFHN

Sequence 1199 Sequence 1199 from patent US 6573361 MSVYRRRLSPLKPNOVTOYODV 1413 from patent US ELLRTFITDOGKILPRRVTGLTA

6573361 KOORAVTKAIKOARVLALLPFV

NRES

Sequence 12 from patlUSI5519115| 12[1610238]Sequence 12 XXMIEXVTAKXFKXAXXLFKGI 1414 paten! US 5519115 from oatent US 5519115 Q.

Sequence 12 from pat!US!5607914| 12i2096792 ]Sequence 12 KLKKALRALARHWKGWLRRTG 1415 patent US 5607 14 from patent US 5607914 RRIERVGOH

Sequence 12 from [4001472 jSequence 12 from patent US HPOYNO 1416 patent US 5798336 5798336

Sequence 12 from patlUSI5856127| 12[5938891]Sequence 12 AARAAGLAARLAALALRA 1417 paten! US 5856127 from oatent US 5856127

Sequence 12 from patiU8j 191254! 121141 19960] Sequence 12 1LPWKWPWWPWWKKPWRR 1418 patent US 6191254 from patent US 6191254

Sequence 12 from pat!USi6492328j 12| 29695222]Sequenee 12 K LRRISRKIil-niKKYG 1419 patent US 6492328 from patent US 6492328

Sequence 12 from Sequence 12 from patent US 6605698 CNY^'VFPAHK 1420 patent US 6605698

Sequence 12 from pat!USi6638531| 12[40163858]Sequence 12 KRKFHEKHHSHRGYC 1421 patent US 6638531 from oatent US 6638531 Sequence 12 from pat!US!6730659| 12153923 ISOlSequence 12 RHFCGGAIJHARFVMTAAHC 1422 patent US 6730659 from Datent US 6730659

Sequence 12 from Sequence 12 from patent US 6743598 IE YFERIGY 1423 patent US 6743598

Sequence 12 from patiUS!6743769| 12[539344691Sequence 12 GLYKRLFKKLLKS 1424 paten! US 6743769 from patent US 6743769

Sequence 12 from Sequence 12 from patent US 6790833 AASYACLHAACA 1425 patent US 6790833

Sequence 12 from pat!US|6818407| 12f 5664645 l]Seq«ence 12 KKW KFIKKIGIGAVLTTPGAK 1426 patent US 6 18407 from patent US 68 18407 K

Sequence 12 from pat|U§|6835536| Ϊ2ί5 7539% Sequence 12 1LKKYPWYPWRRK 1427 patent US 6835536 from patent US 6835536

Sequence 12 from paiiUS!6835713j 2[597559491Sequence 12 RVVRVVRRWVRRVRRVWRRV 142.8 patent US 6835713 from patent US 6835713 VRWRRWVRRVRRVWRRVVR

WRRWVRR

Sequence 12 from pai!US!6838435| 12f59761428iSequence 12 LRC^'MCIKTTSGlHP IOSLEVi 1429 patent US 6838435 from patent US 6838435 GKGTI-ICNOVEVIATLKDGRKIC

LDPDAPRIKKTV OKKLAGDESA D

Sequence 12 from pat!US!6872705| 12162788251 [Sequence 12 RLCRVVIRVCR 1430 patent US 6872705 from patent US 6872705

Sequence 12 from pat!USi6887847j 12[67584690JSequence 12 RVWVVRRWVRRVRRVWRRV 1431 patent US 6887847 from Datent US 6887847 VRWRRWVRRVRRVWRRVVR

WRRWRVV

Sequence 12 from patiUSi6906035i 12R4472295 jSequence 12 KWKSF1 KLTSVLKKVVTTAKP 1432 patent US 6906035 from patent US 6906035 LiSS

Sequence 12 from !pat!US!7071293! 12n i20627051Seqnence 32 LRRIIR IIHTIKK 3433 patent US 7071293 from patent US 7071293

Sequence 12 from !pat!US!7091185! 12|^"115794193]Sequence 12 FA FAKKFAKKFAK FA F 1434 patent US 7091185 from Datent US 7091185 AKK

Sequence 12 from !pat!US!7314858! 12[167246738]Sequence 12 AOAEPLOARADEAAAOEOPGA 1435 patent US 7314858 from patent US 7314858 DDOEMAHAFT WFiE SAALPL SD

SARGLRCICGRGICRLL

Sequence 120 from [340763 USequence 120 from patent US YHRLRDLLLIVRRTVCLL 3436 patent US 5714577 5714577

Sequence 120 from Sequence 120 from patent US 6605698 KARHG8CNYVFPAH CICY 1437 patent US 6605698

Sequence 120 from pat|US!6835536i r20[59754211 |Sequence WRWW VWRWVKW 1438 patent US 6835536 120 from patent US 6835536

Sequence 1200 Sequence 1200 from patent US 6573361 MYKFKRSFRRRLSPIGSGNL1YY 1439 from patent US R MSL1SRF1SEOGK11..SRRV R 6573361 LTLKOORLITIATKOARILSLLPFI

EKOFERIESITRVKGFIKK

Sequence 1201 Sequence 1201 from patent US 6573361 MKYPALlDYK V iLRRFlNFO 1440 fro in patent US GKJiPKRLNKPKLTYKOHRLLR 657336 S SVKOARYLGLLPFKT .DFF

Sequence 1202 Sequence 1202 from patent US 6573361 MNKS RS SRRRMPPIRSGEIIDY 1441 fro patent US SLLRRFVSEOG ILSRRMNR 6573361 LTS OORLLTIAKRARVLALLP

FL NEN Sequence 1203 Sequence 1203 from patent US 6573361 MLAO OKLSPIS O IDYKDl 1442 from patent US DLLKLFITEOGKTLPRRATGVTV 6573361 OOOROIAKAIKRARVLSLLPFV

ASNST

Sequence 1207 Sequence 1207 from patent US 6573361 MAVYRKKISPIKPTEAVDYKM 1443 from patent US DLLRKFTTEOGKILPKRSTGLTS 6573361 KOO KLTK A1KOARTLSLLPFLN

KD

Sequence 121 from j_3407632]Sequence 121 from patent US YHRLLRDLLFVTRIVELL 1444 patent US 5714577 5714577

Sequence 12 ! from pat!US!6835536j 12H597542131Sequence WRWWKVVWRWVKW 1445 patent US 6835536 121 from patent US 6835536

Sequence 121 from pai!US!7314858i l21 [167246843 Sequence VTPAMRTFALLTAMLLLVALA 1446 patent US 7314858 121 from patent US 7314858 OAEPLOARADEAAAOEOSD SA

RGLRCICGRGICRLLRRFGSCAF RGTLHRVCCRTCRI KN I.RFY FESKKFLLLLYL-VL-HFLFSSK1N TLLODFSL

Sequence 1210 Sequence 1210 from patent US 6573361 ARSLKKAPFVANHLLEKVER 1447 from patent US LNTOGDKKVIKTWSRSSTIVPL 6573361 MIGHTIAVHNGREFIIPVFITDOM

VGHKLGEFAPTRTFRGHVKKD KKSKR

Sequence 1211 Sequence 1211 from talent US 6573361 MARSLKKGPFIAHHLLKKVELL 1448 from patent US NTSGKTEVIKTWSRAST1LPMM 6573361 VGHTIAVH GROHLPVFITDOM

VGHKLGEFAPTRTFKGHTKSDK

KM< R

Sequence 1212 Sequence 1212 from patent US 6573361 MII-ISPTLKKNLFVANHLRAKI 1449 from patent US L N NK LSIN i^'WSRAS I^'il Pi 6573361 MIGHMISIHNGKEHLPIYITDH

VGHKLGEFVPTLNFRGHA SD RSRR

Sequence 1213 Sequence 1213 from patent US 6573361 MSRSLKKGPFVFY^'SLIKKVDOM 1450 from patent US NSNRFKSVILTWSRSCTIIPIMIG 6573361 N^'T^'IGV YNG EHIP VLV SDQMIG

H LGEFVOTRNYRGHKXHDKE:

TKTKR

Sequence 1214 Sequence 1214 from patent US 6573361 TRKKTNPFVARHLLAKIEKVNM 1451 from patent U S ΚΕΕΚΕΠ VT WSRAS SiLP AM VGH 6573361 TIAIHTSiGKEHlPlYITNPMVGRK

LGEFVPTRHFTSYESTRKDTKSR

R

Sequence 12 i 5 Sequence 1215 from patent US 657336 i TRSIKKGPFVADHLLKKIENE E 1452 from patent US KKEKKIHTWSRA ST1VPTM1GHT 6573361 lA TINGOEHLPrYTTDR VGHK

EGEFAPTRTFRGHAKNDKKSRR

Sequence 1216 Sequence 1216 from patent US 6573361 MPRSLKKGPFVAYHLLKKIDK 1453 from patent U S MNASG DVITT W SRT STiLPT 6573361 MVGHTlAVYT GROHVPlFiSDO

LVGHKLGEFVSTRTFKSHIKTD

i^'KR Sequence 1217 Sequence 1217 from patent US 6573361 TRKKTNPFVAHHLI.AKIEKVN 1454 from patent US M EE ETiVTWSRASSILPAMV 6573361 GHTIAIHNGKEHiPiYITNPMVG

RKLGEFVPTRHFTSYESARKDT KSRR

Sequence 1218 Sequence 1218 from patent US 6573361 TRSRKKNPFVANHLLKK1KKLN 1455 from patent U S TKGE AlIKTWSRKSTiiPlMlGH 6573361 TIAIHNGKEHLP VYITDRMVGH

LGEFSPTLNFGGFAKNDNKSR R

Sequence 1219 Sequence 1219 from patent US 6573361 MARSL K PFVANHSERKI NL 1456 frosri patent US IKEEKKIIVTWSRA SVIVPAM! 6573361 GHTIAVHNGREHLPIYVTDRMV

DHKLGEFAPTLLFOGHARNDK

KSR

Sequence 122 from [3407633]Sequence 122 from pateni US YHRLRDLLLIVTRIVELL 1457 paten! US 5714577 5714577

Sequence 122 from Sequence 122 from patent US 6605698 IRLEKARHGSCNYVFPAHKC 1458 patent US 6605698

Sequence 1220 Sequence 1220 from oatent US 6573361 MSRS1HKGPFIDVSLLTRIEALN 1459 from patent US TSG KE\1KTWSRASTIIPDMIG 6573361 HTi AVYNGKOHFP VFV SDOMV

GHKLGEFVPTRTFRTHVKGDRK ARR

Sequence 1221 Sequence 3221 from patent US 6573361 TRKKTNPFVAHHLLAKTE VTSi 1460 from patent US MKEE ETIVTWSRASSILPT V 6573361 GHTiAiHNGKEfflPiYlTNPMVG

RKLGEFVPTRHFTSYENARKDT

KSR

Sequence 1222 Sequence 1222 from pateni US 6573361 TRSLK NPFVANIiLLRKINKLN 1461 frosri patent US TKAEKDfflTWSRASTilPTMiGI-l 6573361 TIAIHNGKEHLPiYiTDRMVGHK

LGEFSPTL FRGHAKND RSRR

Sequence 1223 Sequence 1223 from patent US 65733 1 TRSL NPFVANHLLRKIEKLN 1462 from patent US K AEKEIIVTWSRASTIIPTMIGH 6573361 TLA IH GREHLPIYiTDRM VGHK

LGEFAPTLNFRGHAKNDNKSRR

Sequence 1224 Sequence 1224 from patent US 6573361 TRSLK NPFVANHLLKKIDKL1S' 1463 from patent US TKAEKEIIVTWSRAST1IPTMIGH 6573361 TIAIH GKEHLPiYiTDSMVGHK

LGEFAPTLNFRGHAKSDNRSRR

Sequence 1225 Sequence 1225 from patent US 6573361 M ANTKS AIKRIKTiERNRIRNC A 1464 from patent US Y SWKTFIK YLKVLSDYTNA 6573361 PNSNGVE IOTTLG 'TTKIDKA

VKRG HSNKAARMKSKLALK

V\\ I KK

Sequence 1226 Sequence 1226 from patent US 6573361 MA NASAEKR1LINER RLO R 1465 frosri patent US FYKSSVRTLTKLYLKDLEVYKI 6573361 SRNPSDKEKAKNRLSLVYSLID

GSKRNVFH TAARKKS LA SOLKIA Sequence 1227 Sequence 1227 from oatetit US 6573361 MAKNLSAiKRiKTSF.RNEI.rNRK 1466 from patent US YKSVVKTLTKRCLMNIENLENS 6573361 NI7NDVOLSTSQVYSKIDKAIKK

GAFHPNTGARKKARLARIFAYA OKOON

Sequence 123 from [3407634]Sequence 123 from patent US RRGLLEViRTVILPRRLLDRL 1467 patent US 5714577 5714577

Sequence 123 from Sequence 123 from patent US 6605698 RLEKARHGSCNYVFPAH CI 1468 patent US 6605698

Sequence 123 from patlUSI7314858| 123r i672468441Sequence VTPAMRTFALLTAMLLLVALA 1469 patent US 7314858 123 from patent US 73 14858 OAEPLO ARADE A AAOEOPGAD

DOEMAHAFTWHESAALPLSSD SARGLRCICGRRICRLLRRFGSC

AFRGTLHRlCCRACRiKKHKLRi

YFESKKFIXLLYLVLHFLFSSKI

NTLLODFSL

Sequence 1231 Sequence 1231 from patent US 6573361 MKTiTIPRQNLTQYEIMLiMRPD 1470 from patent US LPEEKFL LSEIKEHAKRNLAL 6573361 EFNLSNRGRRKLAYAMRKFQD

GIYIOFNFLGSG YlU SLI RL L EESILRYIVQKT

Sequence 1232 Sequence 1232 from patent US 6573361 MQV1TLQKPSKJGTYRTTY1LKP 1471 from patent US SLTEEEFfKEIEDYO LLID GA 6573361 EDniE TGKCRLAYLINKQNDG

IYFOITYRGANTLVNILORRMRL SINTLRYOTFKV

Sequence 1233 Sequence 1233 from patent US 6573361 MSATKKYEMMILLTEEFNDSEL 1472 from patent US KTWAFNYAKALRKLSASEISVI 6573361 SRGKRDLSYYINNOK GNFIOi

FSSMPKYVD FS NLKFDSNV LRFLiLNK

Sequence 1234 Sequence 1234 from oatent US 6573361 MLQTKNSOEIKLNWYETVYLiK 1473 from patent U S SDLNEDRTLCilNEYKSMLTNG 6573361 GAK IiLOHRGRRHLSYSIKDYR

DGiYVOVNYEGNGKL.YOSFEKS LRFDENiiRYLTNKONKDNKIEG

Sequence 124 from [3407635]Sequence 124 from patent US YHRLRDLALIVTR1VELL 1474 patent US 5714577 5714577

Sequence 124 from Sequence 124 from patent US 6605698 LEKARHGSCNYVFPAHKCIC 1475 patent US 6605698

Sequence 125 from [3407636]Sequence 125 from patent US RRGLLRViRTViLALDiL 1476 patent US 5714577 5714577

Sequence 125 from Sequence 125 from patent US 6605698 EKARHGSCNYVFPAHKCiCY 1477 patent US 6605698

Sequence 125 from !pat!US!73 14858! 125[1672468451Seq«ence VTPAMRTTALLTAMLLLVALA 1478 paten! US 7314858 125 from patent US 7314858 OAEPLOARADEAAAOEOPGAD

DOEMAHAFTWHESAALPLSSD SARGLRCICGRGICRLLRRFGSC

AFRGTLHRlCCRACRiKKHKLRi

YFESKKFLLLLYLVLHFLFSSKI

NTLLODFSL Sequence 12.78 Sequence 1278 from patent US 6573361 SAVKYPELK1KLESYDSTLL 1493 from patent US DLTIKKIVEVVKGV IKIKGPLP 6573361 LPTKKEVITIi SPHVDKA S EOF

EKN HKRLMII.VDVNOGGIDSL KKIKIPVGVTLRF S

Sequence 1279 Sequence 1279 from patent US 657336 i MAGOKIRIRLKAYDHEAIDASA 1492 from patent US RKTVETWRTGANWOPVPLPT

6573361 EKI YCVIRSPH YKDSREHFE

MRTHKRLIDILDPTPKTVDALM RIDLPASVDV IO

Sequence 128 from f34076391Seq«ence 128 from patent US RRGLLEVIRTVILALDRL 3493 patent US 5714577 5714577

Sequence 128 from pat!US!73148581128[ i67246848ll}equenee GICRCICGKR1CRC1CGR 1494 patent US 7314858 128 from patent US 7314858

Sequence 1280 Sequence 1280 from patens US 6573361 M AANAVKYPEL JKLESYDST 1495 fro patent US ULDLTTKKIVEWKGVDVKIKG 657336 ! PLPLPTKKEVrnTR SPHVDKASR

EOFEKNRHKRLMiLVDV OGAI DSLKRIKIPVGVTLRFSK

Sequence 1.283 Sequence 1281 from patent US 6573361 MAGGKiRlRLKAYDHEAIDASA 3496 from patent US R iVETWRTGASWGPVPLPT 6573361 E VYCViRSPHKYKDSREHFE

MRTHKRLiDllDPTPKTVDAL

RiDLPA S VD VNiO

Sequence 1282 Sequence 1282 from patent US 657336 i MOTOKIRiRL AYDYALlDRSA 1497 from patent US QEiVETAKRTGAW GPlPLPTK 657336 i IERF ILRSPH N TSREOLE1RT

HLRLMDIVDWTDKTTDALMKL DLPA.GVDVETKVQ

Sequence 1 283 Sequence 1283 from patent US 6573361 MAGOKIRIRLKAYDHEVIDSSA 3498 from patent US KKIVETVTRTGA VAGPVPLPT 6573361 EK ⁷YCViRSPHNDKDSREHFE

MRTHKRLiDiiDPTPKTVDSLMR LDLPAGVDIS1KL

Sequence 1284 Sequence 3284 from patent US 657336 i MOK AR1KTA STNVR SLDE VANO 1499 from patent U S IKO AERTGVRMSGPIPLPTKRIR 6573361 ITTRKSPDGEGSATFDRWELRV

HKRL1DIEADERAMRQ1MR1RVP EDVTIEIELIS

Sequence 1286 Sequence 1286 from patent US 6573361 MK K1KIRLKSFDHRSLDOATK 3500 from patent US EIVSAVKRTFATINGPiPLPRKiE 6573361 RFTVNRSPHVH K SREQFEIR

HKRLLVIDDPNPAVVDALSKVD LAAGVDWIELESGE

Sequence 1287 Sequence 3.287 from patent US 6573361 MATIQQGKIRIRLKAFDRRLLDT 1501 from patent U S SCE 1VDTANRTGATALGP1PLP 6573361 TKRRIYCVLRSPHVDKDSREHF

ETRTHRRIIDIYOPSS TIDALM KLDLPAGVDIEVKL Sequence 1288 Sequence 1288 from n-atent US 6573361 MANK IRiRLKAYEHRTLDTAA 1 02 from patent US EKIVETATRTGASVAGPVPLPTE 6573361 RSI.YTVIRATHKYKDSREOFEM

RTHKRLroiVNPTO TVDALMK LDLPSGV VEIKL

Sequence 1289 Sequence 1289 from patent US 657336 i MPTK ARIRLWS SNID SENF VVN 1503 from patent US OIRNMAOKTGIOVSGPIPLPTTR 6573361 MEVPVMRLPHGEGKKKWEHW

EMKVHKRilDIAADERVMROl.

MRVRWDDVYFEIELI

Sequence 129 from f3407640]Seq«ence 129 from patent US YHRLRDLLLIVCRTVELL 1 04 patent US 5714577 5714577

Sequence 129 from Sequence 129 from patent US 6605698 C1CYFP 1505 patent US 6605698

Sequence 129 from !pat!US!73 148581129ri672468491Sequence GICRCICGKKICRCICGR 1506 patent US 7314858 129 from patent US 7314858

Sequence 1290 Sequence 1290 from patent US 6573361 MPTKARiRLWST VENLNYVn^' 1507 from patent US OlRGiVEKTGIEMRGPiPLPTS L 6573361 EVPIMRLPHGEGRKKWEKWEM

RVHKRLID1AADERV ROLMR

VRVPEDVYIEIOLI

Sequence 1291 Sequence 1291 from oatent US 6573361 MATLOOOKIRiRLKAFDRRLLD 1508 from patent US TSCDKIVDTANRTNAAAVGPIP 6573361 LPTKRKIYCVLRSPHVDKDSRE

HFETRTFiRRIIDiYOPSS TiDAL MKLDLPAGVDIEVKL

Sequence 1292 Sequence 1292 from patent US 6573361 MVSYKAMSLSGTEHRVVDRVC 1509 from patent US NEIKEIASRTGVEIHGPMPLPTK 6573361 RLWPVRKSPDGEGTNTWDHW

EMRIHKRLIDVDADERTLROLM

RiPIPDGVOlElOI S

Sequence 1293 Sequence 1293 from patent US 6573361 MPGOKIRIKLKAYDHELLDE S A 1510 from patent US K IVEVA STNS VSGPiPLPTE 6573361 RTLYCVLRSPMKHKDSREHFEK

RVHKRETDIIDPSPKTIDALMRT LPAGVDVEIKL

Sequence 1294 Sequence 1294 from patens US 6573361 PKIRIKLRGFDHKTLDASAOKTV 151 1 frosri patent US EAARRSGAOVSGPIPLPTRVRRF 6573361 T\TRGPFKHKDSREHFELRTHN

RLVDHNP RKTIEOL TLDLPT

GVEIEIKTVGGGR

Sequence 1295 Sequence 1295 from oatetit US 6573361 KEOKIRVKLKAFDIELIDOSA 1512 from patent US OSIVASVKKTGARVSGPIPLPTST 6573361 R VTVIR .SPHVNIKSREOFEMRI

Y RLiDIFDVTPOTTESLKKLAL PAGVDVOLK

Sequence 13 from pat!US!55191 i 5| 131 i 6102391Sequence 13 RPGGOIAIAIGESIRKKA S ELK 1513 patent US 5519115 from patent US 5 19115 KATKSLWS

Sequence 13 from patlUSi5607914| 13r2096793]Sequence 13 AIAXFAK ALKSMLALMGEAV 1514 patent US 5607914 from patent US 5607914 Q SequenceJl from i34075241Sequence 13 from patent US RvTSWOGACRAIRRIPRRIR 1515 patent US 5714577 5714577

Sequence 13 from [4001473 ISequence 13 from patent US RHPOYNOR 1516 patent US 5798336 5798336

Sequence 13 from patlUSI5856127| 1.3i59388921Sequence 13 N1AARAAGI.AARLAALA1RAL 1517

from.Bitot yS 85 L27

Sequence 13 from pal! S!6191254| 13i l41 19961 ISequence 13 ILPWfCP RPSKA 1518 patent US 6191254 from patent US 6191254

Sequence 13 from pat|US|6492328| 13[29695223]Sequence l3 KNLRRIERKilHIIK YG 1519 patent US 6492328 from patent US 6492328

Sequence 13 from Sequence 13 from patent US 6605698 FPAHKC1CY 1520 patent US 6605698

Sequence 13 from pat!US!6638531 i 13 [4 163859] Sequence 1 YGRHSHHKEHFKR .C 1521 patent US 663853 1 from patent US 663853 1

Sequence 13 from pai! S!6730659! 13^"[53923^"i8 i |Sequence 13 RHFCGGAL1HARFVMTAARC 1522 patent US 6730659 from patent US 6730659

Sequej ;e j_,3_,from Sequence 13 from patent US 6743598 LFHLSVDNEHRGOGIA ALV J 523 patent US 6743598

Se uenc e 1 iron; patiUS!6743769| 13 Γ53 34470 ISequence 13 ALYKRLFKKLKKF 1524 patent US 6743769 from patent US 6743769

»¾£e l3 frpm Sequence 13 from patent US 6790833 RKSY ALHKRAR 152.5 patent US 6790833

Sequence 13 from paiiUS;683553^"6j i3l59753998iSequence 13 ILK FPWFPWRRK 1526 imtent US .6835536 from patent US 6835536

Sequence 1.3 from pat|US|6835713| 13[597559511Sequence l3 RVTEWOGACRAIRHIPRRIROG 1527 patent US 6835713 from patent US 6835713 LER1L

»¾&e l3_frpm pat!US!6838435i l3[59761430]Sequence 13 AELRCMCI TTSGFHPKNIOSLE 1528 patent US 6838435 from patent US 6838435 ViG GTHCNOVEVIATLKDGR

ICLDPOAPRIKKROK EAGDES AD

Sequence 13 from pai!US!6872705i i3T62788252jSequence 13 WKLFKKIGIGAVLKVLTTGLP 1529 patent US 6872705 from patent US 6872705 ALIX

Sequence 13 from pat|0s|6966035| 13|74472296iSequence 13 KKKSFIKLLTSAKVSVLTTAKPL 1530 patent US 6906035 from patent US 6906035 ISS

Sequence 13 from !pat!U SI 709 ϊ Ϊ 85 ! 13 [ ϊ Ϊ5794 Ϊ94 [Sequence 13 AKKFAKKFA KFA KFAKKFA 1531 patent US 7091185 from patent US 7091185 K F

!patiUS!7314858i l3[1672467391Sequence 13 MRIIALLAAILLVALOVRAGPLO 1532 patent US 7314858 from patent US 7314858 ARGDEAPGOEORGPEDODISISF

AWDKSSALOVSGSTRGMVCSC

RL VF CRRTELRVGN CLIGGV SF TYCCTRVD

Sequence 130 from 13407641 ISequence 130 from patent US YHRLRDLLLIVCRIVELLGRR 1533 patent US 5714577 5714577

Sequence 130 from Sequence 130 from patent US 6605698 ICYFPC J M patent US 6605698

Sequence 130 from patiijS!73 Ϊ 4858| 130f 167246850iSeqi[ence GiCRCiCGRKlCRClCGR 1535 patent US 7314858 130 from patent US 7314858

Sequence 13 1 from [3407642 jSequence 13 1 from patent US YHRERDLLLR^'TRIVELLGRR 1536

B en!lLS .5714577 5714577

Sequence 131 from Sequence 131 from patent US 6605698 VFPAHKCICYFP 1537 patent US 6605698

Sequence 131 from patlUS!7 1485Sj 131 Γ 167246851 ISequence GICRCICGRRICKC1CGR JUS patent US 7314858 131 from patent US 73 14858 Sequence 132 from [34076431Sequence 132 from patent US RRGLLEVIRCVILLLDRL 3 539 patent US 5714577 5714577

Sequence 132 from Sequence 132 from patent US 6605698 FPAHKCICYFPC 1540 patent US 6605698

Sequence 132 from !pa!iUS!73 34858! 132[1672468521Seq«ence GIC CICGRRIC CICGR 1541 paten! US 7314858 132 from patent US 7314858

Sequence 133 from j 3407644 ISequence 133 from patent US RRGLLRVIRTVILLLDRL 1542 patent US 5714577 5714577

Sequence 133 from Sequence 133 from patent US 6605698 OKLCOR 1 43 patent US 6605698

Sequence 133 from pat|tJS|73148581133[ i672468531Sequenee GICRCICGRRICRCICGK 1544 patent US 7314858 133 from patent US 7314858

Sequence 134 from |3407645]8equence 134 from patent US RRGLLEVIRTVILLLRRL 1545 patent US 5714577 5714577

Sequence 134 from Sequence 134 from patent US 6605698 KLCORP 1546 patent US 6605698

Sequence 134 from patlUS!7314S58| 134 1672468541Sequence GVCRCICGRGVCRCTCRR 1 47 patent US 7314858 134 from patent US 73 14858

Sequence 135 from [34Q7646]Sequence 135 from patent US RRGLLEVIRCViLLLDRLRHY 1548 patent US 5714577 5714577

Sequence 135 from Sequence 135 from patent US 6605698 LCORPS 1549 patent US 6605698

Sequence 135 from ipat!USi73 4858i i35f^L167246855 Sequence GVCRCICGRGVCRCICGR 1550 paten! US 7314858 135 from paten! US 7314858

Sequence 1.36 from | 3407647]Sequcnce 136 from patent US RRGLLRVIRTVILLLDRLRHY 1551 patent US 5714577 5714577

Sequence 136 from Sequence 136 from patent US 6605698 OKLCORPSG 1552 patent US 6605698

Sequence 136 from pai|US!7314858j 136[ 167246856]Sequence RXICGXXrC 1553 patent US 7314858 136 from patent US 7314858

Sequence 137 from [3407648]Sequence 137 from paten! US RRGLLEVIRTVILLLRRLRHY 1554 paten! US 5714577 5714577

Sequence 137 from Sequence 137 from patent US 6605698 KLCORPSGT 1555 patent US 6605698

Sequence 137 from !pat|US!73148581137f l67246857 Seq«ence GICYC1CGKGICRCICGR 1556 patent US 7314858 137 from patent US 7314858

Sequence 138 from f3407649]Sequenee 138 from patent US YHKLKLLLiVTKiVELLG K 1557 patent US 5714577 5714577

Sequence 138 from Sequence 138 from patent US 6605698 LCORPSGTW 1558 paten! US 6605698

Sequence 1 38 from pat|USI7314858| 138r i672468581Seauence ( i K ( ( K GR 1559 patent US 7314858 138 from patent US 7334858

Sequence 1381 Sequence 1381 from patent US 6573361 MAKKSMH O RTPKFXVRAYT 1560 from paten! US RCERCGRPHSVYRKFKLCRTCF 6573361 RELAY GOLPGIKKASW

Sequence 1382 Sequence 1382 from patent US 6573361 AKXSMiA OORTPKFKVOEYT 1561 from patent U S RCERCGRPHSVIRKFKLCR1CFR 6573361 EL AY GOIPG VKKAS W

Sequence 1386 Sequence 1386 from patent US 6573361 AKOSMKAREVKRVALADKYFA 1562 from patent US RAELKATISDVNASDEDR WN A 6573361 VLKL0TLPRDSSPSR0R RCR.0

TGRPHGFLRKFGLSRI VREAA MRGEIPGLKKASW Sequence 1387 Sequence 1387 from patent US 6573361 AKOSMKARDVKRVKLAEKFYA 1 63 from patent US KRVEL KIISDWASDEDRWDA 6573361 VLKLOTLPRDS SP SRORNRCRO

TGRPHGVLRKFGLSRIKVREAA MRGEIPGLKKASW

Sequence 1388 Sequence 1388 from patent US 657336 i MAKKSMiA AORKPKFOVRAT 1564 from pat nt US TR ICGRPHSVYRDFGLCRVC 6573361 LRKMGSEGLJPGLRKASW

Sequence 139 from [3407650IS¾uesKe_.I39 ELIRQLIRQLLI^' QPjLQYILQ 1565 patent US 5714577 5714577

Sequence 1 39 from Sequence 139 from patent US 6605698 OKLCORPSGTWS 1 66 patent US 6605698

Sequence 139 from pat!USl731485§i ί39[ϊ 67246859]Sequence RYlCRClCGRGICRCiCG 1567 patent US 7314858 139 from patent US 7314858

Sequence 1392 Sequence 3392 from patent US 657336 i MAKKPWKKKYGYGIRPCORCG 1568 from patent US HVGPGLIRKYGLNLCROCFREI 657336 Ϊ AHKLGFK LD

Sequence 1393 Sequence 1393 from patent US 6573361 MIVLPRKYGKASRKC SRCGDH S 1569 from patent US ALVRRYGLMLCROCFRELAPKI 6573361 GFKKYN

Sequence 1394 Sequence 1394 from patent US 6573361 MTKEPFKT YGOGSKVCKRCG 1570 from patent US R GPGIIRKYGLDLCROCFREL 6573361 APKLGFKKYD

Sequence 1 395 Sequence 1395 from patent US 6573361 MAKKSLKVKDAKHPKFJWRNY 1571 from patent US TRC HCGRPHAVLKKFGICRLC 6573361 FR FAYEGOIPGI KAS

Sequence 1396 Sequence 1396 from patent US 6573361 MA KSLKVKOSRP KI-^'SVRDY 1572 from patent US TRCLRCGRARAVLSHFGVCRLC 6573361 FRELAYAGAJPGVKKASW

Sequence 1397 Sequence 3397 from patent US 657336 i MAKKALVNK AA RKP FT VRGY 1573 from patent US TRCS CGRPRAVFRKFGLCRIC 6573361 LREMAHAGELPGVOKSSW

Sequence 1398 Sequence 1398 from patent US 657336 ί MAKKSL VKOTR PKFAVRAY 1574 frosri patent US TRCORCGRARAVLSHFGVCRL 6573361 CFREL AYA GAIPGV KA S W

Sequence 14 from pat!US!5519i 15| i4] l^"6i 0240]Sequence 14 KAIQTAQGVVAVAPGAKHGDR 1575 paten! US 5519115 from patent US 5519115 1NQG \T E1KKFLKWK

Sequence 14 from pat|L^TS!5607 14| 14|^"2b%794iSequence 14 AIAIFKRIAKINFKALMGEAVOT 1576 patent US 5607914 from patent US 5607914

Sequence 14 from pat!US!5821224j 14[60046061Sequence 14 YCXX XGHCHP RCPGXXRO G 1577 patent US 5821224 from patent US 5821224 TCHGZXHKCCR

Sequence 14 from pat !US ! 5856127| 14 Γ59388931 S equ ence 14 SRA AGFA ARLARI.AL 1 78 patent US 5856127 from patent US 5856127

Sequence 14 from pat|US|619i254| i4i i4119962iSequence 14 IVPW WTLWPWRR 1579 patent US 6191254 from patent US 6191254

Sequence 14 from pat!US!621 1148| 14Γ 1 1083401Sequence 14 XCXXNXGXCXPlRCPGXXROiG 1580 patent US 6211 148 from patent US 621 1 148 TCXGXXXLCCR

Sequence 14 from Sequence 14 from patent US 6329504 ATCE LANTYRGPCFGGCDFHC 158 1 patent US 6329504 KTKEHLLSGRCRDDFRC

Sequence 14 from pai!US!6492328i 14Γ29695224 jSequeuce 14 NLRRIDRKIIHIIKKYG 1582 patent US 6492328 from patent US 6492328 Sequence 14 from Sequence 14 from patent US 6605698 PAH CICYF 1 83 patent US 6605698

Sequence 14 from patiUSi6730659j Ϊ4Γ53 231821Sequence 14 RHFCGGALIHARFVMTAAKC 1584 patent US 6730659 from patent US 6730659

Sequence 14 from Sequence 34 from patent US 6743598 OL S AMGLYOSLGF 1585 paten! US 6743598

Sequence 14 from patjlj S 16743769114? 5393447 ί j Sequence 14 ATKKNG KLCLDLQAAL 1586 patent US 6743769 from patent US 6743769

Sequence 14 from patiUS!6747007| 14[53937639]Sequence 14 WCFXVCXRGXCRXKCRR 1587 patent US 6747007 from patent US 6747007

Sequence 14 from patiOSi6835536| i4i597540O6{Sequence 14 1LKKFPFWP RRK 1588 patent US 6835536 from patent US 6835536

Sequence 14 from patiUS!6838435j 14i597614321Sequence 14 MAELRCMClKTTSGiHPK IOSL 1589 patent US 6838435 from patent US 6838435 EViGKGTHCNOVEVIATLKDGR

JCLDPDAPRJKKFSOK LAGDE S

Sequence 14 from pat! S!6872705| Ϊ4[62788253Sequence 14 KWKGIGAVLKVLTTGX 1590 patent US 6872705 from patent US 6872705

Sequence 14 from patlUSi6906035| 14[744722971Sequence 14 KWK FIKELOKVL PGGLLSNI 1 91 patent US 6906035 from patent US 6906035 VTSL

Sequence 14 from !pat!US!7071293! l 4N 120627081Sequence 14 IR TIRKIIHIIKK 1 92 patent US 7071293 from patent US 7071293

Sequence 14 from ipatiij Si 709 ϊ 185 ! 14 [ 115794 Ϊ96 [Sequence Ϊ 4 Κ ΓΛΚ 1 \KK ; Κ ΗΛ Γ Λ 1593 patent US 7091185 from patent US 7091185 KFA

Sequence 140 from [340765 USequence 140 from patent US FL1ROL1RLLT LFSNCRTLLSE 1594 patent US 5714577 5714577 VY

Sequence 140 from Sequence 140 from patent US 6605698 LCORPSGTWSG 1595 patent US 6605698

Sequence 140 from ipat!US!7314858! 140N 67246860]Seqtience GICRCICGRRICRCICGR 1596 patent US 7314858 140 from patent US 73 14858

Sequence 1403 Sequence 1403 from patent US 6573361 MAK AMV ERDRKRKKLVE Y 1597 from patent U S AAKREALKEOFAAATSOSERLE 6573361 LHRKLOOLPRNSAPNRVRJS1RC

WVTGRPRGYYRDFGLCR VLR EMAHOGLLPGV VKS S W

Sequence 1404 Sequence 1404 from patent US 6573361 MAK SMIERDKRRSRL VAKYA 1598 from patent US A REALKEEFRQAETLED LAV 6573361 HOKLODLPR S APN RRRNRCO

VTGRPRSYYRDFGLCRNVLRE WAHOGLLPGVTKSSW

Sequence 1405 Sequence 1405 from patent US 6573361 ARKAL1EKAKRTPKFKVRAYTR 1599 from patent U S C VRCGRARS V YRFFGLCR1CLR 6573361 ELAHKGOLPGVR ASW

Sequence 1408 Sequence 1408 from patent US 657336 i ALTOERKREliEOFKVHENDTGS 1600 from patent US PEVOIAILTEOINNLNEHLRVHK 6573361 KDHHSRRGLLKMVGK.RRRLLA

YLRNKDVARYREIVE LGLRR

Sequence 1409 Sequence 1409 from patent US 6573361 ATTOERKNOLINEFKTHESDTGS 1601 from patent U S PEVOIAILTDSINNLNEHLRTHK 6573361 DHHSRRGLLKMVGKRRNLLT

YLRNKDVTRYRELr KLGLRR

Sequence 141 from [3407652]Sequence 141 from patent US FLIROLIRLLTWLFSNCRTLL 1602 patent US 5714577 5714577

Sequence 141 from Sequence 141 from patent US 6605698 LCQRPSGTWSGV 1603 patent US 6605698

Sequence 1410 Sequence 1410 from patent US 6573361 MALDSAKKAE1VA FAKKPGD 1604 from patent US TGSTEVOVALLTARIAELTEHL 6573361 KIYK DFSSRLGLLKLVGO K

LLSYLKRKDYNSYSKLITELNL

RDK

Sequence 141 1 Sequence 141 1 from patent US 657336 i SLSTEATAKIVSEFGRDA DTGS 1605 from patent US TEVOVALLTAOINHLOGHFAEH 65733 i KKDHHSRRGLLRMVSORRKLL

DYLKRKDVARYTOL1ERLGLRR

Sequence 1412 Sequence 1412 from patent US 6573361 SLSTE KAAIVAEFGRDAKDTG 1606 from patent U S SSi A Q! Xl ! i AiMN! H ⁽^ ΓΠ ί Α ί ί 6573361 KDHHGRRGLLRMVSRRRKLL

DYLKRTDLALYQSTIARLGLRR

Sequence 1.413 Sequence 1413 from patent US 6573361 MAL LEKKOE1IKAFATKE DT 1607 from patent US G -SCEVOVALL ERIKLLTEHLK 6573361 ANPKDHSSRLGLLKLVAORR.NL

LKYIKRTNFLARY'Y'TLIEKLGIK

DR

Sequence 1416 Sequence 1416 from patent US 6573361 MiTKAKKAEllTRl'GKSEKNTGD 1608 from patent U S ISVOIALLPEDIEKLKLHFE NK 6573361 KDKHSMRGF1AKVNKRK LLN

YLKEKNFASYKETIEALNIRK

Sequence 1417 Sequence 1417 from oatent US 6573361 MKJDKEOIIIOVFIOLHi NDVGSV 1609 from patent US OVOISILTDOIKKLTDHLLANKK 6573361 DFISKRGLYTTCVSKRKRLLKYL

KERN1ETYRDL1KNLNLRG

Sequence 1418 Sequence 1418 from patent US 6573361 MISKARKOEHLKFGKNPKNTG 1610 from patent US TSVOTALLTEDTERLKLHFLKN 6573361 KKDKHSMRGFIAKVNKRKKLL

YLRIN SFDTYKETIE ALN1RK

Sequence 1419 Sequence 1419 from patent US 6573361 M ALTSEO KEILS S Y GLH ATDT 1611 from patent US GSPEAOIALLTKRIADLTEHLKV 6573361 HKHDHHSRRGLLLLVGRRRRLI

KYLSLIDVORYRSLIERLGLRR

Sequence 142 from [3407653]Sequence 142 from patent US LLTRCNSFLWTLLRILORILF 1612 patent US 5714577 5714577

Sequence 1420 Sequence 1420 from patent US 6573361 MQIDKNGIIKSAQLHDKDVGSI 1613 from patent US QVQVSLLTSQIKQLTDHLLANK 6573361 KDFISKRG LYAKV SKRKRLLKY

LKHNDLEAYRNLVKTLNLRG

Sequence 1421 Sequence 1421 from patent US 6573361 MALTAEQKKEILRSYGLHETDT 1614 from patent US GSPEAOIALLTKRIADLTEHLKV 6573361 HKHDHHSRRGLLLLVGRRRRLI

KYISOIDVERYRSLIERLGLRR

Sequence 1423 Sequence 1423 from patent US 657336 i SLSTEAKAOIIAEFGRDANDSGS 1615 from patent US SEVOVALLTAOINHLOGHFSEH 657336 i KKDHHSRRGLLRMVSORRKLL

DYLKRKNVTSYTALIGRLGLRR Sequence 1425 Sequence 1425 from patent US 6573361 SLTOI KOELMTEYOAHETDT 1616 from patent US GSADLOVAFLTERTTOLTGHLK 6573361 ANPKDHASRRGLLKMIGRRKR

LLSFINAREPERYOALIKRLG1R R

Sequence 1426 Sequence 1426 from patent US 6573361 PiTKEEKQKVlOEFARFPGDTGS 1617 from patent U S TEVOVALLTLRINRLSEHLKVH 6573361 KKDHHSHRGLLMMVGQRRRLL

RYLOREDPERYRAL1EKLGIRG

Sequence 143 from [3407654]Sequence 143 from patent US FLIROLIRLLT LFPNCRTLLSR 1618 patent US 5714577 5714577 VY

Sequence 1430 Sequence 1430 from patent US 6573361 SLSVEAKAKIVADFGRDA DTG 1619 from patent US SSEVOVALLTA01NHLOGHFSE 6573361 HKKDHHSRRGLLRMVSTRRKL

LDYLK KDVASYVSLIERLGLR R

Sequence 1432 Sequence 1432 from patent US 6573361 AVKTRLKRMGAKKSPF YRiVVA 1 20 from patent US DSRSPRDGRFTETVXTTYNPVAK 6573361 PAEVKiDEELAL WLOTGAKPS

DTVRNLFSSOGIMEKFHNAKOG

Sequence 1434 Sequence 1434 from patent US 6573361 VTIRLARHGAKKRPFYOVVV 1621 from patent US ADSRNARNGRFIERVGFFNPIAS 6573361 EKEEGTRLDLDRIAHWVGOGA

TISDR.VAALIKEVN AA

Sequence 1437 Sequence 1437 from patent US 6573361 MVTIRLSRGGAKKRPFY01WA 3622 from patent US DSRSPRDGRFTERVGFFNPIAOG 6573361 NAERLRINLER .VNHWVAOGA S

LSDRVASLVKEAOKAA

Sequence 1438 Sequence 1438 from patent US 6573361 MTVIiiLTRlGRKK PFYR\^rVVT 1623 from patent US DSRKRRDGGWIESIGYYNPLSE 6573361 PK L! 1 l DK.ERL >· Y \\ ΙΟΛ GAK 1

SERVEKLSOKA

Sequence 144 from [3407655]Sequence 144 from patent US WRSELTRCNSFIAVTLLRILORI 1624 patent US 5714577 5714577 LF

Sequence 1442 Sequence 1442 from patent US 6573361 MliMGRVHYPLYRIVAVDSRVK 1625 from patent US RNGKYTALIGHLNPALKE KCK 6573361 LDETVALDWLNKGAIPTDTVRS

LFSESGLWKKFIES NK ETSPK K

Sequence 1444 Sequence 1444 from patent US 6573361 MRMGRVHYPTYRIVAVDSRVK 1626 from patent U S RDGKYIAL GHLNPAL E CK 6573361 IDEA VALE WLNKGAKPTDTVRS

LFSOTGLW KFVES KKPVAKS K

Sequence 1447 Sequence 3447 from patent US 6573361 MVTIRL ARHG AKKRPFYOVW 1627 from patent US TDSRNARNGRFIERVGFFNPIAS 6573361 EKEEGTRLDLDRIAHWVGOGA

TISDRVAALIKEVKKAA Sequence 1448 Sequence 1448 from patent US 6573361 IKLRLKRFGKKREVSYRIVA M 1 628 from patent US HSTTRRIXJRPLEELGFYNPRTD 6573361 ETRLDVPATVKRLKEGAOPTDT

VRSILTKAOVFEOL A

Sequence 1449 Sequence 1449 from patent US 6573361 TDK1RSVQGRVVSDKMEKSFW 1 29 from patent US A1ERKVKHPLYGKFIRR.TT LH 6573361 VHDENNEAKLGDLVEVRECRPI

SKTKSWTLVRVVEKAVIA

Sequence 145 from [3407656]Sequence 145 from patent US FLIKQLIKLLTWLFSNCKTLLSK 1 630 patent US 5714577 5714577 VY

Sequence 1450 Sequence 1450 from patent US 6573361 MTD V1RTLOGRV VSHKMEK S1V 163 1 from patent U S VAIERTVKHPIYGKFIKRTTKLH 6573361 VHDENNECG1GDVVE1RECRPL

SKTKSWTLVRVVD AIL

Sequence 1451 Sequence 1451 from patent US 6573361 SERNORKVWGRWSDKMDKT 1632 from patent US ITVLVETYKKHPLYGKRVKYSK 6573361 KYKAHDEHNE AKVGDTVKI E

TRPLSATKRFRLVEiVEKAWL

Sequence 1.452 Sequence 1452 from patent US 6573361 SERNORKVYQGRWSDKMDK.T 1 33 from patent US ITV^VETYKKHTLYGKRVKYS 6573361 KKFKAHDENNQAKIGDIVKJME

TRPLSATKRFRLVEVVEEAVII

Sequence 1454 Sequence 1454 from patent US 6573361 MASDVRGRRKTKIGVWSSKM 1 634 from patent US EKTVWRVERVYSHPOYAXVV 6573361 RDSSKYYAH ELDVKEGDTVRI

OETRPLSKTKRWRVVGRVN

Sequence 1458 Sequence 1 458 from patent US 657336 1 TDKIRTLQGRWSDKMEKSI 1635 from patent US AIERFVKHPIYGKFIKRTTKLHV 657336 1 HDENNECGIGDWEIRECRPLS

KTKSWTLVRWEKAVL

Sequence 1459 Sequence 1 459 from patent US 65733 1 TDKIRSVOGKVVSDKMEKSFV 1636 from patent US VAIERKVKHPLYGKF1RRTTKL 657336 S HVHDENNEAKVGDTVEIRECRP

LSKTKSWTLVRWEK VI

Sequence 146 from [3407657]Sequence 146 from patent US RLVERIROLTASRQLlPQLiOYV 1637 patent US 5714577 5714577

Sequence 1460 Sequence 1 460 from patent US 65733 1 M.NTKEPHKRLVQGKV1SKFAEK 1638 from patent US SAV1LVERKWHEKYRK1VKKF 6573361 KKYTIHDENNQVKVGDFVSAIE

CRPLSKTKSFTLKE1LWGV

Sequence 1466 Sequence 1 466 from patent US 6573361 MQRNSRRVL1GKVVSDKMDKT 1639 from patent US ITVLVETYKNHPIYKKRVKYSK 6573361 KYKAHDENQVAQMGDKVE1M

ETRPLSKTKNFRLVRVIEKATL

Sequence 1467 Sequence 1467 from oatent US 6573361 MKRNQRKQLIGTWSTKNAKT 1640 from patent US ATVKVTSRFKHPLYI-IKSVIRHK 6573361 KYHVHNFGEXYANDGDRVOIIE

TRPLSALKRWRIVKIIERAK Sequence 1469 Sequence 1469 from patent US 6573361 M RNORKVLIGIV ST NAKTA 1641 from patent US TVOVESRFKHPLYHKSWRH

6573361 KYOAH EGEVLAKDGDKVOIV

ETRPLSATKRFRTAKI1ERAK

Sequence 147 from | 3407658]Sequcnce 147 from patent US RLVRRTROLTASROLIPOLTOYV 1 42 patent US 5714577 5714577

Sequence 1472 Sequence 1472 from patent US 6573361 MEKN SR VLOGRViSD LK TI 1643 from patent US TVLVETYKNHPLYKKRVKYSK 6573361 KYLAHDEQNQAHIGDKVSIMET

RPLS T HFRLiEViEKAlG

Sequence 1473 Sequence 1473 from patent US 6573361 MAWERVGVWSDKMDKTVV 1644 from patent US VAIEDRTAHPKYGKTWRTKRY 6573361 KAHDED RAKTGDRVRIOETRP

LSRTKR WT VAEILESVGA

Sequence 1474 Sequence 1474 from patent US 6573361 MAiKERVGrVVSNKMDKTVVV 1645 from patent US AVESRSPHPKYGKIVVKTKKF 6573361 AHDEENQCQEGDKVRIQETRPL

SKTKRWQVINIMSHSS

Sequence 1478 Sequence 1478 from patent US 6573361 AGRKGGRGKRRKVCYFTAN I 1646 from patent US THIDYKDVDLLKKFISERGKILP 6573361 RRVTGTSAKYORKLTVAiKIi.AR

OMALLPYVADE

Sequence 1479 Sequence 3479 from patent US 657336 ' AGGRRGGRA RRKVCYFTSNG 1647 from patent US THIDYKDVDLLKKFVSERGKiL 657336 i PRRVTGTNAKYOR .LT AA.1KRA

ROMALLPYVSGE

Sequence 148 from f3407659]Sequenee 148 from patent US LLSRVYOILOPILORLSATLOAI 1648 patent US 5714577 5714577 REVL

Sequence 1481 Sequence 1481 from patent US 6573361 MNRPVHNEHRRKRFAKKCPFV 1649 from patent US SAGWKTIDYKDVVTLKRFITER 6573361 GKILPRRITG VSSRFQALLAQA V

KRARHVGLLLS

Sequence 1483 Sequence 1483 from patent US 6573361 ARYFRRRKFCRFTAEGVOEIDY 1650 from patent US KDIATLKNYITESGKIVTSRITGT 6573361 RAKYQRQLARAIKRARYLSLLP

YTDRI-IQ

Sequence 1485 Sequence 1485 from patent US 65733 1 ARYFRRRKFCRFTAENVVE1DY 1651 from patent US KDIATLKNYISESGKTVPSR1TGT 6573361 RAKYOROLARAiKRARYLALLP

YTDNHO

Sequence 1486 Sequence 1486 from patent US 6573361 MERKRYSKRYCKYTEAKiSFlD 1652 from patent U S YKDLDMLKHTLSERYKIMPRRL 6573361 TGN SKKW OER VE VAIKRARHM

ALiPYlVDRKKVVDSPFKQH

Sequence 149 from [3407660]Sequence 149 from patent US LLSRVYOILOPILORLCATLORI 1653 patent US 5714577 5714577 REVLR.

Sequence 1490 Sequence 1490 from patent US 6573361 MAKSSKRRPAPEKPVKTRKCVF 1654 from patent US CAKKDOAlDYKDTALLRTYiSE 6573361 RGHRARRVTGNCVOFiORDIAL

AVKNAREVALLPFTSSVR Sequence 1491 Sequence 1491 from patent US 6573361 AROSFKRRKFCRFTAEKIOEV 1655 from patent US DYKOVDLLKDFTSENG IIPARI 6573361 TGTKAFYOROL AV AVKRARFL

ALLPYTDOHK

Sequence 1492 Sequence 1492 from patent US 6573361 M^"NYYRKRLSPLPP .⁾P1DYKDT 1 56 from patent US ELLRKFITERGKILPRRITGLTA 6573361 OORDLTTAVKRSRLVALLPFVN

KEI

Sequence 1494 Sequence 1494 from patent US 6573361 GRSLKKGPFCDEHLMKKIEKLN 1657 from patent US ETGQKQVI T SRRSTIFPQFVG 6573361 HTLAVYDGRRHVPVYiTEDMVG

HKLGEFAPTATFRGI-IAGDDKK

TKR

Sequence 1495 Sequence 1495 from patent US 6573361 ARSLK GPFVDGFILMTKiEKL 1658 from patent US ETDKKO KTWSRRSTIFPOFIG 6573361 HTiAVYDGRKI-IVPVFiSEDMVG

HKLGEFAPTRTY GHASDDK TRR

Sequence 1496 Sequence 3496 from patent US 65733 1 ARSTKKGPFIEKSLYOKVLSSF 1659 from patent US GSEKRWTKTYSRSST1IPEMVSL 657336 ? TISVYNAKTFTP1Y1TEDLVGHKL

GEFSPTRIFRGH A SDKKGRK

Sequence 1498 Sequence 1498 from patent US 6573361 PRSLKKGPF1DLHLL KVEKAV 1660 from patent U S ESGDKKPLRTWSRRSTIFPNMIG 6573361 LTIAVF1 GROHVPVFVTDEMV

GI-IKLGEFAPTRTYRGHAADKK AKK

Sequence 15 from patlUSI5519115| 15[ 1610241 jSequence 15 LAKLAVKAIKGAIAGAKSAMG 1661 patent US 5519115 from patent US 5519115

Sequence 1 5 from patiUSj5607914| 15f2096795!Sequence 15 AIANFERLMKKLIWALMGEAV 1662 patent US 5607 14 from patent US 5607914 QT

Sequence 15 from patjUS!6i91254j l5|^"141 !9963]Sequence 15 TLPCLWPWWPWSI 1663 patent US 6191254 from patent US 6191254

Sequence 15 from pat!US!6492328i 15129695225 jSequence 15 NLRRi AR Κ1ΙΗΠΚ YG 1664 patent US 6492328 from, patent US 6492328

Sequence 15 from Sequence 15 from patent US 6605698 AHKCICYFP 1665 patent US 6605698

Sequence 15 from pat!US!66385311151401 3861 ISequence 15 KRLF EL F SLRKY 1666 patent US 6638531 from patent US 6638531

Sequence 15 from patiUS!6642203j l5i40188732!Sequence 15 PXPXPXP 1667 patent US 6642203 from patent US 6642203

Sequence 15 from Sequence 15 from patent US 6653280 MAKFATTISLLFAALVLFAAFEA 1668 patent US 6653280 PTMVDARLCERPSGTWSGVCG

NNACR OCRNLERAEHGSCN YVFPAHKCICYFPC

Sequence 15 from pat!US!6730659 15[53923183JSequenee 15 QGRFiFSGGALiHARFVMTAA 1669 patent US 6730659 from patent US 6730659 HCFO

Sequence 15 from pat|TJS|6743769| iff 53934472^"|Sequence 15 RFE SKIK 1670 patent US 6743769 from patent US 6743769

Sequence 1 5 from pat!US!6747007i 15153937640]Sequence 15 XRWCFRVCYXGXCXXXCR 1671 patent US 6747007 from patent US 6747007

Sequence 15 from patiUS!6835536j l5[59754002]Sequence 15 ILRYVYYVYRRK 1672 Sequence 1511 Sequence 1511 from patent US 6573361 SR SAKKGAFVDAHLLKKVID 1687 from patent US MN OEKKRPIKTWSRRST1FPEF 6573361 VG TFA.VHNGKTFiNVYV' DD

MVGHKLGEFSPTIi FKOHTA

R

Sequence 1514 Sequence 1514 from patent US 6573361 MARSLKKGPFVADHLLRKVEK 1688 from patent U S LNAKGDKGVIKTWSRASTILPQ 6573361 MIGHTIAVHNGROHVPVYVTE

QM VGHKLGEFAPTRTFRGHTK DKKAGR

Sequence 1515 Sequence 1515 from patent US 6573361 MGR SLKKGPF VAASLLRKiDKL 1689 from patent US NDKGDKQVVKT W ^'SRASTILPQ 6573361 VGHTI AVHNGRQHVP VF V SE

QMVGH LGEFAPTRTFRSHS S

DKKARK

Sequence 1516 Sequence 3516 from patent US 6573361 MGRSR GPYVDRKLLEK1KKE 1690 from patent US

6573361 VGHGiAVYNGMKI-nPVYITE M

IGHRLGEFAPTRRFGGKADKKA KKGELKK

Sequence 152 from [3407663]Sequence 152 from pateni US RLLTWLFSNCRTLLSRVYQILOP 1691 paten! US 5714577 5714577 1L

Sequence 1526 Sequence 1 26 from patent US 6573361 PNIKSAiKRT TN ERGVFfNATi 1692 from patent U S SAMRTAIKQVEASVANNEAD 6573361 KAKTALTEAAKRIDKAM TGL

VHKISITAARYKSRLAKKVNGLS A

Sequence 1527 Sequence 1527 from patent US 657336 i MRKNA SALKR SRQNLKRKIRM 1693 from patent US VSVKSELKTIEKRCINMIKAGK 657336 i DEAIEFFKFVAKKLDTAAR R

liHK AARKKSREWLLLK

Sequence 1529 Sequence 1529 from patent US 6573361 ANIKSAKKRA10SE ARKHNAS 1694 from patent US RRSMMRTFI KVYAAIEAGDK 6573361 AAAQKAFNEMQPIVDRQAAKG

LlHK AARHKANLTAQiNKLA

Sequence 153 from [3407664]Sequence 153 from patent US RLLTWLFSNRRTLLSRVYOILO 1695 patent US 5714577 5714577 EIL

Sequence 1530 Sequence 1530 from pateni US 6573361 A IKSAKKRAVQSEKRRQHNA 1696 from patent US SQRSMM TYI¾WA^AAGE 6573361 SAAEAAFVEMQKWDRMAS

GLIHANKAA HKS EAAOiK KLA

Sequence 1 31 Sequence 1531 from patent US 6573361 MANHKSAE RIRQTIKRTERMR 1697 from patent US FYKTKD N1IKAVREAV AVNDV 6573361 A AOERLKiANKELHKFVS Gl

L NTASRKVSRL ASVKi IAL

A

Sequence 1 33 Sequence 1533 from patent US 6573361 MANIKSNEKRLRODiKRNLN 1698 from patent US GO TKLKTOVK FNKEINLDNL 6573361 SSVYSOADRLAR GilSL RA

REKS NAVILH SNTNSTAKKO Sequence 1534 Sequence 1534 from oatent US 6573361 MTNI SOO NRTNERARLR 1699 from patent US KSVKSSLRTAVRAFREAVHAGE

6573361 KEKAAKLLVSTSR I.D AAS

GViHKNOAAN SALARTL K L

Sequence 1535 Sequence 1535 from patent US 6573361 MANiKSNEKRLRQMKRNLNNK 1700 from patent US GO TKLKTNVKNFH EINLDNL 6573361 GNVY SOADRLARKGI1STNRA

RLKSRNVAVLNKTQVTAVEGK

Sequence 1537 Sequence 1537 from ratent US 6573361 MA TTSAKiCAFRKIARRSAVN 1701 from patent US KARRSRRSFVRKVEEAIASGDO

6573361 ALAAAALKAAOPELMRPATKG

VMHSNTASRKVSRLAORVKSL SA

Sequence 1538 Sequence 1538 from patent US 6573361 MANi SALKRlElAERNRLO KS 1702 from patent US YKSA1KTLMKKTFQSVEAYASD 6573361 PNPEKLDTINTSMAAAFS IDK

AVKCKV1H NNAARKKARLAK

ALOSALPAA

Sequence 154 from j 3407665 ISequence 154 from patent US RLLTWLRRTLLSRVYQILQEIL 1703 patent US 5714577 5714577

Sequence 1540 Sequence 1540 from oatetit US 6573361 MTOIWGENEHIESALRRFKRE 1704 from patent US VSKA GIFODMRKHRHFETPIEK

6573361 SKRKKLALHKOSKRRFRT

Sequence 1541 Sequence 1541 from patent US 6573361 SKTIVRKNESIDDALRRF RAVS 1705 from patent U S KTGTLOEVR REFYEKPSVRRK 6573361 KKSEAARKRK

Sequence 1542 Sequence 1542 from patent US 6573361 SKTWRKNESLEDALRRFKRSV 1706 from patent US SKTGTLOEARKREFYEKPSVKR

6573361 K XSEAARKRKF

Sequence 1543 Sequence 1543 from patent US 6573361 MTTILL E EPFEVAIRRFRRAI 1707 frosri patent US EKNGLIAELREROAYEKPTAVR

6573361 KRK AAAVKRLHKRLRSOMLP

KKLH

Sequence 1544 Sequence 1544 from patent US 65733 1 MONDACiOTVELYVPRKCSSSN 1708 from patent US RIIGPKDHASVOIDFVDVDPETG 657336 i RMIPGK STRYA1CGA1RRMGE S

DDAiLRLAOKDGLVPRDDVKS

N

Sequence 1545 Sequence 1545 from patent US 6573361 PVI VRE EPFDVALRRF RSCE 1709 from patent US AGVLAEVRRREFYEKPTTERK

6573361 RAKASAVKRHAKKLARENARR

TRLY

Sequence 1546 Sequence 1546 from patent US 6573361 PVIKVRENESFDVALRRFKRSCE 1710 from patent US KAGILAEVRAREFYEKPTTIRKR

6573361 EN ATL AKRHAKRNARENAR T

RLY

Sequence 1547 Sequence 1547 from patent US 6573361 MPGIKVREGDAFDEAYRRFK 171 1 from patent U S OTDRNL TECRARRFFES TE

6573361 R KOKISAKK VL RL YMLR

RYESRL Sequence 1548 Sequence 1548 from patent US 6573361 MONDAGEFVDL PRKCSASN 1712 from patent US RnGAKDHASIOM VAEVD VT

6573361 GRFNGOFKIYAICGAIRRMGES

DDSILRLAKADGIVSKNF

Sequence 1549 Sequence 1549 from patent US 6573361 MQNEEG TVDLYVPRKCSATN 1713 from patent US RiiTAKDHA SVQT IGHLDANGL 6573361 YDGHFTTFALSGFVRAQGDADS

SLDRLWO K A FJKQ

Sequence 155 from [3407666]Sequence 155 from patent US RIAGYGLRGLAVURCIIRGLNLI 1714 patent US 5714577 5714577 FEI1R

Sequence 1550 Sequence 1550 from patent US 6573361 MPG1RVKEGES1ESALKRF KAT 1715 from patent U S EKAGILSE1RKREHYEKPSVKRK 6573361 KKALAAKKRAVKKARKSF

Sequence 1551 Sequence 3551 from patent US 657336 i MONEEGOMVDLYVPRKCSATN 1716 from patent US RIITAKDHASVOI TGHVDENGL

6573361 YDGRFTTFALSGFIRAOGDADS

AI.DRLWO RKAF.VKOO

Sequence 1552 Sequence 1552 from patent US 6573361 MQNDAGEFVDLYVPRKCSASN 1717 from patent US RUAAKDHASIQMNVAEVDRST

6573361 GRFNG FKTYGICGAIRRMGES

DDSILRLAKADGIVSKNF

Sequence 1553 Sequence 1553 from oatent US 6573361 MTOWVGONEP1ESALRRFKRO 1718 from patent US VA AGIYTDFKKHOFFETPOEK 6573361 HKRKEATRRRORSRRR

Sequence 1554 Sequence 1554 from patent US 6573361 MKSNRQARHILGLDHKISNQRK 1719 from patent US IVTEGDKSSWNNPTGR RPAE

6573361 K

Sequence 1555 Sequence 1555 from patent US 657336 i TRS SVLAD ALNAINNAEKTGKR 1720 frosri patent US OVL1RPSSKV1TKFLOVMOKHGY

6573361 IGEFEYIDDHRSGKIWOL GRL

NKCGVISPRFNVKIGDIEKWTA NLLPAROFGYVILTTSAGIMDH EEARRKHVSGKILGFVY

Sequence 156 from [3407667]Sequence 156 from pateni US Ri AGYGLRGLA VilRIICRGLNLI 1721 patent US 5714577 5714577 FEIIR

Sequence 157 from [3407668]Sequence 157 from patent US RIAGYGLRGLAVIPRRiCIRGLN 1722 patent US 5714577 5714577 LiFEiiR

Sequence 158 from [3407669]Sequence 158 from pateni US RilEFILNLGRICIRilV ALGRLG Y 1723 patent US 5714577 5714577 GAIR

Sequence 1580 Sequence 1580 from patent US 6573361 MVLSSD1DLLNPPAELEKTKHK 1724 from patent U S RKRLVOSPN SFFMDVKCOG CF 6573361 NiTTVFSHSOTVVMCGSCSSVL

CTPTGWPRRLTEGCSFRRK8D

Sequence 1581 Sequence 1581 from patent US 6573361 MPLIEVDLLNPTAASEAKAHKM 1725 from patent US KRLVPTPNSYFLEIKCP CGATT

6573361 TTFSHAi-IROILCOKCGOPLGOP

TGGKLKLTOOCKFRI K

Sequence 1585 Sequence 1585 from pateni US 6573361 MMELIPQPRTKFLRVQCPECNN 1726 from patent US EOrVFGSPATWKCLTCGKVLV 6573361 EPRGGKGKVKAK1LEILG Sequence 1588 Sequence 1588 from patent US 6573361 DSOIKHAVVVK.VMGRTGSR.G 1727 from patent US OVTOVRVKFTDSDRF1MRNVK 6573361 GPVREGDVI.TLLESEREARRLR

Sequence 1589 Sequence 1589 from patent US 6573361 MDTSRVOP1 LARVTKVLGRTG 1728 from patent U S SOGOCTOVRVEF DDTSRS1I 6573361 NVKGPVREGDVLTLLESEREAR

RLR

Sequence 159 from [34Q7670]Sequence 159 from patent US KLAGYOLKGLAVII ICIKGL LI 1729 patent US 5714577 5714577 FEIIK

Sequence 1590 Sequence 1590 from patent US 6573361 MDTQVKUAVVVKVMGRTGSR 1730 from patent US GOVTOVRVKFLDDONRL1MR

6573361 VKGPVCEGDILTLLESEREARRL

R

Sequence 1591 Sequence 1591 from patent US 6573361 MMRMEDEFVYKEAVAAEV1EV 173 1 from patent US IGRTGVTGGIIQVRCKILGGKDT 6573361 GRVLVRN VKGPVK VGDI1MLRE

TEREARPLDRRR

Sequence 1592 Sequence 1592 from patent US 6573361 MDSSKVPVKLAKVI VLGRTGS 1732 from patent US RGGVTOVRVEFMDDTSRSnRN 6573361 V GP VREDDIL V LLE SEREARR

LR

Sequence 1 594 Sequence 1594 from patent US 6573361 GHOOLYWSHPRKFGOGSRSCR 1733 from patent US VCSNRHGLIRKYGLNMCROCF 6573361 ROYAKDTGFIKLD

Sequence 1 595 Sequence 1595 from patent US 6573361 KVHGSLARAGKVRGRHOKVA 1734 from patent US KODKKK PRGRAFI RLOFINRR 6573361 F VTAWGFG K RGPNS SEK

Sequence 1597 Sequence 1597 from patent US 6573361 AKVHGSLARAGK VKSOTPK VE 1735 from patent U S TEKPKKP GRAYKRLLYTRRF 6573361 VNVTLVNGKRRMNPGPSVO

Sequence 1599 Sequence 1599 from patent US 65733 1 MDTKTPVTLAKVIKVLGRTGSR 1736 from patent US GGVTOVRVEFLEDTTRT1VR V 657336 i GPVREGD1LVLMESEREARRL

R

Sequence 16 from pal!USi5519115| 16f l6102421Sequence 16 R SLPKVAYATA 1737 patent US 5519115 from patent US 5519115

Sequence 1 6 from patiUS|5607914| 16f2096796!Sequence 1 KLKKALRALARHWK 1738 patent US 5607914 from patent US 5607914

Sequence 16 from [4001476]Sequence 16 from patent US liGGRESRW-iSRPYMAYLOi 1739 patent US 5798336 5798336

Sequence 1 from Sequence 1 from patent US 6605698 H CiCYFPC 1740 patent US 6605698

Sequence 16 from pa!!USi663853 !j l6[40163862]Sequence 16 KRLFK LKF SLR Y 1741 paten! US 6638531 from patent US 6638531

Sequence 1 6 from pat!US!6642203| 16140188733 |Sequence 16 cxxcxxxxxxxxxxccxxxx 1742 patent US 6642203 from patent US 6642203 xcc

Sequence 1 6 from patiU8j6730659j 16[53923184]Seq«ence 16 OGRHFSGGALIHARFVMTAA 1743 patent US 6730659 from patent US 6730659 RCFQ

Sequence 16 from patlUSI6743769| 16[ 53934473^'jSequence 16 SAIHPS SILKLEVICIGVLO 1744 paten! US 6743769 from patent US 6743769

Sequence 1 6 from pat!US!6747007i 16153937641 ISequence 16 RR WCFX VCXRGXCYXXCRX 1745 patent US 6747007 from patent US 6747007 Sequence 17 from patlUSI5607914| 17i20967971Sequence 17 IORVAOKLKKALRALARHWK 1767 patent US 560791 from patent US 5607914 AL

Sequence 17 from [3407528]Seqnence 17 from patent US RVISWOGACRAIRRIPRRIROG 1768 patent US 5714577 5714577 LERIL

Sequence 17 from [400i477]Sequence 17 from patent US OSPAGOSRCGGFLVREDFVL 1769 patent US 5798336 5798336

Sequence 17 from pat!US!5821224j 17!^"6004609]Sequence 17 OTGTCFGRPVK. 1770 patent US 5821224 from patent US 5821224

Sequence 17 from patjUSi6191254|17[14119965]Sequence 17 ILKKWPWWPWKRR 1771 patent US 6191254 from patent US 6191254

Sequence 17 from pat !U SI621 11481 71151083431 Sequence 17 OIGTCFGRPVL 1772 patent US 6211 148 from patent US 621 1 148

Sequence 17 from Sequence 17 from patent US 6605698 CIRLEKARHGSC 1773 patent US 6605698

Sequence 17 from pat|US|6638531 j 17j 40163863 lSequence 17 DSHA RHHGYKRKFHEKHHSH 1774 patent US 6638531 from patent US 663853 1 RGY

Sequence 17 from pat!USi6642203j 17140188734]Sequence 17 PXPXPXPXXXPXX 1775 patent US 6642203 from patent US 6642203

Sequence 17 from patiUS!6730659| 17[53923185]Sequence 17 NQGRHFSGGALIiiARFVTViTAA 1776 patent US 6730659 from patent US 6730659 CFQ

Sequence 17 from patlUS!6743769| 17[539344741Sequence 17 YAERLCTC SIKAEY 1777 patent US 6743769 from patent US 6743769

Sequence 17 from pat|USi6747007| 17i539376421Sequence 17 RXWCXXXCYRGFCXXXCR 1778 patent US 6747007 from patent US 6747007

Sequence 17 from pat!USi6818407i l7[56646456]Sequence 17 ALWKTMLKKAAI GKHVGKA 1779 patent US 6818407 from patent US 6818407 ALTHYL

Sequence 17 from pat uSi68355½|i7T59754006iSequence 17 WWRWPWWPWRRK 1780 patent US 6835536 from patent US 6835536

Sequence 17 from pat!US!6838435| 17159761438]Sequence 17 MGHHHHHHHHHHSSGHTEGRH 3781 patent US 6838435 from patent US 6838435 MYAELRCMCIKTTSGIHPKN10S

LEVTGKGTHCNOVEVIATLKDG RKICLDPDAPRIK IVOKKLAG DESAI

Sequence 17 from pat|US|6906035| 17[744723001Sequence 17 KKWWRRALOALKNGPALS V 1782 patent US 6906035 from patent US 6906035

Sequence 17 from !pat!US!7071293! 17N 120627141Sequence 17 RRTIR UHTIK 1783 patent US 7071293 from patent US 7071293

Sequence 17 from Sequence 17 from patent US 7078380 XTXXXFXXXT 1784 patent US 7078380

Sequence 1 7 from !pat!US!7091 18511711 157941991Seauence 37 LKXLLK LLKKLLK LLKi LLK 3785 patent US 7091 185 from patent US 7091 1 85 KLLK L

Sequence 17 from pa†iUS!7314858117Γ 1.67246741 lSequence 17 MRTFAI.LTAMLLLVALHA.OAE 1786 patent US 7314858 from patent US 7314858 AROARADEAAAOOOPGADDO

GMAH SFTRPENA LPL SES ARG LRCLCRRGVCQLL

Sequence 1734 Sequence 1734 from patent US 6573361 MRSVWKGCFY l 'NNNGLSKSS 1787 from patent U S T ViNTML FTLHDGKSYKSl 6573361 LIDRSMVGLKIGEFVFTRXMGV

LHKKKVTKKKGKK Sequence 19 from f3407530]Sequence 19 from patent US RVIEWOGACRAIRHIPRRIRQG 1 81 1 patent US 5714577 5714577 LRRIL

Sequence 19 from [4001479]Sequence 19 from r>a! eat US RRENTOOHITARRAIRIIPOY 1812 paten! US 5798336 5798336

Sequence 1 from pat!US!6191254j l91141 199671 Sequence 19 ILPWKWPWYVRR 1 813 patent US 6191254 from patent US 6191254

Sequence 19 from pat!USi6211148j l9[15108345JSequence 19 PVPMR 1814 patent US 6211148 from patent US 6211148

Sequence 1 from pat|US|6492328| Ϊ .9[29695229 jSequence 19 KNLRRIIRKSIHIIKKYG 1815 patent US 6492328 from patent US 6492328

Sequence 19 from Sequence 19 from patent US 6605698 ARHGSC YVFP 1816 paten! US 6605698

Sequence 1 from pat !IJ S i 663853111 f 40163865 J S equence 19 GMASKGAIAGKIAKVALKAL 1 817 patent US 6638531 from patent US 6638531

Sequence 19 from paliUS!6642203| 19Γ40188736]Sequence 19 PXPXPP 1 818 patent US 6642203 from patent US 6642203

Sequence 1 from pat|U¾673~0659| Ϊ9Γ53923187 {Sequence 19 OGRHFCGGALIHARFVMTAA 1819 patent US 6730659 from patent US 6730659 RSFQ

Sequence 1 from pat;US!6743769j 19f53934476 [Sequence 19 KGYFYFLFKFK 1 820 patent US 6743769 from patent US 6743769

Sequence 1 9 from patiUS16747007| 19i539376441Sequence 19 RRWCFRVCYRGXFCYRKCR 1 821 patent US 6747007 from patent US 6747007

Sequence 1 from patiUSi683 8407119|^'56646458jSequence 19 GWGSFFKKAAHVGKHVGKAA 1822 patent US 6818407 from patent US 6818407 LGAAARRRK

Sequence 1.9 from pat|US|6835536| 19r597540101Seguence 19 1LRRWPWWPWRK 1 823 patent US 6835536 from patent US 683553

Sequence 19 from patiUS!6906035j 19 74472302{Sequence 19 KKWWRRALOGLKTAGPAIOSV 1824 patent US 6906035 from patent US 6906035 LNK

Sequence 19 from lpatlUSI7071293| 19[ l 120627171Sequence 19 GLRKRLRKFRNKIKEKLKKIG 1825 paten! US 7071293 from patent US 7071293

Sequence 1 9 from Sequence 19 from patent US 7078380 KWKLFKKIGIGAVLKVLTTGLP 1 826 patent US 7078380 ALTLTK

Sequence 1 from !patiUS! 7091 185 ! 191 1 15794201 J Sequence 19 FAFKFAFKFAF FAFKFAFKF 1827 patent US 7091 185 from, patent US 7091 185 AFKFAF

Sequence 2 from pat|US|5221732|2i34425576]Sequerice 2 IGKFLHAAKKFAKAFVAEIM S 1 828 patent US 5221732 from patent US 5221732

Sequence 2 from pat|US!5607914|2f2096782JSequence 2 from ¹ KLKKALRALARI-IWKAGPGVTI 1829 patent US 5607914 patent US 5607914 GIAHAKSOLW

Sequence 2 from j 3941 162 [Sequence 2 from patent US GFF KAXRKVKHAGRRVLDTA 1830 patent US 5734015 5734015 KGVGRHYVNNWLNRYR

Sequence 2 from [4001462 JSequence 2 from patent US IVGGR 1831 patent US 5798336 5798336

Sequence 2 from pat ilJS 15856127| 2 [5938 S 81 JSequence 2 from MASRAAGLAARLARLALRA 1832 paten! US 5856127 patent US 5856127

Sequence 2 from pat|i)S|5994308|2r i0064836]Sequence 2 RRRFPWWWPFLRRR 1833 patent US 5994308 from patent US 5994308

Sequence 2 from Sequence 2 from patent US 6127336 RSVXROIKJXRRRGGXYYKXT 1 834 patent US 6127336 RPT

Sequence 2 from pa!iUS!6191254|2[141199501 Sequence 2 HKPWKWPWWPWRRKK 1835 paten! US 61 1254 from patent US 6191254 Sequence 2 from Sequence 2 from patent US 6300489 ARSrVTMAFLVLATLFVAYGV 1 836 patent US 6300489 OGKEJCCKELTKPVKCSSDPLC

OKLCMEKEKYEDGHCFTILSKC

I MKRC AKTLATELLA

Sequence 2 from Sequence 2 from patent US 6329504 RTCENLAD YRGPCFSGCDTHC 1 837 patent US 6329504 TT ENAVSGRCRDDFRCWCTK

RC

Sequence 2 from patiUSI64201 !6j2[23319331]Sequence 2 DPVTCLXSGAICHPVFCPRRYK 1838 patent US 64201 i 6 from patent US 6420116 QIGTCGLPGTKCCK

Sequence 2 from Sequence 2 from patent US 6605698 CiRLEKARHGSCNYV 1839 paten! US 6605698

Sequence 2 from pat|US!66241 0| 2[40151050 ] Sequence 2 GKWKLFXXAFKXFLK1LAC 1 840 patent US 6624140 from patent US 662 140

Sequence 2 from pat!US!6642203|2[40188727]Sequence 2 MRLWCLVFLASFALVCOGEA 1841 patent US 6642203 from patent US 6642203 YRGGYTGPIPRPPPIGRPPFRPV

C ACYRLSVSDARNCCIKFGSC

CHLVKG

Sequence 2 from Sequence 2 from patent US 6653280 RLCERPSGTW SG V CG N A CR 1 842 patent US 6653280 OCR LERAEHGSCNYVFPAH

KCTCYFPC

Sequence 2 from patlUSi6730659|2[53923170]Sequence 2 RUFCGGALIHARFVMTAASC 1843 patent US 6730659 from patent US 6730659

Sequence 2 from Sequence 2 from patent US 6743598 XPAXXXYXXXGX 1844 patent US 6743598

Sequence 2 from patlUSi6743769|2[53934459]Sequenc 2 SDDPKESEGDLHCVCV TTSLV 1845 paten! US 6743769 from patent US 6743769 RPGHiTNLELl AGGHCPTANLi

AT XNGRKLCLDLOAALYK X. IIKKLLES

Sequence 2 from pat|US|6747007|2f539376271Seauence 2 WCFAVCYRGRCRRKCRR 1846 patent US 6747007 from patent US 6747007

Sequence 2 from patlUSI6753407|2[53972392]Sequence 2 FFHi-nFRGIVHVG TIHRLVTG 1847 paten! US 6753407 from patent US 6753407

Sequence 2 from Sequence 2 from patent US 6790833 RERDHELRHRRHHHO 1 848 patent US 6790833

Sequence 2 from Sequence 2 from patent US 6809181 OKYYCRVRGGRCAVLSCLPKE 1849 patent US 6809181 EOIG KC STRGRKCCR

Sequence 2 from patlUSI6835536|2[59753976]Sequence 2 KXAAAKAAAAAKAAWAAKAA 1850 paten! US 6835536 from patent US 6835536 AKKKK

Sequence 2 from patiUSI6838435|2f597614 Ϊ SlSequence 2 AELR 1851 patent US 6838435 from patent US 6838435

Sequence 2 from pai!US!6884776[2f67580421 ]Sequence 2 KVHGSLARAGKVRGOTPK 1852 patent US 6884776 from patent US 6884776

Sequence 2 from pa!!US!6887847j2[67584678]Sequence 2 RVIRWQRACRAIRHIVRRIRQG 1853 paten! US 6887847 from patent US 6887847 LRRILRW

Sequence 2 from pat!0S!6906035j2[74472285iSeqiieiice 2 WKSF1KKLTSAAKKVVTTAKP 1854 patent US 6906035 from patent US 6906035 LiSS

Sequence 2 from pat| S|6911524|2!7¾798^"00]Sequence 2 MKATILLAVLVAVFVAGTEAHS 1 855 patent US 6911524 from patent US 6 1 1524 HACTSY CGKFCGTASCTHYL

CRVLHPGKMCACVHCSRVNNP FRVNOVAKSITNDLDYTPIMKSM ENLD GMDML Sequence 21 from patlUSI55191 15|21 il6102471Sequence 21 MGRIARGS SSLIVSIXWLV 1 88 1 patent US 55191 15 from patent US 55 191 15 SLNLASETTA

Sequence 21 from pallUSI5607914|21 [2096801 lSequence 21 GAYRAIRHIPRRIR 1882 paten! US 5607914 from patent US 5607914

Sequence 21 from [3407532]Sequence 21 from patent US RVIEWRGACRATRHIPRRIR 1 883 patent US 5714577 5714577

Sequence 21 from [400i481]Sequence 21 from patent US R\¾RNR V PVALPRAOEGL 1884 patent US 5798336 5798336

Sequence 21 from pat|US|582l224|21 [60046 Ϊ 3 Sequence 21 XXXYCXXNXGXCXPIRCPGXX 1885 patent US 5821224 from patent US 5821224 R01GTCXGZXXKCCR

Sequence 21 from pat|US|6191254Ι21 Π41 199691 Sequence 21 ILPWKWFFPPWPWRR 1 886 patent US 6191254 from patent US 6191254

Sequence 21 from pat!US!6211148j21 [15108347]Sequence 21 XXXXCXX XGXCXPIRCPGXX 1887 patent US 6211148 firom patent US 6211148 ROIGTCXGXXXKCCR

Sequence 21 from pa!!US!6492328i21 [29695231]Sequence 21 NLRRIIRKDIHIIKKYG 1888 patent US 6492328 from patent US 6492328

Sequence 21 from Sequence 21 from patent US 6605698 HGSClslYVFPAHK 1 889 patent US 6605698

Sequence 21 from patiUS!6638531|21[40163867]Sequence 21 LLASDEEIQDVSGTWYLKA 1890 patent US 6638531 from patent US 6638531

Sequence 21 from pat|US!6642203|21 i401887381Sequence 21 PXPXPPXXXPXX 1891 patent US 6642203 from, patent US 6642203

Sequence 21 from patlUSI6730659|21[53923189]Sequence 21 RHFSGGAL1HARFVMTAAHC 1892 paten! US 6730659 from patent US 6730659

Sequence 21 from Dai!lJS!67 3769121 [53 34478] Se suence 2 ! PRI KIVOK LAG 1 893 patent US 6743769 from patent US 6743769

Sequence 21 from pat!US|6818407j21 [56646460]Sequence 21 SIG S AFKKAAHVGKHVGKAAL 1894 patent US 6818407 from patent US 6818407 GAAARRRK

Sequence 21 from pai!US!6835536i21 [59754013]Sequeiice 21 iLKKWPWWPWRK 1895 paten! US 6835536 from patent US 6835536

Sequence 21 from Sequence 21 from patent US 6864068 RVCMKGSAGFKGLC RDONC 1 896 patent US 6864068 AOVCLOEGWGGGNCDGVMRO

C CiROC

Sequence 21 from patlUSI6906035|21 T744723041Sequence 21 KKWWKAKKFANSGP ALOTL 1 897 patent US 6906035 from patent US 6906035

Sequence 21 from pat!US!7071293i21 [ 112062720]Sequenc 21 RKRLRKFR KIKEKL KIGOKI 1898 paten! US 7071.293 from patent US 7071.293

Sequence 21 from ipat!U Si70911 S5!21 [ l 157942031 Sequence 21 KFAKKJAKKFAKKFAKKFAKK 1899 patent US 7091185 from patent US 7091185 FAKKFAK

Sequence 21 from |pat!US!7314858121 [1672467441Sequence 21 RCiCRRGIC 1900 patent US 7314858 from patent US 7314858

Sequence 22 from patlUSI5519115|22[ 16102481Sequence 22 MGKNG SLCCF SLLLLLLLAGLA 1901 paten! US 5519115 from patent US 5519115 SGHOVL

Sequence 22 from patoai|USi5607914|22f20968021Sequence 22 RRiYRAIRHIPRRiR 1902 patent US 5607914 from patent US 5607914

Sequence 22 from [3407533 lSequence 22 from patent US RViE OGICRAiRHiPRRiR 1903 patent US 5714577 5714577

Sequence 22 from [4001482]Sequence 22 from patent US RPGTLCTVAGWGRVSMRRGT 1904 paten! US 5798336 5798336

Sequence 22 from pat|US|5856127|22r5938894]Scquence 22 MGECVRGRCPSGMCCSOFGYC 1905 patent US 5856127 from patent US 5856127 GKGPKYCG

Sequence 22 from pat!US!6191254i22[ 141 19970jSequence 22 ILPWK WPPWPPWP WRR 1906 patent US 6191254 from patent US 6191254 Sequence 22 from pat!U8i621 1148|22il51083481Sequence 22 XXCXCXXXXCXXXXRXXGXC 1907 patent US 6211148 from patent US 621 1 148 xxxxxxxxxec

Sequence 22 from patlUSI6492328|22[296952321Sequence 22 KNL.RRIIRKAIHIIKKYG 1908 paten! US 6492328 from patent US 6492328

Sequence 22 fr m: Sequence 22 from patent US 6605698 ARHGSC YVFPAHKCICYF 1909 patent US 6605698

Sequence 22 from patiUS!6642203j22j;40188739!Sequence 22 PXPXPPXXXPXPXXPXXP 1910 patent US 6642203 from patent US 6642203

Sequence 22 from pat!iJ¾!6730659|22[53 23 Ϊ 90 jSequence 22 RHFSGGALIHARFVMTAARC 191 1 patent US 6730659 from patent US 6730659

Sequence 22 from pallUSI6743769l22r539344791Sequei.ee 22 WVREYI SLEMS GLAG 1912 paten! US 6743769 from patent US 6743769

Sequence 22 from pal! Si6835536!22 59754015 jSequence 22 ILKWPWWPWRK 1913 patent US 6835536 from patent US 6835536

Sequence 22 from Sequence 22 from patent US 6864068 O LCMRPSGTWSGVCG N AC 1914 patent US 6864068 KNOCIRLEKARHGSCNYVFPAH

KCiCYFPC

Sequence 22 from pat|US!6906035|22i74472J05{Sequence 22 KKWWKF1KKAVNSGTTGLOTL 1915 patent US 6906035 from patent US 6906035 AS

Sequence 22 from jpatjU Si 7071293122( 112062722l^"Sequenee 22 LRKFRNKIKEKLKKIGQKI 1916 patent US 7071293 from patent US 7071293

Sequence 22 from !patlUSi709118512211157942041 Sequence KAA. . AA .KAA .KAAK AAK 1917 patent US 7091185 22 from patent US 7091 185 KAAKKAAK

Sequence 22 from !pat|US!73 14858Ι22Π 67246745jSequence 22 RCiCTRGIC 1918 paten! US 7314858 from patent US 7 14858

Sequence 23 from pat!US!5519i 15|23( 1610249]Sequence 23 GGGGSGGGGSGGGGS 1919 patent US 5519115 from patent US 5519115

Sequence 23 from [3407534]Sequence 23 from patent US RV1E QGACRAIRRIPRRIR 1920 patent US 5714577 5714577

Sequence 23 from (4001483 ]Sequence 23 from patent US DTLREVOLRVORDROCLRIF 1921 patent US 5798336 5798336

Sequence 23 from pa!!US!6191254j23[ 141 199711Sequence 23 XXPXXXPXXPXXPXXXXXXX 1922 paten! US 6191254 from patent US 6191254

Sequence 23 from Sequence 23 from patent US 6605698 ASHGACHKRENHWKCFCYF 1923 patent US 6605698

Sequence 23 from pat!US!6642203|23i401887401Sequence 23 RLWCLVFLA SFALVCOGOV 1924 patent US 6642203 from patent US 6642203 YKGGYTRPVPRPPPFVRPLPGG

PIGPYNGCPVSCRGiSFSQARSC CSRLGRCCHVG GYSG

Sequence 23 from pat! SI673 659123 5392319 ί (Sequence 23 RHFSGGALIHARFVMTAARC 1925 patent US 6730659 from patent US 6730659

Sequence 23 from pat!US!6743769|23i539344801Sequence 23 EWVOKYVSDLELSAWKKILK 1926 patent US 6743769 from patent US 6743769

Sequence 23 from pat|U¾68 i8407|23i^'56646462 jSequence 23 ALWKTML KLGTMAL'HAGKA 1927 patent US 6818407 from patent US 68 i 8407 ALGAAADTISOTO

Sequence 23 from Sequence 23 from patent US 6864068 OKLCORPSGGWSGVCGNNNAC 1928 patent US 6864068 KNOCIRLEKARHGSCNYVFPAH

KCiCYFPC

Sequence 23 from pat!USi6906035|231744723061Sequence 23 K SFFKKLT SVAS S VLS 1929 patent US 6906035 from patent US 6906035

Sequence 23 from patiUSi707i293|23fi 12062723 [Sequence 23 LRKFRNK1KEKLKK1G0 1OG 1930 patent US 7071293 from patent US 7071293 Sequence 23 from lpatlUSI7091185Ι23Π 157942051Sequeace 23 Κ Λ Κ Λ Κ Λ Λ Κ ΚΚΛ Κ 193 1 patent US 7091185 from patent US 7091 185 Κ Λ Κ Λ Κ

Sequence 23 from !pa!:iUS!7314858!23f l67246746]Seqiienc 23 RCICVRGIC 1932 patent US 7314858 from patent US 7314858

Sequence 24 from [3407535]Sequence 24 from patent US RVIRWOGACRAIRH1PRRIROG 1933 patent US 5714577 5714577 LER1L

Sequence 24 from f4001484]Sequence 24 from patent US GSYDPRROTCVGDRRERKAA 1934 patent US 5798336 5798336

Sequence 24 from patiUSi6191254|24f 141 i9972]Sequence 24 XXPXXXXXXXXXXXPXXX 1935 patent US 6191254 from patent US 6191254

Sequence 24 from paiiUSi6492328!24i29695234]Sequence 24 KNLRRIIRKIGHIIKKYG 1936 patent US 6492328 from patent US 6492328

Sequence 24 from Sequence 24 from patent US 6605698 AAHGACHVRNGKPIMCFCYF 1937 patent US 6605698

Sequence 24 from pat!US!6642203j24[40188741 iSequence 24 MRLVVCLVFLASFALVCOGOV 1938 patent US 6642203 from patent US 6642203 YKGGYTRPIPRPPFVRPVPGGPI

GP YNGCPV SCRGiSF SQARSCCS RLGRCCHVG GYSG

Sequence 24 from pat!US!6730659i24j^"53923192]Seinience 24 RHFCGGALIHARFVMTAAHS 1939 patent US 6730659 from paient US 6730659

Sequence 24 from pat|USi6743769|24i539344811Sequence 24 SWVOEYVYDLEL 1940 patent US 6743769 from patent US 6743769

Sequence 24 from patlUSi6835536|24[597540191Sequence 24 RRWPWWPWRLI 1941 patent US 6835536 from patent US 6835536

Sequence 24 from Sequence 24 from patent US 6864068 OKLCORPSGTSSGVCG NNAC 1942 patent US 6864068 KNOCIRLEKARHGSC YVFPAH

KCTCYFPC

Sequence 24 from pat!US!6906035|24174472307]Sequence 24 WKVFKSFIKKASSFAOSVLD 1 43 patent US 6906035 from patent US 6906035

Sequence 24 from ipat|US!7071293|24|^"l 12062725 [Sequence 24 RKFR KIKEKLKK1G 1944 patent US 7071293 from patent US 7071293

Sequence 24 from !pa!iUS!709118512411157942061Sequence 24 FKKFKKFKKFKKFK 1945 paten! US 7091 185 from patent US 7091 185

Sequence 24 from ipat!U Si 73 Ϊ 4858124 ί 167246747 ISequence 24 RC1CGLG1C 1946 patent US 7314858 from patent US 7314858

Sequence 246 from Sequence 246 from patent US 6478825 ALSSOIWAACLLLLLLLASLT 1947 patent US 6478825 SGSVFPOOTGOLA.ELOPODRAG

ARASWMPMFORRRRRDTHFPI

CiFCCGCCHRSKCGMCC T

Sequence 25 f m: j^'3407536^"|Sequence 25 from patent US RVIEWRGACRATRHTPRRIROG 1948 patent US 5714577 5714577 LER1L

Sequence 25 from 40014S5|Sequence 25 from patent US F GDSGGPLLCN VAHGiVSY 1949 patent US 5798336 5798336

Sequence 25 from pa!!US!6191254j25[14119973]Sequence 25 XXXPWXXXXXXXXXXXXXXX 1950 paten! US 61 1254 from patent US 6191254

Sequence 25 from patiU8i6492328!25i29695235]Sequence 25 KNLRRIIRKITHIIKKYG 195 i patent US 6492328 from patent US 6492328

Sequence 25 from patiUS!6730659|25f539231931Seq«ence 25 RHFCGGALII-LARFV TAARS 1952 patent US 6730659 from paient US 6730659

Sequence 25 from patiUSi6743769i25[53934482jSequence 25 ADSGEGDFL EGGGVR 1953 patent US 6743769 from patent US 6743769

Sequence 25 from pa!!USI6835536i25 59754021]Sequeiice 25 ILWPWWPWRR 1954 patent US 6835536 from patent US 6835536

patent rom patent Sequence 29 from Sequence 29 from patent US 6864068 OKLCORPSGWSGVCG NNAC 2.004 patent US 6864068

OCICYFPC

Sequence 29 from pat USI6906035l29!^'74472312]Sequence 29 KWKXXXXXXXXXXXXGGLLS 2005 patent US 6906035 from patent US 6906035 iV SL

Sequence 29 from |patiUS|7071293i29[ n2062732iSequence 29 RGLRALGRK1 AHG V AYG 2006 patent US 7071293 from patent US 7071293

Sequence 29 from Sequence 29 from patent US 7078380 GIGAVL VLTTGLPALISW1KRK 2.007 patent US 7078380 ROO

Sequence 29 from !pat!US!709i 18512911157942121Sequence 29 fKKFKKFKKFKKFKKFKKFK 2008 patent US 7091185 from patent US 7091 185 PKKFK FK

Sequence 29 from ipat!USi7314858!29fl67246752]Sequence 29 RCLCVRGIC 2009 patent US 7314858 from patent US 7314858

Sequence 296 from pat|US|6727066|296[539203231Sequence MRTSYLLLFTLCLLLSEMASGG 201 patent US 6727066 296 from patent US 6727066 FLTGLGHRSDHY CVSSGGO

CLYSACPIFTKIOGTCYRGKAK CCK

Sequence 3 from pa1iU5i5221732|3i344255771Sequence 3 GIGKFLHAAKKFAKAFVAEIMN 2 1 1 patent US 5221 732 from patent US 5221732 s

Sequence 3 from pat!US!5519i 15j3j 1610229iSequence 3 from GiGKXXXXAXXXXKAFVXXlX 2012 patent US 5519115 patent US 5519115 XX

Sequence 3 from patlUS!5607914|3f2096783]Sequence 3 from ORAVRRiYRAiRFiiPRRlRIRALA 2.013 patent US 5607914 patent US 5607914 GPGVTIGIAHAKSOLW

Sequence 3 from [3407514]Sequence 3 from patent US DLWETLRRGGRWiLAlPRRiRO 2014 patent US 5714577 5714577 GLELTL

Sequence 3 from £3 41163J Sequence 3 from patent US GXFKKAXRKVKNAGRRVLKG 2015 patent US 5734015 5734015 VGIHYGVGL1

Sequence 3 from [4001463]Seq«ence 3 from patent US HPOYNOR 2016 paten! US 5798336 5798336

Sequence 3 from patiUS|5856127|3i5938882]Sequence 3 from MASRAAGLAARLARLALRAL 2017 patent US 5856127 patent US 5856127

Sequence 3 from pat!USi5998374j3f l0066310]Sequence 3 MKTTILILL1LGLGINAKSLEERK 2018 patent US 5998374 from patent US 5998374 SEEE VFOFLGKllHHVGNFVli

GFSHVFGDDOODNGKFYGHYA

EDNGKHWYDTGDO

Sequence 3 from pat!US!6191254|3 341199 l^"jSequence 3 1L PW WPWWPWRR 2019 patent US 6191254 from patent US 6191254

Sequence 3 from pat US[6211148I3[ 151083291Sequence 3 EGVRNHVTCRINRGFCVP1RCP 2020 patent US 6211148 from patent US 621 1148 GRTRQIGTCFGPRIKCCRSW

Sequence 3 from Sequence 3 from patent U S 6476189 ALRLAIRKR 2021 patent US 6476189

Sequence 3 from pat!US!6492328|3i296952131Sequence 3 KNERRGiR lIHIiK YG 2022 patent US 6492328 from patent US 6492328

Sequence 3 from Sequence 3 from patent US 6605698 EKARHGS CN Y VFP AH 2023 patent US 6605698

Sequence 3 from pat!US!6624140|3i4015 1051] Sequence 3 GKWKAFKKAF KFAKILAG 202.4 patent US 6624140 from patent US 6624140

Sequence 3 from pat| S|6638531 |3r40i63849]Sequence 3 KRLFKELKKSER Y 2025 patent US 6638531 from patent US 6638531 Sequence 3 from pat!US!6696559(31472353221 Sequence 3 MSRRYTPLAWYLLALLGLGAA 2026 patent US 6696559 from patent US 6696559 ODCGSIVSRGKWGALAS CSO

R i .KOI'YK VVN YSH^'i^'AGSYCN ΓΡ

ASCOROAO VOYYHVRERGW

CDVGYNFKIGEDGKVYEGRGW TKGDHSGPTWNP1AIGISFMG

NY HRVFFASALRAAOSLLAC

GAARGYLTP YEVKGHRDVOO

TLSPGDELYKHOOWPHYRRV

Sequence 3 from patlUS|6730659j3[53923171]Sequence 3 NQGRFIFSGGALiHARFVMTAAS 2027 patent US 6730659 from patent US 6730659 CFQ

Sequence 3 from Sequence 3 from patent US 6743598 iEDlSVAKSEOGKKLGYYLV 2028 patent US 6743598

Sequence 3 from pat IUSI674376913153934460 ] Sequence 3 ALYKKFKKKLLKSLKRLG 2029 patent US 6743769 from patent US 6743769

Sequence 3 from patlUS!6747007|3[53937628]Sequence 3 FRWCFRVCYKGRCRYKCR 2030 patent US 6747007 from patent US 6747007

Sequence 3 from Sequence 3 from patent US 6790833 SPKSHFELPHYPGLLAHOKPFTR 2031 patent US 6790833 KSYKCLHKRCR

Sequence 3 from pat|USi6818407|3| 56646442 ISequence 3 KWKSF1KKLTSAAKKWTTAKP 2032 patent US 6818407 from patent US 681 8407 LALiS

Sequence 3 from pat|US!6838435|3f5976 i 420]Sequence 3 AELRCMCI TTSGTHPKN10SLE 2033 patent US 6838435 from patent US 6838435 VIGKGTHCNOVEV1ATLKDGRK

ICLDPDAPRiKKiVOKKLAGDES

Sequence 3 from patlUSI6872705|3[62788242jSequence 3 G i( , l ! .K Λ Κ ϋ ί .ΜΑ Κ Π . λ 2034 patent US 6872705 from patent US 6872705

Sequence 3 from pat|US|6884776|3f6758(M22 ]Sequence 3 TGRAKRRMOYNRR 2035 patent US 6884776 from patent US 6884776

Sequence 3 from pat!US!6887847j3[67584679^"j8equence 3 RWiR ORW^'CRAiRHiWRRIRQ 2036 patent US 6887847 from patent US 6887847 GLRRWLR

Sequence 3 from patlUSI6906035|3[74472286]Sequence 3 WKSFI NLTKGGSKILTTGLP 2037 patent U S 6906035 from patent US 6906035 ALIS

Sequence 3 from lpatiuSI707129313fl 120626921Sequence 3 KLAHGVKKYGPTVLRHRIAG 2038 patent US 7071293 from patent US 7071293

Sequence 3 from Sequence 3 from patent US 7078380 GTGAVLKVLTTGLPALTSW1KRK 2039 patent US 7078380 ROOC

Sequence 3 from lpatlUSI7091185l3r i l57941821Sequence 3 KFAKKFAKKFAKKFAKKFAK 2.040 patent US 7091 185 from patent US 7091 1 85 FAK

Sequence 3 from pat!USI7244710|3il557164501Seqiience 3 SYSMEHFR.WGKPV 2041 patent US 7244710 from patent US 7244710

Sequence 3 from jpatjij Si 73 Ϊ4858131^' 367246730] Sequence 3 G1CRCYCGRGICRCICGR 2042 patent US 7314858 from patent US 7314858

Sequence 30 from f3407541]Seq«ence 30 from patent US WORACRAIRRIPRRTR 2.043 patent US 5714577 5714577

Sequence 30 from [4001490jSequence 30 from patent US HPOYNPQ 2044 patent US 5798336 5798336

Sequence 30 from pa!!US!6399370|30[215 170391Sequence 30 MRLHHLLLALLFLVLSAWSGFT 2045 patent US 6399370 from patent US 6399370 OGVGNPVSCVR KG1CVPIRCP

GSMKOIGTCVGRAVKCCRKK

Sequence 30 from pa!iUS!6730659j30[53923198^"j Sequence 30 jSrOGRHFSAGALIl-IARFVMTAAS 2046 paten! US 6730659 from patent US 6730659 CFQ Sequence 32 from ipat!U8!707129313211120627371Sequence 32 R IIRKITHII 2071 patent US 7071293 from patent US 7071293

Sequence 32 from Sequence 32 from patent US 7078380 GiG FLHSAK FGKAFVAEL l 2072 patent US 7078380 s

Sequence 32 from !pa!iUS!709118513211157942151Sequence 32 KPKKFKKPKKFKKFKKFKKFK Hi ! -> paten! US 7091 185 from patent US 7091 185 KPKKFKKPKKFKKFKKFKKFK

KPKKFKKPKKFKKFKKFKKFK

Sequence 32 from |patjUS|7314 58J32[l67 46755iSequence 32 RCLCGRGFC 2074 patent US 7314858 from patent US 7314858

Sequence 33 from [3407544]Sequence 33 from patent US OGACRAIRRTPRRIRGLERIL 2075 patent US 5714577 5714577

Sequence 33 from J40Q1493]Sequence 33 from patent US HPQKNTY 2076 patent US 5798336 5798336

Sequence 33 from pat!US!6492328i33[29695243 jSequence 33 KNLRRIIRKGIRII KYG 2077 patent US 6492328 from patent US 6492328

Sequence 33 from pat!US!6730659i33 53923201]Sequence 33 OGRHFCAGALIHARFVMTAA 2078 patent US 6730659 from patent US 6730659 SSFO

Sequence 33 from pat|US!6S35536|33|^"59754037]Sequence 33 KRKWPWWPWRLI 2079 patent US 6835536 from patent US 6835536

Sequence 33 from Sequence 33 from patent US 6864068 OKLCORPSGTWSGVCG NNAC 2080 patent US 6864068 KNOCIRLEKARHGSC AVFPAH

CiCYFPC

Sequence 33 from pal!US!6906035|33f74472316]Seqoence 33 KKWWKX 2081 patent U S 6906035 from patent US 6906035

Sequence 33 from !pat|USi7071293|33f 1 120627381Se<roence 33 RliRKIlHTIK 2082 patent US 7071293 from patent US 7071293

Sequence 33 from Sequence 33 from patent US 7078380 2083 patent US 7078380 s

Sequence 33 from |pat!US!7091 1 85 ^"S 1 1 15794216jSequence 33 FKAFKA 2084 patent US 7091 185 from, patent US 7091 185

Sequence 33 from !pat!US!7314858!33[ 167246756JSeqtsenc 33 RCICRRGVC 2085 patent US 7314858 from patent US 7314858

Sequence 34 from !^"3407545]Sequence 34 from patent US GACRATRRIPRRIR 2086 patent US 5714577 5714577

Sequence 34 from [4001494]Sequence 34 from patent US HPOFNOR 2087 patent US 5798336 5798336

Sequence 34 from Sequence 34 from patent U S 6605698 QKLCERPSGTWSGVCGN^'NNAC 2088 patent US 6605698 KNQCINLEKARHGSCNYVFPAH

KCICYFPC

Sequence 34 from pa !US 16730659j 34f 5392.3202] Sequence 34 OGRHFCGAALiHARFVMTAA 2089 patent US 6730659 from patent US 6730659 SSFO

Sequence 34 from pat!USi6835536|34i597540391Sequence 34 ILKWVWWV RRK 2.090 patent US 6835536 from patent US 6835536

Sequence 34 from Sequence 34 from patent U S 6864068 OKLCORPSGTWSGVCGNNNAC 2091 patent US 6864068 KNOCIRLEKARHGSCNYVAPA

HKCICYFPC

Sequence 34 from pat!US!6906035|34i744723171Sequence 34 KWKSFIKK ?0Q patent US 6906035 from patent US 6906035

Sequence 34 from ipaiiUSi707i293i34fl 12062740jSeqisence 34 RIIRKIIHII 2093 patent US 7071293 from patent US 7071293

Sequence 34 from Sequence 34 from patent US 7078380 AAGKFLHSAKKFGKAFVGDTM 2094 patent US 7078380 NS

Sequence 34 from !pa!iUS!7091185!34il 1579421 SISequence 34 FKAFKAFKAFKA 2095 patent US 7091185 from patent US 7091 185

Sequence 34 from ipatiUSi7314858i34ri672467571Seqoence 34 RCICRRGFC 2096 patent US 7314858 from patent US 73 14858

Sequence 35 from |3407546]Sequence 35 from patent US GACRA1RRIPRR1RGLER1L 2097 patent US 5714577 5714577

Sequence 35 from [4001495 jSequence 35 from patent US HPNYNOR 2098 patent US 5798336 5798336

Sequence 35 from patiUSi619i254|35il4i 19983]Sequence 35 FFKKWPWWPWRR 2099 patent US 6191254 from patent US 6191254

Sequence 35 from Dat!US!6492328i351296952451Sequence 35 KRLRR1IRKG1H1IK YG 2100 patent US 6492328 from patent US 6492328

Sequence 35 from Sequence 35 from patent US 6605698 OKLCORPSGTWSGVCGN NAC 2101 patent US 6605698 K OCIRLEKARUGSC YVFPAI-I

KCiCYFPC

Sequence 35 from pafiUSi6730659j35[53923203 [Sequence 35 NOGRHFCAAAL1HA FVMTAA 2102 patent US 6730659 from patent US 6730659 SSFO

Sequence 35 from p at ! I J S i 6835536135 Γ 59754041 [Sequence 35 IL KWAWWPWRRK 2103 patent US 6835536 from patent US 6835536

Sequence 35 from Sequence 35 from patent US 6864068 QKLCQRSGTWSGVCG NNACK 2104 patent US 6864068 NQCIRLE ARHGSCNYVFPAHK

CICYFPC

Sequence 35 from patiUSi6906035i35j74472318]Sequence 35 WWRRXXXGL TAGPAIOSV 2105 patent US 6906035 from patent US 6906035 L.X.K

Sequence 35 from Sequence 35 from patent US 7078380 GGKFLHSAKKFGKAFVGEIMNS 2106 patent US 7078380

Sequence 35 from !pat!US!7091185!35|^"115794219^'jSequence 35 FKAFKAFKAFKAFKAFKA 2107 patent US 7091185 from aSent US 7091185

Sequence 35 from |pat!US!7314858I35N 672467581Sequence 35 RCICTRGVC 2108 patent US 7314858 from patent US 7314858

Sequence 36 from [3407547]Sequence 36 from patent US ORACRAIRHIPRRTR 2109 paten! US 5714577 5714577

Sequence 36 from | 4001496 |Sequence 36 from patent US HPEYNQR 2110 patent US 5798336 5798336

Sequence 36 from patlUSI6191254|36Γ141 19984] Sequence 36 FFKKFPFFPFRRK 211 1 patent US 6191254 from patent US 6191254

Sequence 36 from Sequence 36 from patent US 6605698 KLCERSSGTWSGVCGNNNACK 2112 patent US 6605698 OCiRLEGAOHGSCNYVFPAHK

CICYFPC

Sequence 36 from pa<IUS!6730659|36[53923204]Sequence 36 NOGRHFCGGALIHARFVMTAA 21 1 paten! US 6730659 from patent US 6730659 TCFO

Sequence 36 from patiUS!6835536|36i597540431Seq«ence 36 ILKKWPWWAWRR 2.114 patent US 6835536 from patent US 6835536

Sequence 36 from Sequence 36 from patent US 6864068 OKLCORPSGTWSGVCGNNNAC 2115 patent US 6864068 KNOCIRLEKARHGSCNYVPAH

KCiCYFPC

Sequence 36 from pai!US!6906035i36| 74472319 jSequence 36 KWKLFKKiGlGAVLKVLTTGLP 2116 patent US 6906035 from patent US 6906035 ALTS

Sequence 36 from Sequence 36 from patent US 7078380 GGKf IHSAKKFGKAFVGEIMNS 2117 patent US 7078380

Sequence 36 from |pat|US|7091185Ι36Γ l i5794220^'|Sequence 36 ' FKAFKAFKAPKAFKAFKAFKA 2118 patent US 7091185 from patent US 7091185

Sequence 36 from !pat!US!7314858Ι36ΙΊ 672467591Sequence 36 RCICTRGFC 2119 patent US 7314858 from patent US 73 34858

Sequence 37 from [3407548]Sequence 37 from patent US RACRAIRHIPRRIR 2120 patent US 5714577 5714577

Sequence 37 from [400 ί 497]Sequenee 37 from patent US HPLYNQR 2121 patent US 5798336 5798336

Sequence 37 from pat!US!6191254i37[ 141 39985jSequence 37 FF FPFFPFKKK 2122 patent US 6391254 from patent US 6191254

Sequence 37 from pat!US!6492328i37^"i29695247iSequence 37 RRLRRIiRKGIRliKKYG 2123 patent US 6492328 from patent US 6492328

Sequence 37 from Sequence 37 from patent US 6605698 OKLCER SSGTW SG VCG N A C 2124 patent US 6605698 KNOCINLEGA RHGSCNYIFPYH

RCiCYFPC

Sequence 37 from pat!US!6730659j37[53923205]Sequence 37 NOGRIiFCGGALKLARFLMTAAS 2125 patent US 6730659 from patent US 6730659 CFQ

Sequence 37 from patlUS!6835536|37f597540451Sequence 37 WWKKWPWWPWRRK 2126 patent US 6835536 from patent US 6835536

Sequence 37 from Sequence 37 from patent US 6864068 OKLCORR SGTW SGVCGNMN AC 2127 patent US 6864068 KNOCIRLEKARHGSC YVFPAH

KCiCYFPC

Sequence 37 from patlUS!6875907|37[62793188]Sequence 37 MVTKYICFLVLA SVLLAVAFPV 2128 patent US 6875907 from patent US 6875907 SALROOVKKGGGGEGGGGGSV

SGSGGGNLNPWECSPKCGSRCS KTOYRKACLTLCN CCAK.CLC VPPGFYGN GACPCYNNWKT EGGP CP

Sequence 37 from patiUS!6906035j37i^"74472320]Sequence 37 KWKLFKKIGIGAVLKVLTTGLP 2129 patent US 6906035 from patent US 6906035 ALKKTK

Sequence 37 from Sequence 37 from patent US 7078380 GiG ^'lHSAK FGKAFVGEIMNS 2130 patent US 7078380 K

Sequence 37 from |pat|US|70 1185Ι37Γ ΪΪ5794221 ISequence 37^" ' FKAFKAFKAFKAFKAFKAFKAF 2131 patent US 7091185 from patent US 7091 185 KA

Sequence 37 from jpatjU SI 7166769|37[ Ϊ 2516 Ϊ 893 [Sequence 37 MVTKVICFLVLASVLLAVAFPV 2132 patent US 7166769 from patent US 7166769 SALROOVKKGGGGEGGGGGSV

SGSGGGNLNPWECSPKCGSRCS

K^'T^'OYR ACLTLCNKCCAKCLC

VPPGFYGNKGACPCYNNWKTK

EGGPKCP

Sequence 37 from !pat!US!7314858!37i l 67246760]Sequence 37 RCICTLGIC 2133 patent US 7314858 from patent US 73 34858

Sequence 38 from [400i498]Sequence 38 from patent US RPGLTLCTVAGWG 2134 patent US 5798336 5798336

Sequence 38 from pat|US|6191254|38i l 41 39986iSequence 38 LKKWPWWPWWPWRRK 2135 patent US 6391254 from patent US 6191254

Sequence 38 from patlUSI6730659|38[53923206]Sequence 38 2136 paten! US 6730659 from patent US 6730659 CFO

Sequence 38 from patiUS 16743769j 38 [53934488 J Sequence 38 YAERLCXCSIKAEV 2137 patent US 6743769 from patent US 6743769

Sequence 38 from pat!US!6835536i38[59754047]Sequence 38 LKKWPWWPWRRK 2138 patent US 6835536 from patent US 6835536 Sequence 39 from ipat!U8i7 ! 66769!391125161897]Sequence 39 APSKLAVWALVASLLLLTTS 2.156 patent US 7166769 from patent US 7166769 NTKLGLFVLGOAAPGAYPPRAP

PPHOTVDLAKDCGGACDVRCG

AHSRKN1CTRACLKCCGVCRCV PACT AGNOOTCG KCYTDWTTH G KTKCP

Sequence 39 from ipat!US!7314858!39fl67246762]Sequence 39 RCiCRLGIC 2157 patent US 7314858 from patent US 7314858

Sequence 4 from patjUS!5221732|4f 34425578]Sequence 4 GTGKFLHSAKKFAKAFVAE1MN 2158 patent US 5221 732 from patent US 5221732 S

Sequence 4 from pat|USI5519115|4[1610230]Sequence 4 from xxxx 2159 paten! US 5519115 patent US 5519115

Sequence 4 from patjUSi56079!4!4i2096784]Sequence 4 from ORAVK TEKAI HIPK IKIRAL 2160 patent US 5607914 patent US 5607914 AGPG VTIGIA HAKSQL W

Sequence 4 from [3407515]Sequenee 4 from patent US FLIROLIRLLTWLFSNCRTLLSR 2161 patent US 5714577 5714577 YI

Sequence 4 from [3941 164] Sequence 4 from patent US GFFKKAWRKVKHAGRRVLDTA 2162 patent US 573401 5734015 KGVGRHYVNNWL RYR

Sequence 4 from [40Q1464]Sequence 4 from patent US HXXXXXX 2163 patent US 5798336 5798336

Sequence 4 from patiUS15856i27|4i5938883iSequence 4 from ASRAAGLAARLA LALR 2164 patent US 5856127 patent US 5856127

Sequence 4 from patlUSi6191254|4[ 34119952]Sequence 4 1LPW WPWWRWRR 2165 patent US 6191254 from patent US 6191254

Sequence 4 from pat ! Ό¾^" ! 6211 Ϊ48 i ij Ϊ 5 ί 08330^"i S equeiice 4 ERVRNPQSCRWNMGVCIPFLCR 2166 patent US 6211148 from patent US 621 1148 VGMRQ1GTCFGPRVPCCRR

Sequence 4 from Sequence 4 from patent US 6300489 MAGFS VVATIFLMMKVFATD 2167 patent US 6300489 MMAEAKiCEALSGNFKGLCLSS

RDCGNVCRREGFTDGSCIGFRL QCFCT PCA

Sequence 4 from patlUSI6399370|4[21517028 lSequen e 4 DHYNCVSSGGOCLYSACP1FTKI 2168 patent US 6399370 from patent US 6399370 OGTCYRGKAKCCK

Sequence 4 from Sequence 4 from patent US 6476189 ALLLAIR R 2169 patent US 6476189

Sequence 4 from pat|US|6492328|4i296952141Sequence 4 NLRR.TTR T1H1TKKYG 2170 patent US 6492328 from, patent US 6492328

Sequence 4 from Sequence 4 from patent US 6605698 HGSC YVFPAHKC1C 2171 patent US 6605698

Sequence 4 from pat|US|662414014140151052 lSequence 4 GKWKLFKKAFKKFLKJLLAG 2172 patent US 6624140 from patent US 662 140

Sequence 4 from patlUSI6638531|4f401638501Sequence 4 KRLF ELL SLRKY 2173 patent US 6638531 from patent US 6638531

Sequence 4 from pat!lJS!6642203|4 40i 88728] Sequence 4 MRLVVCLVFLASFALVCOGOV 2174 patent US 6642203 from patent US 6642203 YKGGYTRPIPRPPPFV^'RPLPGGP

IGPYNGCPVSCRGISFSOARSCC

SRLGRCCHVGKG

Sequence 4 from patlUSi673Q659|4[53923172]Sequence 4 RHFSGGALIHARi MTAASC 2175 patent US 6730659 from patent US 6730659

Sequence 4 from Sequence 4 from patent US 6743598 NVGFYEKCGY 2176 patent US 6743598

Sequence 4 from pai!US!6743769|4j ^"53934461 jSequence 4 Λ ίΟ Κ Κ Ι^' Κ Κ ! i .K S 2177 patent U S 6743769 from patent US 6743769 L

Sequence 40 from !pai!US! 7091185 !40 115794224] Sequence 40 FKAFKAFKAFK FKAFKAPKAF 2200 paten! US 7091185 from patent US 7091185 \ i s i \l^;K .\ i Λ Γ Κ \l KM

KAF KAFKA

Sequence 40 from jpatili Si 7166769|40[ Ϊ 25161900Ϊ Sequence 40 MAVA PPLOTAAVLLLLLLW 2201 patent US 7166769 from patent US 7166769 AAASWLOTVDAASGFCSSKCS

VRCGRAASA ARGACMRSCGL

CCEECNCVPTRPPRDVNECPCY

RDMLTAGPRKRPKCP

Sequence 40 from |pai|US|73 Ϊ4858|40Γ 167246763^'ISequence 4θ^" ' RCICVRGVC 2202 patent US 7314858 from patent US 7314858

Sequence 41 from pat!US!54479 i4j41 [998245]Sequence 41 IIGGRESRPHSRPYMAYLOTOSP 2203 patent US 5447914 from patent US 5447914 AGOSRCGGFLVREDFVLTAAH

CWGS iN LGAiF IDRRE TO

OHITARRAIRHPOYNORTIONDI

MLLOL SRRVRRNRNVNPVALP

RAOEGLRPGTLCTVAGWGRVS RRGTDTLREVOLRVORDROC

LRIFGSYDPRROICVGDRRERK

AAFKGDSGGPLLCNNVAHGIVS

YGKSSGVPPEVFTRVSSFLPW1R

TTMR

Sequence 41 from [400150 ljSequence 4 i from patent US nGGRESRPHSRPYMAYLQIQSP 2204 patent US 5798336 5798336 AGOSRCGGFLVREDFVLTAAH

CWGS INVTLGAHNIDRRENTO

OHITARRAIRHPOYNORTIONDI

MLLOLSRRVRRNRNV A'ALP

RAOEGLRPGTLCTVAGWGRVS

MRRGTDTLREVOLRVORDROC

LRIFGSYDPRROICVGDRRERK

AAFKGDSGGPLLCNNVAHGIVS

YGKSSGVPPEVFTRVSSFLPWIR

TTMR

Sequence 41 from pat|US|6191254|4i r i41 199891Seauence 41 IL KWPWWPWPPRRK 2205 patent US 61 1254 from patent US 6191254

Sequence 41 from patiU8i6 1470 i |41 Γ297142571Sequence 4 ί NOGRHF CGGAI JHAR YVMT AA 2.206 patent US 6514701 from oatent US 65 14701 SCFO

Sequence 41 from Sequence 41 from patent US 6605698 OKLCERPSGTWSGVCGNNNAC 2207 patent US 6605698 KN

Sequence 41 from patiUSj6835536[41 |^"59754053]Sequenee 41 ILKKWPWWPWRRMILKKAGS 2208 patent US 6835536 from rjafent US 6835536

Sequence 41 from Sequence 41 from patent US 6864068 OKLCORPSGTW SGVCGNNN AC 2209 patent US 6864068 NOCiRREKARHGSCNYVFPAH

CiCYFPC

Sequence 41 from pallUSi6875907|411627931921Sequence 41 TTMKKKKOOOOLLLLSLM 2210 patent US 6875907 from patent US 6875907 FLVAVTAAAVAADPHPOOVOV

OOOOOA MRXNRATR8LLPQPP

P LDCPSTCSVRCGNNWKNOM

CNKMCM' CCN CSCVPPGTGO

DTRHLCPCYDTMLNPHTGKLK

CP Sequence 41 from Sequence 41 from patent US 6936432 LRLLTPIOFKRLGLTVAKKHLK 221 1 patent US 6936432 RAHERNRIKRLVRELDFVFFAQI

L

Sequence 41 from patiUS!7091 Ϊ85|411^" I Ϊ 57942261 Sequence 4 Ϊ !· ΚΛ ! \FK.\ i AFK \ i^' .\i \F 2212 patent US 7091185 from patent US 7091 185 AFKAF AF AFKAF AFKAF

AFKAF AF AFKAF AFKA

Sequence 41 from pat!US!7166769|41 [ 12516! 9031Sequence 41 M TTMKKKKOOOOLLLLSLM 2213 paten! US 7166769 from patent US 7166769 FLVAVTAAAVAADPHPOOVOV

OOOOOAOMRINRATRSLLPOPP

PKLDCPSTCSVRCGN WK OM CNKMCNVCCNKCSCVPPGTGO DTRHLCPCYDTMLNPHTGKLK CP

Sequence 41 from !patlUS! 7314858|41 [ 1672467641 Sequence 41 RCICGRGFC 2214 patent US 7314858 from patent US 7314858

Sequence 42 from [3407553]Sequence 42 from patent US LTRELGORIRRPTHR1ARCAGOV 2215 patent US 5714577 5714577 VEiVR

Sequence 42 from [4001 02^'jSequence 42 from patent US PGOTCSVAGWGOTAPLG S 2216 patent US 5798336 5798336

Sequence 42 from ρ8⁽!ϋ§!619Ϊ254|42ΪΪ4ί 19990 Sequence 42 ILKKWPWWPWPPFFRRK 2217 patent US 6191254 from patent US 6191254

Sequence 42 from Sequence 42 from patent US 6605698 OKLCERPSGTWSGVCG. NNAC 2218 patent US 6605698 KNOC

Sequence 42 from pat!USi6730659j42i539232101Sequence 42 OGRHFCGGALil-LARFVMTAA 2219 patent US 6730659 from patent US 6730659 SCYO

Sequence 42 from patiUSI6835536|42i597540551Sequence 42 ILK WPWWPWRRIMILKKAGS 2220 patent US 6835536 from patent US 6835536

Sequence 42 from Sequence 42 from patent U S 6864068 O LCORPSGTWSGVCGNNNAC 2221 patent US 6864068 KNQCIRLEKARHGSCRYVFPAH

CiCYFPC

Sequence 42 from pat[US|6875907|42[62793193 JSequence 42 MKAIPVALLLLVLVAAASSFKH 2222 patent US 6875907 from, patent US 6875907 LAEAA DGG VPDGVCDG C S

RCSLKKAGRCMGLCMMCCGK COGCVPSGPYASKDECPCYRD MKSPKNORPKCP

Sequence 42 from: Sequence 42 from patent US 6936432 KRLLTPRHFKRLGLVIGK SVK 2223 patent US 6936432 LA VOR RLKRLMRDLDIVILHO

HF

Sequence 42 from !pat|US!7091185j42 l 15794227]Sequence 42 LKLK 2224 patent US 7091185 from Daient US 7091185

Sequence 42 from ipatjUSI 7166769142 Γ 125161.905] Sequence MKAIPVALLLLVLVAAASSFKH 2225 patent US 7366769 42 from patent US 7166769 LAEAA..DGG AVPDGVCDGKCR S

RCSLKKAGRCMGLCMMCCGK COGCVPSGPYASKDECPCYRD MKSPKNORPKCP

Sequence 42 from !pat!US!7314858!42[ 1672467651Sequence 42 RCICGLGFC 2226 patent US 7314858 from patent US 7314858

Sequence 43 from [3407554]Seq«ence 43 from patent US LIRF.LGORIRRPTHRIARCAGOV 2227 patent US 5714577 5714577 VEIVR

Sequence 43 from [4001503]Sequence 43 from oat ent US KI^ODVCYVAGWGRMAPMGKY 2228 patent US 5798336 5798336 Sequence 47 from 400i 507]Sequence 47 from patent US AAGTTCVTTGWGLT YT A 2.267 patent US 5798336 5798336

Sequence 47 from Sequence 47 from patent U S 6605698 QRPSGTWSGVCGNNN 2268 patent US 6605698

Sequence 47 from pal !US 16730659| 47Γ5392.32151 Sequence 47 RHFSGGALIHARFIMTAASC 22.69 paten! US 6730659 from patent US 6730659

Sequence 47 from pat!US|6835536j47i59754065]Sequence 47 1LK WPWWPWRR1M 2270 patent US 6835536 from patent US 6835536

Sequence 47 from patiUS!6875907|47[62793198]Seq«ence 47 M LRTTTI.AI.LLLLVFLAASS 227 i patent US 6875907 from patent US 6875907 LRAAMAGSAFCDGKCGVRCS

ASRHDDCLKYCGiCCAEC CVP

SGTAG KDECPCYRDKTTGHG

ARKRP CP

Sequence 47 from Sequence 47 from patent US 6936432 iRLPATSTRIGLTVAK WRRA 9979 paten! US 6936432 HERNR!KRLTRELDF LSEAL

Sequence 47 from ipat!US ! 7091185147 11 794232 J Sequ e nee 47 LKLKLKLKLKLKLKLKLKLKLK 2273 patent US 7091185 from patent US 7091 1 85

Sequence 47 from ipat!USi 71667ό9ί47Τ 1251619171 Sequence 47 ' MKKLRTTTLALLLLLVFLAASS 2274 patent US 7166769 from patent US 7166769 LRAAMAGSAFCDGKCGVRCSK

ASRHDDCLKYCGICCAECNCVP

SGTAGNKDECPCYRDKTTGHG

ARKRPKCP

Sequence 48 from j 3407559 [Sequence 48 from patent US LIRRLGORIRRPIHRIARCAGOV 2275 patent US 5714577 5714577 VEIVR

Sequence 48 from [4001508 ISequence 48 from patent US GiGKFLHSAKKFKAFVGElMN 2276 patent US 5798336 5798336

Sequence 48 from Sequence 48 from patent US 6605698 GTWSGVCGNNNA CKN 2277 paten! US 6605698

Sequence 48 from pati¾S|6730659|48i539232f61Sequence 48 RHFSGGALIHARFAMTAASC 2278 patent US 6730659 from patent US 6730659

Sequence 48 from patiUSj6835536|48[59754067]Sequence 48 ILKKWWWPWRK 2279 patent US 6835536 from patent US 6835536

Sequence 48 from pai|US|6875907|48i62793199jSeq«ence 48 MKKLRTTTATTTLALILLLVLIA 2280 patent US 6875907 from patent US 6875907 ATSLRVAMAGSAFCDSKCGVR

CSKAGRHDDCLKYCGICCAEC NCVPSGTAGNKDECPC^'YRDKT

TGHGARTRPKCP

Sequence 48 from Sequence 48 from patent US 6936432 LRLLTPEHYQRLGLAVPKKQIK 2281 paten! US 6936432 TAVGRNRFKRICRELDFVVLFN

LL

Sequence 48 from. ipat!lJSi7091185!48n i5794233]Sequence 48 LKLKLKLKLKLKLKLKLKLKLK 2282 patent US 7091 185 from patent US 7091 185 LK

Sequence 48 from pallUSI7166769|48[125161919JSequence 48 MKKLRTTTATTTLALILLLVLIA 2283 patent US 7166769 from pa!ent US 7166769 ATSLRVAMAGSAFCDSKCGVR

CSKAGRHDDCLKYCGICCAEC NCVPSGTAGNKDECPC^'YRDKT

TGHGARTRPKCP

Sequence 48 from !pa!!US! 7314858148 [ 167246771 J Sequence 48 RCLCTRCVC 2284 paten! US 7314858 from patent US 7314858

Sequence 49 from [3407560]Sequence 49 from patent US RIRRPfflRIARCAGOWEFVR 2285 patent US 5714577 5714577

Sequence 49 from [4001509]Sequence 49 from patent US HPOYNPK 2286 patent US 5798336 5798336

Sequence 49 from Sequence 49 from patent US 6605698 GVCGNNNACKNOCIR 2287 patent US 6605698

Sequence 49 from pat|USj673^"0659i49i53923217iSequenee 49 KHYSGGALIHARFVMTAASC 2288 patent US 6730659 from patent US 6730659

Sequence 49 from pat!US!6835536i49i59754069jSequence 49 ILKKWPWWWRK 2289 patent US 6835536 from patent US 6835536

Sequence 49 from pat!US!6875907i49 62793200jSequence 49 MKPLPVTLALLALFLVASYODL 2290 patent US 6875907 from patent US 6875907 TVAADADADAAGAGDVGAVP

VPDS VCEGKCK C SOKV AG R CMGLCMMCCGKCAGCVPSGPL APKDECPCYRDMKSPKSGRPK

CP

Sequence 49 from Sequence 49 from patent US 6936432 KRLLTAROFSRLGLV1GKK VK 2291 patent US 6936432 LA VORNRLKRLIRELDIV VLHO

F

Sequence 49 from !patlUS!7091185!49[115794234]Sequence 49 LKLKLKLKLKLKLKLKLKLKLK 2292 patent US 7091185 from patent US 7091185 LKLKLKLKLKLKL

Sequence 49 from !pat!US! 7166769!49f 125161922] Sequence 49 MKPLPVTLALLALFLVASYODL 2293 patent US 7166769 from patent US 7166769 TVAADADADAAGAGDVGAVP

VPDS VCEGKCKNRC SOKV AG R CMGLCMMCCGKCAGCVPSGPL APKDECPCYRDMKSPKSGRPK CP

Sequence 49 from !pat|USi7314858|49f l 672467721Sequence 49 RCLCTRGFC 2294 patent US 7314858 from patent US 73 14858

Sequence 5 from patlUSi5221732|5f34425579]Sequence 5 IGKFLHSA KFAKAFAFVAEIM 2295 patent US 5221732 from patent US 5221732 M

Sequence 5 from pai|US!5519115i5[16l^"023 liSequenee 5 from xxxxx 2296 patent US 5519115 patent US 5519115

Sequence 5 from pai!US!5607914|5!20967851Sequence 5 from IORVAO LKKALRALARH KR 2297 patent US 5607914 patent US 5607914 ALAGPGVTIGIAHAKSOLW

Sequence 5 from j^"3407516jSequence 5 from patent US LLSRVYOILOPILORLSATLORIR 2298 patent US 5714577 5714577 EVER

Sequence 5 from |4001465]Sequence 5 from patent US HPAYNPK 2299 patent US 5798336 5798336

Sequence 5 from patiTJS!5856127|5f5938884]Se<fuence 5 from ' VSRAAGLAARLARLALR 2300 patent US 5856127 patent US 5856127

Sequence 5 from pat|US|5998374|5f 100663121Sequence 5 MKTTTLTLL1LGLGINAKSLEERK 2301 patent US 5998374 from patent US 5998374 SEEEKVFHLLGKJIHHVGNFVY

GFSHVFGDDOODNG FYGHYA

ED GKHWYDTGDO

Sequence 5 from pat 1 US!621 ί Ϊ4815i Ϊ 510833 Ϊ ] S equeiice 5 EVVRNPOSCRW MGVCIPISCP 2302 patent US 6211148 from patent US 621 1148 GNMRQ1GTCFGPRVPCCR

Sequence 5 from Sequence 5 from patent US 6476189 AWLLAiRKR 2303 patent US 6476189

Sequence 5 from pat!US|6492328j 5 [29695215]8equence 5 KNLRRSIRKilHiiKKYG 2304 patent US 6492328 from patent US 6492328

Sequence 5 from Sequence 5 from patent US 6605698 CN YVFPAHKC 2305 patent US 6605698

Sequence 5 from pat!US!6624140|5i4015 i 053] Sequence 5 CGGGGGGGGGKWKAFKKAFK 2306 patent US 6624140 from patent US 6624140 KFAKILACG

Sequence 5 from pat !US 1663853 1 j 5 [401.63851 ] S equ ersce 5 XXLFXELXXSLXXY 2307 patent US 6638531 from patent US 6638531

Sequence 5 from pat!US!6642203|5i401887291Sequence 5 YRGGYTGPiPRPPPIGRPPLRLV 2308 patent US 6642203 from patent US 6642203 VCACYRLSVSDARNCCIKFGSC

CHLVK

Sequence 5 from pat!USi6696559i5[47235323]Sequence 5 MKl'AC^'ALLALLGLATSCSFIVF 2309 patent US 6696559 from patent US 6696559 RSEWRALPSECSSRLGHPVRYV

VISHTRGSFCNSFDSCEOOARN

VOHYHK ELEWCDVAY KED

HTEPIYNPMSIGITFMG FMDR

VRKAALRAALNLLESGVSRGFL

RS YEVKGHRDVOSFLSFGDO

KYOVIO S WEHYRE

Sequence 5 from patiUS!6730659j5i539231731Sequence 5 NOGRHFCGGALIHARFVMTAA 2310 patent US 6730659 from patent US 6730659 SSFO

Sequence ^ from Sequence 5 from patent US 6743598 i i iA V VHK YQGQG i i i U ! !'« i 2311 patent US 6743598

Sgquencejjrom ρ ί!υ5ίό743769|5ί53934462 |8_ε¾ιιεηοε 5 KLYRKF NKLLKLK 2312 a US 74376 from patent US 6743769

Sefli!OTce.5 from paliUSj6747007|5[53937630]Sequence 5 RRWCFRVCYRGFCRYFCR 2313 patent US 6747007 from patent US 6747007

Sequence 5 from patiUS!6753407|5i53972395!Sequence 5 H1FR 2314 patent US 6753407 from patent US 6753407

Sg^g!Ke S. from Sequence 5 from patent US 6790833 KPF1RKS YK CLH RCR 2315 patent US 6790833

Sequence 5 from pat|US|68 i 84l)7|5[56646444iSequence 5^" KWK F1KSLTKSAAKTVVKTA 2316 patent US 6818407 from patent US 6818407 E PLIV

Sequence 5 from pat|US|6838435|5[597614241Sequence 5 AGDES 2317 patent US 6838435 from patent US 6838435

Sequence 5 from patiUSi6872705|5r627882 41Sequence 5 KWKLF XIEKVGO 1RDGI1KA 2318 patent US 6872705 from patent US 6872705 GPAVAVVGQATQIAK

Sequence 5 from p_atlUS|6884776|5 6758Q424jSequence S VA OEKK K TGRAKRR 2319 patent US 6884776 from patent US 6884776

Sequence 5 from ^r"pat|US|6887847|5r6758468 ] jSequence 5 RRWRRVRRWRRWRW RV 2320 patent US 6887847 from patent US 6887847 VRR

Sequence 5 from pat|US|6906035|5f744722881Sequence 5 KWKSFIKNLEK.VLKPGGl.LSNi 2321 patent US 6906035 from patent US 6906035 VTSL

Sequence 5 from pat|US!691 J 524!5j74479802 ]Sequence 5 HXHXCTSYXCXKFCGTAXCTX 2322 patent US 691 1524 from patent US 69 ! 1524 YXCRXLHXGKXCXCXHCSR

Sequence 5 from !paljUS!7071293j5[l 12062695]Sequence 5 RGLRRLGRKIAHGVKKYG 2323 patent US 7071293 from patent US 7071293

Sequence 5 from Sequence 5 from patent US 7078380 GSSKSPSKKKKKKPGD 2324 patent US 7078380

Sequence 5 from !pat|USj709 185|5j 1 5794185 JSeqiience 5 KFAKKFAKKFAKKFAKKFAKK 2325 patent US 7091 185 from patent US 7091 185 FAKKFAKKFAK

Sequence 5 from CKPV 2326 i[OmiHjtejiLiJS 244710

Sequence 5 from !pat!US!7314858Ι5Π 67246732]Sequence 5 GYCRCiCGRGICRCICGR 2327 patent US 7314858 from patent US 7314858

Sequence 50 from [3407561]Sequence 50 from patent US RIRRPIHRTARC AGOWRIVR 2328 patent US 5714577 5714577

f4001510jSequence 50 from patent US HPOY PR 2329

_EatOTt US 798336 579J336 patent US 5798336 5798336

Sequence 52 from pat!US!6730659|52i539232201Sequence 52 RHFCGAALTHARFVMTAASS 2348 patent US 6730659 from patent US 6730659

Sequence 52 from patilJ¾6875 b7[52I62793203 ]Sequence 52 MLLLALAAHHQAASDPPATHG 2349 patent US 6875907 from patent US 6875907 GMRASGTRSLLOOOPPPPRLDC

P VCAGRCANNWR EMC D CNVCCORCNCVPPGTGODTRHi CPCYATMTNPHNG L CP

Sequence 52 from Sequence 52 from patent US 6936432 TSLKNO EFELGIKVSRKLNKK 2350 patent US 6936432 AWRNKIKRR1RIISNAIIILOYEL

Sequence 52 from jpat[USi709l i85[52iii57¾^"238iSequence 52 ' LRLRLRLRLRLRLRLRLR 2351 patent US 7091185 from patent US 7091185

Sequence 52 from !pa!iUS!73 ! 485815211 672467751Sequence 52 RCiCGRGIC 2352 patent US 7314858 from patent US 7314858

Sequence 53 from [3407564]Sequence 53 from patent US RiRRPIRRIARCAGOVVEIVR 2353 patent US 5714577 5714577

Sequence 53 from 14001513]Sequence 53 from patent US HPDY OR 2354 patent US 5798336 5798336

Sequence 53 from pai!USi6730659|53| 539232211Sei uence 53 RHFCAAALIHARF V TAAS S 2355 patent US 6730659 from patent US 6730659

Sequence 53 from pai|US!6875907|53i627932041Sequeoce 53 DCVGACDARCSEHSHKKRCS 2356 patent US 6875907 from patent US 6875907 RSCLTCCSACRCVPA.GTAG RE

TCGRCYTDWVSHN TK.CP

Sequence 53 from Sequence 53 from patent US 6936432 ERLRKRPDFLRVGFTATKKIGG 2357 patent US 6936432 AVERNRAKRRLREPLHDYVFLL

DDVKTAL

Sequence 53 from !pat!U S! 709 Ϊ 185 ! 53 [ ϊ Ϊ5794239 jSequence 53 LRLRLRLRLRLRLRLRLRLRLR 2358 patent US 7091185 from patent US 7091185

Sequence 53 from !patilJS!7 ! 66769i53ni25 i6i93 HSequence 53 MAPGKLAVFALI.ASLI.LLNTIK 2359 patent US 7166769 from patent US 7166769 AADYPPAPPLGPPPHKIVDPG

DCVGACDARCSEHSHKKRCSR SCLTCCSACRCVPAGTAGNRET CGRCYTD\ SH NMT CP

Sequence 53 from !pat!US! 7166769153 N 25 i 61 93 1 lSequence 53 MLLLALAAHHOAASDPPA.THG 2360 patent US 7166769 from patent US 7166769 GMRASGTRSLLOOOPPPPRLDC

PKVCAGRCANNWRKEMCNDK CNVCCORCNCVPPGTGODTRHI

CPCYATMTNPHNGKLKCP

Sequence 53 fr m: ipatiUSi7314858i53f l672467761Seoueace 53 RCICRLGVC 2361 patent US 7314858 from patent US 73 \ 4858

Sequence 54 from [3407565]Sequence 54 from patent US RiRRPiHRIIRCiGOVVRIVR 2362 patent US 5714577 5714577

Sequence 54 from [4001514|8equenee 54 from patent US YPCYDEY 2363 patent US 5798336 5798336

Sequence 54 from pat!US!6730659i54f53923222]Sequence 54 RHFCGGALIHARFLMTAASS 2364 patent US 6730659 from patent US 6730659

Sequence 54 from patiU8j6835536j54i59754079]Sequence 54 ILKKWPWWPWRRK 2365 patent US 6835536 from patent US 6835536

Sequence 54 from patiUS!6875907|54[62793205]Sequence 54 LRPWECSPKCAGRCSNTOYKK 2366 patent US 6875907 from patent US 6875907 ACLTFCNKCCAKCLCVPPGTYG

NKGACPCYNNWKTKEGGPKCP Sequence 54 from Sequence 54 from patent US 6936432 DSLKN SEFDKLGLSVSKKVGN 2.367 patent US 6936432 AV RNUK ELRSCOALVFLEK

HFLEML

Sequence 54 from IpatlUSI 70 Ϊ Ϊ 85154Γ ϊ Ϊ 5794240^'i Sequence 54 ' KGK GKJ GKKG KGKKGK G 2368 patent US 7091185 from patent US 7091 185 KKGKKGKKGKKGK

Sequence 54 from ipat!US!73 4858!54[ 167246777i ence 54 CICRLGFC 2369 patent US 7314858 from patent US 7314858

Sequence 55 from [3407566]Sequence 55 from patent US RiRRPIRRIiRCIGOWEIVR 2370 patent US 5714577 5714577

Sequence 55 from [40Q1515]Sequence 55 from patent US HPDYNPK 2371 patent US 5798336 5798336

Sequence 55 from Sequence 55 from patent US 6605698 YVTPAHKCICYFPC 2. j / 1 paten! US 6605698

Sequence 55 from patjij SI6730659! 55] 53 23223 j Sequence 55 RHFCGGALIHARF1MTAASS 2373 patent US 6730659 from patent US 6730659

Sequence 55 from pat!US!6835536 55f5975408 l]Seqwence 55 ILKK V VWRRK 2374 patent US 6835536 from patent US 6835536

Sequence 55 from pat|USi6875907|55i627932^'06{Sequence 55 MK V AF VA VLLiCLVLS S SLFE VS 2375 patent US 6875907 from patent US 6875907 MAGSAFCSS CA RCSRAGM

DRCTOFCGICCSKCRCVPSGTY GNKliECPCYRDMK SKGKPKC P

Sequence 55 from ipaiili Si 709 ϊ i 85 ! 55 f ϊ Ϊ5794241 [Sequence 55 GKKGKKGKKG GKKGKKG 2376 paten! US 7091185 from patent US 7091185 KKGK GK GK GK GKKGKK

GK G

Sequence 55 from |pat!US!7314858!55i l 67246778]Sequence 55 RCiCTLGVC 2377 patent US 7314858 from patent US 73 1 858

Sequence 56 from [3407567]Sequence 56 from patent US LiRELGORIRRPIHRlARCAGOV 2378 patent US 5714577 5714577 V

Sequence 56 from [400!516]Sequenee 56 from patent US HPDYNPD 2379 patent US 5798336 5798336

Sequence 56 from Sequence 56 from patent US 6605698 DGVKLCDVPSGTWSGHCGSSS 2380 paten! US 6605698 CSOOCKDREI-1FAYGGACHYO

FPSVKCFC ROC

Sequence 56 from pat! SI673 659! 56? 539232241 Sequence 56 RHFCGGALIHA FAMTAASS 2381 patent US 6730659 from patent US 6730659

Sequence 56 from patiUS!6835536|56f59754083]Seq«ence 56 1L WPWWVWRR 2382 patent US 6835536 from patent US 6835536

Sequence 56 from pat|US|6875907|56|^'627932^'07{Seq«ence 56 MK V AF AA VLLiCLVLS S SLFE VS 2383 patent US 6875907 from patent US 6875907 MAGSAFCSSKCSKRCSRAGMK

DRCMKFCGiCCSKO CVPSGTY GN HECPCYRDMKNS GKAKC

£

Sequence 56 from Sequence 56 from patent US 6936432 D F ST EEF S IAV VA SKKVGK 2384 paten! US 6936432 AWRNRSKRILRALQKYIFLEK

LKWGL

Sequence 56 from Sequence 56 from patent US 7001924 OPHRLLKKNHFDFVFOSAKKTP 2385 patent US 7001924 TDDFiFLFRENKLGYARLGLALS

KKMIAKAHDRNRTKRLLRESFR HTNLP AVDiiTL ARPGL A KTNL G1NTKLNKTWEKLASCYGK

Sequence 56 from |pat|USI7091 185156! 115794243JSequence 56 KTi TK TKKTi TKJ -TK TK 2386 patent US 7091185 from patent US 7091 185

Sequence 56 from ipat!U8!7314858!5611672467791Sequence 56 RCICTLGFC 2387 patent US 7314858 from patent US 7 14858

Sequence 57 from |3407568]Sequence 57 from patent US LIRELRQRIRRPIHRIARCARQ V 2388 patent US 5714577 5714577 V

Sequence 57 from f4001517]Sequence 57 from patent US HPDY AT 2389 patent US 5798336 5798336

Sequence 57 from Sequence 57 from patent US 6605698 LC ERPSOTWSGNCGNTAHCD 2390 patent US 6605698 OCODWEKASHGACHKRENH

W CFCYFNC

Sequence 57 from ^'pai!USi6730659!57153923225]Sequence 57 RHYCGGAL1HARFVMTAASS 2391 patent US 6730659 from patent US 6730659

Sequence 57 from pat!US!6835536j57[59754085]Sequence 57 ILKKWVWWPWRRK 2392 patent US 6835536 from p _x atent US 6835536

Sequence 57 from Sequence 57 from patent US 6864068 GKLCERP8RTWSGVCGNNNAC 2393 patent US 6864068 NOC1NLE ARHGSC YVFPAH

CiCYFPC

Sequence 57 from pal|US!6875907|57j^"62793208]Sequence 57 MKLEFA VLLLCLVLSSSFLEIS 2394 paten! US 6875907 from patent US 6875907 MAGSPFCDS CAORCAKAGVO

DRCLRFCGICCEKC CVPSGTY GNKDECPCYRDMKNS GKDKC

£

Sequence 57 from Sequence 57 from patent US 6936432 YRLE TDDFSRiGLWGKKTA 2395 patent US 6936432 RAMiR YMKRVIRDLDFWAR

AEL

Sequence 57 from !pat!US!7091185!57|^"115794244]Sequence 57 KI^'AK 2396 patent US 7091185 from paient US 7091185

Sequence 57 from !pat!US!7i66769!57N 25161 942]Sequence 57 MKLEFANVLLLCLVLSSSFLEIS 2397 patent US 71 6769 from paient US 7166769 MAGSPFCDSKCAORCAKAGVO

DRCLRFCGICCEKCNCVPSGTY GNKDECPCYRDMKNSKGKDKC

Sequence 57 from ipat!US!731485815711672467801Sequence 57 RCICVLGVC 2398 patent US 7314858 from patent US 73 1 858

Sequence 58 from [3407569]Sequence 58 from patent US LiRELGORiRRPIHRlARCAGRV 2399 patent US 5714577 5714577 V

Sequence 58 from 14001518]Sequence 58 from patent US HPAYDDK 2400 patent US 5798336 5798336

Sequence 58 from Sequence 58 from patent US 6605698 ELCEKASKTWSGNCGNTGHCD 2401 patent US 6605698 NOCKS WEGAAHGACHVRNGK

HMCFCYFNC

Sequence 58 from pati¾S|6730659|58i539232261Sequence 58 RHFCGGALIHAR YVMTAAS S 2402 patent US 6730659 from patent US 6730659

Sequence 58 from pat!USi6835536|581597540871Sequence 58 ILRWVWWVWRR 2.403 patent US 6835536 from patent US 6835536

Sequence 58 from Sequence 58 from patent US 6864068 QKLCERPSGTWSGVCGNNNAC 2404 patent US 6864068 KNOCINLEKARHGSCNYRFPAH

KCiCYFPC patent US 6835536 from oaient US 68.35536

Sequence 60 from Sequence 60 from patent US 6864068 iXMRPSGTWSGVCG NNAC 245 I patent US 6864068 \On\!.HK.\R}-KiS( \V\TP\H

KCiCYFPC

Sequence 60 from patiUS!6875907|60f 62793211 ^Sequence 60 MAISKSTVVVViLCFiLiOELGlY 2452 patent US 6875907 from oaient US 6875907 GEDPHMDAAKKIDCGGKCNSR

C ^'SKARROKMC1RACNSCCKKC RCVPPGTSGNRDLCPCYARLTT HGGKLKCP

Sequence 60 from Sequence 60 from patent US 6936432 DRLROKVAiORLGLAVSR VG 2453 paten! US 6936432 NAVVR RiKRRLRETDVLVMG

AYL

Sequence 60 from Sequence 60 from patent US 70 1924 MANFiSLK NEDlLDTlK OOKI 2454 patent US 7001924 HSMJiVVYFRKTNLKNVRLAlSi

SKKKl'KLAl^'ORNRlRRLI AWFI AADIP1KSYD1VVLVKPSFIDGSF VLNCNNLKHLORIINKEKR

Sequence 60 from ipat|US|70911851601115794247]8equence 60 LKLKL LKLKL L 2455 patent US 7091185 from patent US 7091185

Sequence 60 from jpa!:iUSi7314858j60p 67246783]Sequence 60 RCLCGLGIC 2456 paten! US 7314858 from patent US 7 14858

Sequence 61 from j 3407572 ISequence 61 from patent US LIRELGIR1RRPIHRIARCAGQVV 2457 patent US 5714577 5714577

Sequence 61 from Sequence 61 from patent US 6605698 2458 patent US 6605698

Sequence 61 from patiUS!6835536|6i Γ59754093 ISequence 61 ILRWWVWWVWWRRK 2459 patent US 6835536 from patent US 6835536

Sequence 61 from Sequence 61 from patent US 6864068 OKLCERPSGTWSGVCMN AC 2460 paten! US 6864068 NOCINLEKARHG -SCNYVFPAH

KCiCYFPC

Sequence 61 from palOSi687597|6il627932r2jSeqoence61 MMG1LLLVCLAKVSSDVNMOK 2461 paten! US 6875907 from patent US 6875907 EEDEELRFPNHPLJVRDGNRRL

MODIDCGGLCKTRCSAHSRPNV CNRACGTCCVRCKCVPPGTSG RELCGTCYTDMITHGN TKCP

Sequence 61 from Sequence 61 from patent US 6936432 NRLRRREDFARAGF SKAVG 2462 patent US 6936432 GA\^rVRNOVKRIlLRI-iLPLV ^rVL

ARDL

Sequence 1 from Sequence 61 from patent US 7001924 LRLLTPSOFTFVFRTGLTVAKKN 2463 patent US 7001924 VRRAHERNRIKRLTRE SFRLRO

HELDFVVVAKKGVADLDNRAL SEALE

Sequence 61 from ipatiUSi 7091185i6i i 15794248]Sequence 61 K!-A ! ΛΚ ί Κ Ι Λ Κ!· \KK 2464 patent US 7091185 from oaient US 7091185 ΓΛΚ Ι \ Ki \ Κ!· \ k.r \ i

AK iAKKFAKKFAK FAK FA KKFAKKFAKKFAKKFAK

Sequence 61 from ipatiUSi7i66769i6iri251619521Seqoeace61 MMG1LLLVCLAKVSSDVNMOK 2465 patent US 7166769 from oaient US 7166769 EEDEEERFPNHPI.iVRDGNE.RL

MODIDCGGLCKTRCSAHSRPNV

CNRACGTCCVRCKCVPPGTSG

NRELCGTCYTDMITHGNKTKCP Sequence 61 from lpallUSI7314858l6i ri672467841Sequence 61 RCLCTLGVC 2.466 patent US 7314858 from patent US 73 14858

Sequence 62 from [3407573 ]Sequence 62 from patent US LiRRLGORI RPIHRIARCAGOV 2467 patent US 5714577 5714577 V

Sequence 62 from Sequence 62 from patent US 6605698 EKARHGSCNYVFP 2468 paten! US 6605698

Sequence 62 from pat|US|6835536|62f5 7540 5^"|Sequence 62 RLWVWWVWRRK 2469 patent US 6835536 from patent US 6835536

Sequence 62 from patiUS!6875907|62f62793213]Seq«ence 62 MAPRVFLVI.GMLLMVCLVKVS 2470 patent US 6875907 from patent US 6875907 SDPKREEEiLEEELHFPDNEPLiV

RDGNRRLMODIDCGGLCKTRC SAPISRPNLCTRACGTCCVRCKC VPPGTSG RELCGTCYTDMTTH GNKTKCP

Sequence 62 from Seqiience 62 from patent US 6936432 NRLRRREDFARAGF SKAVG 2471 patent US 6936432 VAVVRN VKRilLRl-iLPLV VL

ARDL

Sequence 62 from Sequence 62 from patent US 7001924 LRLLTPKHFNFVFRiGLTiAKKN 2472 patent US 7001924 VKRAHERIs'RlKRLAREYFRLHO

HOLDF WLVRKGVAELDNHOL TEVLG

Sequence 62 from ipat!US!7091185!62[115794250]Sequence 62 r K S^' K F 2473 patent US 7091185 from paient US 7091185

Sequence 62 from ipatiUSi 7166769162 Γ 125 i 61 954] Sequence 62 APRVFLVLGMLLMVCLVKVS 2474 patent US 71 6769 from paient US 7166769 SDPKREEEILEEELHFPDNEPLIV

RDGNRRLMODIDCGGLCKT C

SAHSRPNLCTRACGTCCVRCKC

VPPGTSGNRELCGTCYTDMTTH

GNKTKCP

Sequence 62 from pa!!US!7314858|62[ 167246785]Sequence 62 RCLCTLGiC 2475 paten! US 7314858 from patent US 7314858

Sequence 63 from 13407574 [Sequence 63 from patesit US LIRELGORIRRPIHRIARCAG 2476 patent US 5714577 5714577

Sequence 63 from Sequence 63 from patent US 6605698 KARHGSCNYVFPA 2477 patent US 6605698

Sequence 63 from paiiUS!6875907|63i627932i4iSeq«ence 63 MALRVLLVLGMLLMLCLVKVS 2478 patent US 6875907 from paient US 6875907 SDPKIEEEILEAEEELOFPDNEPL

rVRDANRRLMODMDCGGLCKT RCSAFISRPNLCTRACGTCCVRC KCVPPGTSG RELCGTCYTDMT THGNKTKCP

Sequence 63 from Sequence 63 from patent U S 6936432 RRVRTPAEFRRAGF W SKA VG 2479 patent US 6936432 NAVTRNRVKRRLRALPVLVOV

LRRETVGAL

Sequence 63 from Sequence 63 from patent US 7001924 IJiLLTPIOFKNA'FRLGLTVAKK 2480 paten! US 7001 924 HLKRAHERNRIKRLVRESFRLS

OHRLDF VA NG1GKLD NTF

AGILE

Sequence 63 from |patiUSi709l 185i63 fl 15794251^'iSequence 63 ' .T .K1' J K. 2481 patent US 7091185 from patent US 7091185 Sequence 63 from ipat!U8i7 ! 66769!63i!251619561Secjuence 63 MALRVLLVLCyMLLMiXLVKVS 2.482. patent US 7166769 from patent US 7166769 SDPKIEEEILEAEEELOFPD EPI.

rVRDA RELMOD DCGGLC T

RCSAHSRP LCT ACGTCCVRC

KCVPPGTSGNRELCGTCYTDMT

THGNKTKCP

Sequence 63 from ipat!US!7314858!63|T67246786]Sequence 63 RCLCVLGVC 2483 patent US 7314858 from patent US 7 14858

Sequence 64 from [3407575 jSequence 64 from patent US LIRELGORI RPIHRIARCAR 2484 patent US 5714577 5714577

Sequence 64 from Sequence 64 from patent US 6605698 ARFIGSCNYVFPAH 2485 paten! US 6605698

Sequence 64 from pat!US|6835536i64i59754099 |Sequence 64 RLGGGWVWWVWRR 2486 patent US 6835536 from patent US 6835536

Sequence 64 from pailUS!6875907|64[627932151Sequence 64 MALSKLIIASLLASLLLLHFVDA 2487 patent US 6875907 from pat nt US 6875907 DOSAHAOTOGSLLOOiDCNGA

CAARCRLSSRPRLCORACGTCC RRCNCVPPGTAGNOEVC^'PCYAS LTTHGGKRKCP

Sequence 64 from Sequence 64 from patent US 6936432 NRMRRSADFER VGLIiAKSVG S 2488 paten! US 6936432 AVERHRVARRLRHLHDHV ILE

001,

Sequence 64 from Sequence 64 from patent US 7001924 KNLLTPRHFKAVFRLGLViGKX 2489 patent US 7001924 S VKLAVORNRLKRLMRDSFRL

NOOLLDIV1VARKGLGEIENPEL

HOHFG

Sequence 64 from !pat!US!7091185!64f l l5794252]Sequence 64 GKKGKKGKKG KGKKGKKG 2490 paten! US 7091185 from patent US 7091185

Sequence 64 from !pat!US!71 6769Ι64Γ 125161958] Sequence MALSKLIIASLLASLLLLHFVDA 2491 patent US 7166769 64 from patent US 7166769 DOSAHAOTOGSLLOOIDCNGA

CAARCRLSSRPRLCORACGTCC

RRCNCVPPGTAGNOEVCPCYAS

LTTHGGKRKCP

Sequence 64 from |pat|US|73 i4858|64ri67246787^'|Sequence 64^" ' RCLCVLG1C 2492 patent US 7314858 from patent US 7314858

Sequence 65 from [3407576]Sequence 65 from patent US LIRELGORIRRPIHRIARCAI 2493 paten! US 5714577 5714577 ^"

Sequence 65 from Sequence 65 from patent US 6605698 RHGSCNYVFPAHK 2494 patent US 6605698

Sequence 65 from patlUS!6S35536|65[597541011Sequence 65 RLWWWWWRR 2.495 patent US 6835536 from patent US 6835536

Sequence 65 from pai|US|6875907|65|^'627932i6jSequence 65 MEKKRKTLLLLLLMAATLFCM 2496 patent US 6875907 from patent US 6875907 PiVSYAVSSV QGHLTHSELVK

GPNRRLLPFVDCGARCRVRCSL HSRPKICSRACGTCCFRCRCVPP GTYGNREMCGKCYTDMITHGN

KPKCP

Sequence 65 from Sequence 65 from patent US 6936432 RMRRSSEFDHVGLTIAKTVGS 2497 patent US 6936432 AVERHRVARRLRHLGDOWIL

AQQL Sequence 65 from Sequence 65 from patent US 70 1924 SKLLKSTNFOYVFRLGLSISRKN 2.498 patent US 7001924 iKHAYRRNKIKRI.iRETFRI.LOH

R ! .! ⁾1^;Y V!.\ K K\) Y Y! \\K K !VM LE

Sequence 65 from Ipat USI70911851651115794253 [Sequence 65 FAKKFA KFKKP^'AKKFAKFAF 2499 patent US 7091185 from patent US 7091 185 AF

Sequence 65 from !pat!US!7 ] 667 )9!65n2516i960jSequence 65 MEKKRKTLLLLLLMAATL-FCM 2500 patent US 7166769 from patent US 7166769 PIVSYAVSSVNIOGHLTHSELVK

GPNRRLLPFVDCGARCRVRCSL HSRPK1CSRACGTCCFRCRCVPP GT Y GNREMCGKC YTDMITHGN KPKCP

Sequence 65 from |pat|USI7314858|65r i 672467881Seauence 65 VTPAMRTFALLTAMLLLVALA 2501 patent US 7314858 from patent US 73 1 858 OAEPLOARADEAAAOEOPGAD

DOEMAHAFTWHESAALPLSDS

ARGLRCICGRG1CRLLRRFGSCA FRGTLHRICCRACRIKKHKLRIY

FE SKKFLLLL YL VLHFLF S SKIN TLLODFSL

Sequence 66 from [3407577]Sequence 66 from aient US LiRELGORIRRPIHRiARCIG 2502 paten! US 5714577 5714577

Sequence 66 from Sequence 66 from patent US 6605698 HGSCNYV.FPAKKC 2503 patent US 6605698

Sequence 66 from pai!USi6835536j66j^"597541031Sequenee 66 RLWWWWRR 2504 patent US 6835536 from patent US 6835536

Sequence 66 from pat!US!6875907i66i62793217iSequence 66 MA SN SILLLCiFLW ATKVF S YD 2505 patent US 6875907 from patent US 6875907 EDLKTVVPAPAPPVKAPTLAPP

VKSPSYPPGPWTPTVPTPTVKV PPPPOSPWKPPTPTVPPPTVKV PPPPOSPWKPPTPTPTSPWYP

PPVAPSPPAPVVKSNKDCiPLCD YRCSLHSRKKLCMRAC1TCCDR CKC VPPGT YGNREKCGKC Y'TD MLTHGNKFKCP

Sequence 66 from Sequence 66 from patent US 7001924 LRLLTPAHFTF VFRiGLT VAKK 2506 patent US 7001 924 VRRAHERXRIKRLTRE SFRLRO

HELDFVWAKKGVADLDNRAL

SEALE

Sequence 66 from Ipat US[70911851661115794254 [Sequence 66 FKLRAKIKV RLRAKIKL 2507 patent US 7091185 from patent US 7091 185

Sequence 66 from !pa!iUS!7166769:66N 25 i 619621Sequence 66 MA SNSILL-LCIFLW ATKVF S YD 2508 paten! US 7166769 from patent US 7166769 EDLKTVVPAPAPPVKAPTLAPP

VKSPSYPPGPVTTPTVPTPWKV

PPPPOSPWKPPTPTVPPPTVKV

PPPPOSPWKPPTPTPTSPWYP

PPVAPSPPAPVVKSNKDCiPLCD

YRCSLHSRKKLC RAC1TCCDR

CKCVPPGTYGNREKCGKCYTD

MLTHGNKFKCP Sequence 66 from lpallUSI7314858l66il672467891Sequeace 66 WPA RTFALIAAMLLLVALA 2.509 patent US 7314858 from oaient US 73 14858 EAEPLOA ADETAAOEOPGAD

DOEMAHAFT WDE 8 A TLPLSD S

ARGLRCICRRGVCRFLRHL-GSC

AFRGTLHRICCRACR1KKNKLRI

YFESKKFVFLLYLALHFLFSSKI TLLODFCL

Sequence 67 from j 3407578 ^"jSequence 67 from patent US LIRELGORIRRPIRRIARCAG 2510 patent US 5714577 5714577

Sequence 67 from Sequence 67 from patent US 6605698 GSCNYVFPAHKCI 251 1 patent US 6605698

Sequence 67 from pai|US|68355 6|67i59754i^'05{Sequence 67 RLFVWWVFRR 2512 patent US 6835536 from patent US 6835536

Sequence 67 from pat!US!6875907j67[627932i 81Sequeace 67 MAKFFAAMILALFAISILOTW 2513 paten! US 6875907 from patent US 6875907 MAANEQGGHLYDNKSKYGSGS

VKSYOCPSOCSRRCSOTOYHKP

CMFFCOKCCRTCTXVPPGYYG NKAVCPCYNNWKTKEGGPKCP

Sequence 67 from Sequence 67 from patent US 6936432 NRMTRSTEFDRVGL GKAVG 2514 patent US 6936432 TAVORHRVARRLRHLEDRLVIL

AQEL

Sequence 67 from Sequence 67 from patent: US 7001924 LRLLTPSHFTFVFRIGLTVAKKI-I 2515 patent US 7001924 VKRAHER RiKRLTRESFRLHO

HALDFVVLVKKGVADLDNRAL TEALE

Sequence 67 from jpat!lJS!7091 18516711157942551Sequence 67 KFAKKFAKKFAKKAAK 2516 patent US 7091185 from patent US 7091 1 85

Sequence 67 from !patiUS!7i66709!67[125 i 61965]8equence 67 MAKFFAAMILALFAISILOTW 2517 patent US 7166769 from patent US 7166769 MAANEOGGHLYDNKSKYGSGS

VKSYOCPSOCSRRCSOTOYHKP CMFFCOKCCRTCLCVPPGYYG NKAVCPCYNNWKTKEGGPKC^'P

Sequence 67 from !pat!US!7314858!67[ 167246796iSequence 67 VTPAMRTFTVLAAMLLWALO 2518 patent US 7314858 from patent US 7314858 AOAEPLRARADETAAQEOPGA

DDQEMAHAFT WDE SAALPL SD SARGLRCICRRGVCRFLRHLGS CAFRGTLI^CCRACRIKKNKL RIYFESKKFVFLLYLALHFLFSS KJNTLLQDFCL

Sequence 68 from f3407579]Sequence 68 from patent US LIRELGIRTRRPIHRIARCAG 2519 patent US 5714577 571.4577

Sequence 68 from Sequence 68 from patent US 6605698 SCNYVFPAHKCiC 2520 patent US 6605698

Sequence 68 from: pat!USi6835536|68L59754107]Sequence 8 RLVVWWWRR 2521 patent US 6835536 from patent US 683553

Sequence 68 from paiiUS!6875907|68[62793219]Sequence 68 MAKFFAAMILALIAISMLOTVV 2522 patent US 6875907 from patent US 6875907 MAANEOGGHLYDNKSKYGSGS

VKRYOCPSOCSRRCSOTOYHKI

CMFFCOKCCRKCLCVPPGYYG

NKAVCPCYNNWKTKEGGPKC^'P Sequence 7 from ipat!U8!70712931711 120626991Sequence 7 KNiRRIIIi IIHil KYG 2561 patent US 7071293 from patent US 7071293

Sequence 7 from Sequence 7 from patent US 7078380 DGPKKKKKKSPS SSK 2562 patent US 7078380

Sequence 7 from !pa!iUS!709118517111 794 ! 871Sequence 7 KFAKKFAKKFAKKFA KPA 2563 paten! US 7091 185 from patent US 7091 185 FAKKFA KFAKKFA FA F

AKKFA KFA FAK FAKKFA KKFA

Sequence 7 from ipat|US!7244710Ι7Γ 1557 i 6454 Ϊ Sequence 7 VPKXXKPV 2564 patent US 7244710 from patent US 7244710

Sequence 7 from !pat!US!7314858!7j 67246734]Sequence 7 G YCiCGRGICRCICGR 2565 patent US 7314858 from patent US 7314858

Sequence 70 from [3407581]Sequence 70 from patent US RATRRAIRGAPRAIL 2566 patent US 5714577 5714577

Sequence 70 from Sequence 70 from patent US 6605698 YVFPAHKCICYF 2567 patent US 6605698

Sequence 70 from pat|USi6835536|70|^'59754111 jSequence 70 RLWVWWVWRR 2568 patent US 6835536 from patent US 6835536

Sequence 70 from Sequence 70 from patent US 6936432 ERLYLRDEINTVFS LVSVAKK 2569 patent US 6936432 RFRRAV RNRVRRLVRELDVL

LPDFRTVER

Sequence 70 from Sequence 70 from patent US 7001924 LRLLTPEHYOKVFRLGLAVPKK 2570 patent US 7001924 Oi TAVGRNRFKRiCRESFRLHO

NQLDFVVIAKKSAQDLSNEELF NLLG

Sequence 70 from !pa!iUS!7166769!70N 25 i 61 97 i lSequence 70 MAM AKVFCVLLL ALLGTSMITT patent US 7166769 from patent US 7166769 OVMATDSAYHLDGRNYGPGSL

KSSOCPSECTRRC80TOYHKPC MVFCKOCCKRCFCVPPGWG SVCPCYNNWKTKRGGPKCP

Sequence 70 from ipatiUSi7314858i70ri672467931Seqoeace 70 VTPAMRTFALLTAMLLLVALA 2572 patent US 7314858 from paten US 73 14858 OAEPLO ARADE A AAOEOPGAD

DOEMAHAFTWDESAALPLSDS ARGLRCIGGRGICGLLORRFGS

CAFRGTLHRICCRACRIKKNKL RIYSESKKFI.LLLYLVLHFLFSS

ΙΜΊ .1.01 )1 Si

Sequence 71 from j 3407582 [Sequence 71 from patent US RAIRRA1RGAPRAILRA1L 2573 patent US 5714577 5714577

Sequence 71 from Sequence 71 from patent US 6605698 1RI.EKARHGSC YV 2574 patent US 6605698

Sequence 71 from pai[US|6835536|7i Γ59754Ϊ 13 lSequence 71 WVRL WRRVW 2575 patent US 6835536 from patent US 6835536

Sequence 71 from Sequence 71 from patent US 6936432 LRGEREFRRIGL SKKTLKHA 2576 patent US 6936432 VKRNRARRRVRELLRAILLAOA

LORGA

Sequence 71 from Sequence 71 from patent US 7001924 KRLLTAROFSAVFRLGLVIGKK 2577 patent US 7001924 V LAVORNRLKRLIRESFPJIN

OETLDlYViARKGLGELENPELH

QQFG Sequence 71 from patiUSi7314858|7iri672467941Sequeoce 71 VTPAM TFALLTAMII.LV ALA 2.578 patent US 7314858 from oaient US 73 14858 OAEPLOARADEAAAOEOPGAD

DOEMAHAFTWDESAALPLSDS ARGLRCIGGRGICGLLORRVGS

C AFRGTLHRICCRACRIKKNKL

RiYSESK FLLLLYLVLHFLFSS KINTSLODFSL

Sequence 72 from j 3407583 jSequence 72 from patent US KVIEVVOGACKAIKHIPKK1KO 2579 patent US 5714577 5714577 GLEK1L

Sequence 72 from Sequence 72 from patent US 6605698 RLEKARHGSCNYVF 2580 patent US 6605698

Sequence 72 from pa!|USI6835536j72[59754115]Sequerice 72 1KKWPWWPWRRK 2581 paten! US 6835536 from patent US 6835536

Sequence 72 from pat!US!6875907j72i62793223]Sequence 72 MAARSYSPiMVALSLLLLVTFS 2582 patent US 6875907 from patent US 6875907 N\'AEAYTRSGTLRPSDC PKCT

YRCSATSHKKPCMFFCO CCA KCLCVPPGTYGNKQICPCYNSW KTKEGGPKCP

Sequence 72 from Sequence 72 from patent US 6936432 ARLKGGFLRVLFTVGKKLVPRA 2583 patent US 6936432 VDR R1 RLMRELTDHO ^'VLERF

RA1RH

Sequence 72 from Sequence 72 from patent US 7001924 LRLLTPAOFKSVFRLGLTVA R 2584 paten! US 7001 924 WKRA ORNRIKRVIIiDSFRLN

Oii IDiWLVR GVMEMENAE UNGLIE

Sequence 72 from !pat!Us 7i66769!72if251619761Sequence 72 ' MAARSYSPiMVALSLLLLVTFS 2585 patent US 7166769 from patent US 7166769 NVAEAYTRSGTLRPSDCKPKCT

YRCSATSHKKPCMFFCOKCCA KCLCVPPGTYGNKOICPCY SW KTKEGGPKCP

Sequence 72 from ipat!U SI 73 Ϊ4858172[ Ϊ 67246795 ISequence 72 VTPAMRTFALLTAMLLLVALH 2586 patent US 7314858 from patent US 7314858 AOAEAROARADEAAAOOOPGA

DDOGMAHSFTRPENAALPLSES ARGLRCLCRRGVCOLLRRLGSC

AFRGLCRICCRASRIKKNTLRSY FE SXKKFLLLL YL VLN FLF S SOI NTFSODFCL

Sequence 73 from Sequence 73 from patent US 6605698 LEKARHGSCNYVFP 2587 oaten! US 6605698

Sequence 73 from pat|tJS|6835536i73?5 754i HlSequence 73 1LKKPWWPWRRK 2588 patent US 6835536 from patent U S 6835536

Sequence 73 from Sequence 73 from patent US 6936432 RLKK EDFORVGL S VSKKIG 2589 patent US 6936432 AVMR RIKRLIROLKDYRTKKS

L

Sequence 73 from Sequence 73 from patent U S 7001924 WRIRTTAEFRRIYRLGVVASKR 2590 patent US 7001924 NVRKAVWRNRVRRVVKEAFRI

RKKDLDIWVAKASSVEADNK ELYECIN Sequence 76 from Sequence 76 from patent US 6936432 RVIKKNFEFOKYGISVG KIGN 2.609 patent US 6936432 AVTRNKVKRQIRMIGDillLSKLL

Sequence 76 from Sequence 76 from patent US 7001924 DSLKN SEFDRVYKLGLSVSK 2610 paten! US 7001924 VG AV RNLiKRRLRSLTLi HA

ALCALVFVPRSDCYHLDFWAL

EKHFLEMLT

Sequence 76 from !pat!US!7i66769!76N 251619861Seauence 76 SYOCGGOCTRRCSNT YHKP 261 1 patent US 7366769 from patent US 7166769 CMFFCOKCCAKCLCVPPGTYG

OVCPCYNNWKTOOGGPKCP

Sequence 76 from ipa!:iUSi7314858!76[ 167246799]Sequence 76 RCICRRRIC 2612 patent US 7314858 from patent US 7314858

Sequence 77 from [3407588]Sequence 77 from patent US DLWETLRRTIRWTLA1PRRIROGL 2613 patent US 5714577 5714577 ELCL

Sequence 77 from Sequence 77 from patent US 6605698 RHGSCNYVFPAHKC 2614 patent US 6605698

Sequence 77 from patlUSI6835536|77[59754125]Sequence 77 ILKKWPWWPWRR 2615 paten! US 6835536 from patent US 6835536

Sequence 77 from, Sequence 77 from patent US 6936432 HHLRDRKVFARAAVSTSKTKY 2616 patent US 6936432 LA VERNLiRROV ALNDVLV

QTIF

Sequence 77 from Sequence 77 from patent US 70 1924 DSL KSEFDRVTKLGLSVSKK 2617 patent US 7001924 VG AVKR LIKRRLR SLVTRH A

ALCALVFVPRSDCYHLDFWAL EKHFLEMLT

Sequence 77 from |pat|USI7166769Ι77Γ 1251619881Seauence 77 LRPTDCKPRCT YR C S AT SHKKP 2618 patent US 7166769 from patent US 7166769 CMFFCOKCCATCLCWKGVYG

NKOSCPCY NWKTOEGKP CP

Sequence 77 from lpatlUSI7314858l77ri672468001Sequence 77 RCICTRRIC 2619 patent US 7314858 from patent US 73 14858

Sequence 78 from [3407589]Sequenee 78 from patent US LWETLRRGGRW1LA1PRRIROG 2620 patent US 5714577 5714577 LELTL

Sequence 78 from Sequence 78 from patent US 6605698 HGSCNYVFPAHKCl 2621 patent US 6605698

Sequence 78 from patjUS!6835536j78|^"59754127!Sequence 78 ILKKWPWWPWK 2622 patent US 6835536 from patent US 6835536

Sequence 78 from Sequence 78 from patent US 6936432 HSLRERKVFTRVAISi AKTK YKL 2623 patent US 6936432 AVORNLI ROIRSLEDILVKQ L

F

Sequence 78 from Sequence 78 from patent US 7001924 DKF STNEEF S S VYKIA WA SKK 262.4 paten! US 7001 924 VGKAWR RSKRILRALFAKFE

RYLKYTFVAKNEiTELSFSRLEK LKWGLK

Sequence 78 from !patlUS! 7166769Ι78Π 25 i 61991 [Sequence 78 iFLLTLlVLFMLOTMVMASSGS 2625 patent US 7166769 from patent US 7166769 MVKWSOKRYGPGSLKRTOCPS

ECDRR CKKTOYHKA CITFC K.C CRKCLCVPPGYYGNKOVCSCY NW TOEGGP CP

Sequence 78 from: loat|USI7314858|78f l 672468011Seauence 78 RCICVRR1C 2626 patent US 7314858 from patent US 7314858

Sequence 79 from [3407590]$equence 79 from patent US LWETLRRGGRWTLAIPRRiROG 2627 patent US 5714577 5714577 LELCL patent US 6884776 from patent US 6884776

Sequence 8 from pat!US|6887847i8[67584686]SequeiJce 8 R RWRR RRVRRVVRR 2652 patent US 6887847 from patent US 6887847 RWRRWRRVRR.VVRRWRW

RRWRR

Sequence 8 from patiUSi6906035j8[7447229r!8equence 8 WKKHKELOKVLAPGGLLSNI 2653 patent US 6906035 from pa!ent US 6906035 VTSL

Sequence 8 from ipa!!USi 707 Ϊ293 ! 8 [^" 1 Ϊ 2062700] Seq u ence 8 KNLRRIIRKIIHIIKKYG 2654 paten! US 7071293 from patent US 7071293

Sequence 8 from Sequence 8 from patent US 7078 80 SKDGKKKKKK SKT 2655 patent US 7078380

Sequence 8 from lpatlUSI7091185l8fll57941881Sequence8 rAK lAKKiA KlAk lA 2656 patent US 7091185 from patent US 7091185 ΙΛΚΚί Λ Κ1 Ak l A k A r

Λ Κ! Λ 1Λ .1ί!·Λ 1^;ΛΚ Ι Λ

1·Λ Κ1^;ΛΚ .1^;ΛΚ ί Λ Κ! Λ

Sequence 8 from paiiUSI7314858|8fl672467351Sequence 8 GiCICICGYGTCRCICGR 2.657 patent US 7314858 from patent US 7314858

Sequence 80 from [3407591 jSequence 80 from patent US LW ETLRRGCR W f L AIPRR1ROGL 2658 patent US 5714577 5714577 ELTL

Sequence 80 from Sequence 80 from patent US 6605698 SCNYVFPAHKCiCY 2659 patent US 6605698

Sequence 80 from patiUSi6835536|805975413 llSequence 80 LWPWWPWRRK 2.660 patent US 6835536 from patent US 6835536

Sequence 80 from patiUSi6875907i80j^'62793231]Sequence 80 SVS LVOAARGGGKL POOCN 2661 patent US 6875907 from patent US 6875907 SKCSYRCSATSHKKPC FFCLK

CC KCLCVPPGTFGN OTCPCY NNWKTKEGRPKCP

Sequence 80 from Sequence 80 from patent US 6936432 YRV SDKDFORVGLSVGKRLG 2662 patent US 6936432 AWRNAIKRKLRHLGDFVVM

KK L

Sequence 80 from Sequence 80 from patent US 7001924 YRLLKTDDF S S VFRIGL VVGEK 2663 patent US 7001924 TAKRANERNYMKRVIRDWFRL

NKNRLDFVVRVRRKFDRATAK OARAELA

Sequence 80 from !pat|US!7166769|80125161995]Sequenc 80 SVSMAOX \RGCG i Ρί. Χ 2664 patent US 7166769 from patent US 7166769 SKCSYRCSATSHKKPCMFFCLK

CCKKCLCVPPGTFGNKOTCPCY NNWKTKEGRPKCP

Sequence 80 from !pat!US!7314858!80[167246803]Sequence80 RCICGRRVC 2665 patent US 7314858 from patent US 731 858

Sequence 81 from [3407592]Sequence 8i from patent US LWRTLRRGGRWILAIPRRIROG 2666 patent US 5714577 5714577 LELTL

Sequence 81 from Sequence 81 from patent US 6605698 C YVFPAHKCiCYF 2667 paten! US 6605698

Sequence 81 fr m: pat|US|6835536|8H597541331Sequence8I LRWWWPWRRK 2668 patent US 6835536 from patent US 683553

Sequence 81 from Sequence 81 from patent US 6936432 FR\¾JiEKDFKRVGLSVSKKLG 2669 patent US 6936432 NAVTRNOiKRRiRl-iLVDFVYME

KNL Sequence 81 from Sequence 81 from patent US 70 1924 ARLHRPSEFAAALRLGLVTAKR 2670 patent US 7001924 FAARAVTR TLKRVIREAFRAR

RLALDYWRLHSKLTPASLTAL KRSARAEVD

Sequence 81 from Ipat!USj 7 i 66769! 81 [ 125161997] Sequence 81 GRLHPQDCQPKCTYRCSKTSY 267 ! patent US 7166769 from patent US 7166769 KPCMFFCO CCAKCLCVPAGT

YGNKGSCPCYMNWKTKRGGPK CP

Sequence 82 from [34075931Sequenee 82 from patent US LWETLRRGGRWILAIPRRIRQG 2672 patent US 5714577 5714577 LRLTL

Sequence 82 from Sequence 82 from patent U S 6605698 1RLEKARHGSCNYVF 2673 patent US 6605698

Sequence 82 from pat!US!6835536|82[59754135]Sequei!ce 82 LRWPWWPW 2674 patent US 6835536 from patent US 6835536

Sequence 82 from Sequence 82 from patent US 6936432 YRi NADFQRLGlSVSKKLG 2675 patent US 6936432 AVLRNKiKRAiREiLDiiViONSL

Sequence 82 from Sequence 82 from patent US 7001924 DRLRO VAIORTLRLGLAVSRK 2676 patent US 7001924 VGNAVVR R1KRRLREAFROOS

VRTDVL ARPSAROLSMRAM GAYLO

Sequence 82 from !patlUS!7166769l82[125161999]Sequence 82 AAEDSQVGEGVVKIDCGGRCK 2677 patent US 7166769 from patent US 7166769 GRCSKSSRPNLCLRACNSCCYR

CNCVPPGTAGNHHLCPCYASiT

TRGGRLKCP

Sequence 83 from i34075941Sequen.ce 83 from patent US LWETLRRGGRWILA TPRRIRRGL 2678 patent US 5714577 5714577 ELTL

Sequence 83 from Sequence 83 from patent US 6605698 RLEKARHGSCNYVFP 2679 paten! US 6605698

Sequence 83 from patiUSi6835530|83i59754137]Sequence 83 WPWWPWRRK 2680 patent US 6835536 from patent US 6835536

Sequence 83 from Sequence 83 from patent US 7001924 RLRRREDFATAVRAGFWSK 2681 patent US 7001924 AVGGAVVRNOVKRRL HLVC

DRLSALLVWRALPGAGDADH AOLARDLD

Sequence 83 from ipat!U Si 7 ! 66769! 83 f Ϊ 25162001 jSequence 83 YELHVHAADGAKVGEGVVK1D 2682 patent US 7166769 from patent US 7166769 CGGRCKDRCSKSSRTKLCLRAC

NSCCSRCNCVPPGTSGNTHLCP CYAS1TTHGGRLKCP

Sequence 83 from lpatlUSI7314858l83[ 1672468061Sequence 83 RCLCTRRiC 2683 patent US 7314858 from patent US 7314858

Sequence 84 from: | 3407595]Sequence 84 from patent US LWETLRRGGRWILA TPRRIRROT 2684 patent US 5714577 5714577 ELTL

Sequence 84 from Sequence 84 from patent US 6605698 LEKARHGSCNYVFPA 2685 patent US 6605698

Sequence 84 from patlUSI6696238|84[47232988]Sequence 84 MRVLYLLFSFLF1FLMPLPGVFG 2686 patent U S 6696238 from patent US 6696238 GiSDPVTCLKSGAICHPVFCPRR

YKOIGTCGLPGTKCCKKP

Sequence 84 from pat! S!6835^"536!84]59754i39 |Sequence 84 RWWWPWRRK 2687 patent US 6835536 from patent US 6835536

Sequence 84 from Sequence 84 from patent US 6936432 KGLKKDSDFRRVGISVSKKVGK 2688 patent US 6936432 AITR RVRRLIKEKi DIVFIKNL Sequence 84 from Sequence 84 from patent US 7001924 NRLRRREDFATAVRAGFWSK 2689 patent US 7001924 AVGVAWRNKVKRRLRHLMR

DRTOLLLWVRALPGAGDADH AOLARDLD

Sequence 84 from jpat|USj7 ! 66769|84[ 1251620031Sequetice 84 ADVESSO NGYA K.1DCGSA 2690 patent US 7166769 from patent US 7166769 CVARCRLSRRPRLCHRACGTCC

YRCNCVPPGTYGNYD COCYA SLTTHGGRRKCP

Sequence 84 from !patJLJS!7314858|84[ l 67246807 [Sequence 84 RCLCVRRIC 2691 patent US 7314858 from patent US 7314858

Sequence 85 from [3407596]Sequence 85 from patent US LWELLRRGGRW1LA1PRRIROG 2692 patent US 5714577 5714577 LELTL

Sequence 85 from pa!!US!6696238|85[472329891Sequei!ce 85 MRVLYLLFSFLFIFLMPLPGVFG patent US 6696238 from patent US 6696238 GIGDPVTCLKSGAICHPVFCPRR

YKOIGTCGLPGTKCCKKP

Sequence 85 from patlUSi6835536|85[597541411Sequence 85 ALRWPWWPWRRK 2694 patent US 6835536 from patent US 6835536

Sequence 85 from Sequence 85 from patent US 6936432 LRLKHWODFORFGITVSOKVSK 2695 patent US 6936432 K AT VRNR L ROTR ATKD V ViFLR

EL

Sequence 85 from Sequence 85 from patent US 7001924 RRVRTPAEFRHLGRAGFWSKA 2696 patent US 7001924 VGNAVTRNRV RRLRAWAEQ

MRLVLVQVRALPAAAEADYAL LRRETVGALG

Sequence 85 from |pat!US!7 i 6676918511251620061Sequen.ce 85 GSLHPODCOPKCTYRCSKTSFK 2697 patent US 7166769 from patent US 7166769 KPCMFFCO CCA CLCVPAGT

YGNKOTCPCY NWKTKEGGP

CP

Sequence 86 from j 3407597 jSequence 86 from patent US L WRLLRRGGR WlLAlPRRiROG 2698 patent US 5714577 5714577 LELTL

Sequence 86 from Sequence 86 from patent US 6605698 KARHG SCN YVFP AHK 2699 patent US 6605698

Sequence 86 from pa!!US!6835536j86[597541431Sequence 86 IARWPWWPWRRK 2700 paten! US 6835536 from patent US 6835536

Sequence 86 from Sequence 86 from patent US 6936432 NRLRRREDFAR1GIVVSKKVSK 2701 patent US 6936432 LAVTRNRFKROLRALKQIVVLG

DDL

Sequence 86 from: Sequence 86 from patent US 7001 24 RMRRSADFETTVRVGLITAKS 2702 patent US 7001924 VGSAVERHRVARRLRHVAGSIV

KELDHVVIRALPSSRHVSSARLE QQLR

Sequence 86 from pat|LJS|7166769186? Ϊ25162008 jSequence 86 LVTSAGKG SSPKKIDCGGACA 2703 patent US 7166769 from patent US 7166769 ARCQL S SRPHLCKRACGTCC AR

CACWPGTAGNQEMCPKCYAS LTTHGGKRKCP

Sequence 87 from [3407598]Sequence 87 from patent US DLWETLRRIIRWILAIPRRIR 2704 paten! US 5714577 5714577

Sequence 87 from Sequence 87 from patent US 6605698 ARHGSCNYVFPAHKC 2705 patent US 6605698

Sequence 87 from patiUS!6696238|87[47232991]Sequence 87 SRRSCHR KGVCALTRCPRmi 2706 patent US 6696238 from patent US 6696238 ROiGTCFGPPV CCR Sequence 87 from patiUS!6835536|87i597541451Sequence 87 ILAWPWWPWRRK 2.707 patent US 6835536 from patent US 6835536

Sequence 87 from Sequence 87 from patent US 6936432 ISLKSK1EIORILVTFSKGFRGSV 2708 patent US 6936432 KRNRIRRLF ELEDilFIESLM

Sequence 87 from Sequence 87 from patent US 7001924 MRRSSEFDATVHVGLITAKT 2709 patent US 7001924 VGSAVERHRVARRLRHVARTM

LGELDOWIRALPSSR VSSAW LAOOLR

Sequence 87 from !pat!US!7166769!87[125 i62011]Sequence 87 MMISLLVFNPVEADG^'VVVNYG 2710 patent US 7166769 from patent US 7166769 QHASLLAKIDCGGACKARCRLS

SmiLCKRACGTCCORCSCVPP GTAGNYDVCPCYATLTTHGGK RKCP

Sequence 87 from lpatlUSI7314858l87[167246810]Sequence 87 RCLCGRRFC 2711 patent US 7314858 from patent US 7314858

Sequence 88 from p407599]Sequence 88 from patent US DLWETLRRGGR WILAIPRRIR 2712 patent US 5714577 5714577

Sequence 88 from Sequence 88 from patent US 6605698 RHG8CNYVFPAHKCI 2713 patent US 6605698

Sequence 88 from pat|US|6696238|88r472329921Sequence 88 NHR .SCYRNKGVCAPARCPRNM 2714 patent US 6696238 from patent US 6696238 ROIGTCHGPPV CCR

Sequence 88 from patiUSi6835536|88| 5975 ] 47]Sequence 88 ILRAPWWPWR K 2715 patent US 6835536 from patent US 6835536

Sequence 88 from Sequence 88 from patent US 6936432 ERLRGSCRVRRFLATFRRGYGK 2716 patent US 6936432 AVARNRARRLSKEEVDLVLLLC

VL

Sequence 88 from jpatiUS|7166769i88[ 125162013]Sequence 88 LVTSAS GSSFP KIDCGGACA patent US 7166769 from patent US 7166769 ARCOLSSRPHLCKRACGTCCAR

SRCVPPGTAGNOEMCPCYASLT THGGKRKCP

Sequence 88 from !pat!U S! 7314858 ! 88 [ 167246811 ] Sequence 88 R( 1CK K ( 2718 patent US 7314858 from patent US 7314858

Sequence 89 from | 3407600]Sequence 89 from patent US DLWETLRRGGR WILAIPRRIR 2719 patent US 5714577 5714577

Sequence 89 from patjUS!6835536j89i597541491Sequenee 89 ILRWAWWPWRRK 2720 patent US 6835536 from patent US 6835536

Sequence 89 from pat!US!6875907i89[62793240iSequence 89 YEFREIKFFFLCVYVQGDELESQ patent US 6875907 from, patent US 6875907 AOAPAIHKNGGEGSLKPEECP

ACEYRC S AT SHR PCLFFCNKC CNKCLCVPSGTYGHKEECPCY NWTTKEGGPKCP

Sequence 89 from Sequence 89 from patent US 6936432 ARLLKRKOFV VGrrVS KFGK 2722 patent US 6936432 AHORNRFKRiVRELOVVILSEEL

WM

Sequence 89 from Sequence 89 from patent US 7001924 RMTRSTEFDATVRVGLVVGK 2723 patent US 7001924 AVGTAAORHRVARRLRHVARA

LLGELDRLVIRALPGSRTASSAR LAOELO Sequence 89 from ipatiUS!7 i 66769189112 16201 SlSeqoence 89 YEFREKFFFLCVYVOGDELESO 2724 patent US 7166769 from patent US 7166769 AOAPAfflKNGGEGSLKPEECPK

ACE YRC SAT SFIRKPCLFFCN C

C KCLCVP5GTYGHKEECPCYN WTTKEGGPK.CP

Sequence 89 from !pat:!US!73 1485818911 672468121Seq¾ence 89 RCICRRRFC 2725 patent US 7314858 from patent US 7314858

Sequence 9 from pai!US!55191 15|9| 1610235 ISequenee 9 from SKMiEG VF AKGFKGASHLFKGI 2726 patent US 5519115 patent US 5519115 G

Sequence 9 from pai|USi5607914|9(2O 6789|Sequence 9 from RRIYRAIRHIPR IRGWLRRIGR 2727 patent US 5607914 patent US 5607914 RIERVGQH

Sequence 9 from [3407520]Sequence 9 from patent US GACRATRHTPRR1R 2728 patent US 5714577 5714577

Sequence 9 from [4001469] Sequence 9 from patent US HPQY OA 2729 patent US 5798336 5798336

Sequence 9 from pat!US!5856127|9i5938888 ]Sequenee 9 from MA SRA AGL ARRL ARL ARR A 2730 patent US 5856127 patent US 5856127

Sequence 9 from pat!US!5998374|9il00663 ! 61Sequence 9 MKTTILILLILGLGI AKSLEERK patent US 5998374 from patent US 5998374 SEEEKLFKLLGKIIHHVGNFVHG

FSHVFGDDOOD GKFYGYYAE DNGKHWYDTGDO

Sequence 9 from pai|USi6107460i9i 12822631 ISequenee 9 OGRHFCGGALIHARFVMTAA 2732 patent US 107460 from patent US 6107460 HCFQ

Sequence 9 from pat!USio ! 91254|9i 14119957]Sequence 9 PWKWPWWPWRR 2733 patent US 6191254 from patent US 6191254

Sequence 9 from pat!USl6211148j9[ 15108335^'jSequence 9 2734 patent US 6211148 from patent US 6211148 HRROiGTC^'LGPOiKCCR

Sequence 9 from Sequence 9 from patent US 6605698 OCIRLEKAR 2735 patent US 6605698

Sequence 9 from pat!US!6624i40|9i401510571Sequence 9 IKISGKW AOKRFLKMSGC 2736 patent US 6624140 from patent US 662 140

Sequence 9 from paijUS!663853 l|9f40i63855iSeq ieiice 9 LLLFLLKKRKKRKY 2737 patent US 6638531 from patent US 6638531

Sequence 9 from pat|USi6730659|9l53923177]Sequence 9 RHFSGGALIHARFV TAASS 2738 patent US 6730659 from patent US 6730659

Sequence 9 from Sequence 9 from patent US 6743598 LEDFFVMSDYRGFGIGSEIL 2739 patent US 6743598

Sequence 9 from pat!US!6743769i9i539344663Sequence 9 ALYKKWKNKLLKS 2740 patent US 6743769 from patent US 6743769

Sequence 9 from patiUS!6747007|9f539376341Sequence 9 RVWCRYRCYRGFCRRFCR 2741 patent US 6747007 from patent US 6747007

Sequence 9 from Sequence 9 from patent US 6790833 CLH RCR 2742 patent US 6790833

Sequence 9 from patlUSI6818407|9[56646448]Sequence 9 KLWKLFKKIGIGA^KVLKVLT 2743 patent US 6818407 from patent US 6818407 TGLPALKLTLK

Sequence 9 from patlUSI6835536|9[597539901Sequence 9 ILI IPIiPiRRK 2744 patent US 6835536 from patent US 6835536

Sequence 9 from pat|US|6872705|9f627882481Sequence 9 CYCRiPACiAGERRYGTCiYOGR 2745 patent US 6872705 from patent US 6872705 LWAFCC

Sequence 9 from pat!US!6884776i9i67580428 ISequenee 9 MOYNRR 2746 patent US 6884776 from patent US 6884776

Sequence 9 from paiiOS!6l87847|9 67584687]Seqiience 9 RV VRVYRRWVRR 2747 patent US 6887847 from patent US 6887847

Sequence 9 from pat!US|6906035j9[74472292]Sequence 9 KW SFIK LTSVLKKWTTALP 2748 patent US 6906035 from patent US 6906035 ALIS

Sequence 9 from Sequence 9 from paten! US 7078380 GIGKFLHSAGKFGKAFVGETMK 2749 paten! US 7078380

Sequence 9 from |pat|TJS|709fi 85|9i ^" i l5794l90^"|Sequence 9 R ! AR RFAR R i A R R ; A RR i \RR ! 2750 patent US 7091185 from patent US 7091185 AR

Sequence 9 from |pat|US|73 i4858|9i l67246736jSequence 9 GiClCiCGRGlCYCiCG 2751 patent US 7314858 from patent US 7314858

Sequence 90 from Sequence 90 from patent US 6605698 GSC YVFPAHKCICY 2752 paten! US 6605698

Sequence 90 from pat! Si6835536|90]59754i5 ί jSequence 90 1LRWPAWPWRR 2753 patent US 6835536 from patent US 6835536

Sequence 90 from Sequence 90 from patent US 6936432 ARIU RKOFVKVGVTVS FG 2754 patent US 6936432 I IHORNRFKRIVRELO VLSA

DLLKHI

Sequence 90 from Sequence 90 from patent US 7001924 HKLSOFRATIRFGLWSKAVGN 2755 patent US 7001924 AVTRHRVSROLRFIFFf ELRA

i)\^'0 \ \ :.D

Sequence 90 from !Pat|USi7166769l90n 25 i 620171Seauence 90 CGGKCNVRCSKAGOHEECLKY 2756 patent US 7366769 from patent US 71 6769 CNiCCOKCNCVPSGTFGHKDEC

PCYRDMKNSKGGSKCP

Sequence 90 from pa!!US!7334858j90[ 1672468131Sequence 90 RC ^'TRRVC 2757 paten! US 7314858 from patent US 7314858

Sequence 1 from Sequence 91 from patent US 6605698 SCNYVFPAHKCICYF 2758 patent US 6605698

Sequence 91 from pat!US!6835536|91T59754153]Sequence 93 ILRWPWAPWRRK 2759 patent US 6835536 from patent US 6835536

Sequence 1 from Sequence 91 from patent U S 6936432 SRVLKR OFLRMG1TVSKKFGK 2760 patent US 6936432 AHERNSFKRVVRELQIVVLLQD

FI QI

Sequence 91 from !pa!:|US!7i 66769191 |Ί 25 i 62019]Sequence 91 EOKOGOYGEGSLRPSECGORCS 2761 patent US 7366769 from patent US 7166769 YRCSATSHKKPCMFFCQ CCA

CLCVPPGTFGNKQVCPCYNN W TOOGGP CP

Sequence 91 from |pat|US|73 i4858|9i ri67246814^'|Sequence 91 ' RCICTRRFC 2762 patent US 7314858 from patent US 7314858

Sequence 92 from Sequence 92 from patent US 6605698 IRLEKARHGSC Y\'FP 2763 paten! US 6605698

Sequence 92 from pat! S!6835536!92i59754i55]Sequence 92 ILRWPWWAWR K 2764 patent US 6835536 from patent U S 6835536

Sequence 92 from pat!US!6875907|92i62793243]Sequence 92 OSKDGPALEKWCGOKCEGRCK 2765 patent US 6875907 from patent US 6875907 EAGM DRCLKYCGICC DCOC

VPSGTYGNKHECACYRDKLSS

KGTP CP

Sequence 92 from Sequence 92 from patent US 7001924 NRLKRSDDFRKVFRVGLSVSKK 2766 patent US 7001924 GNAVMRNRIKRLiROFFOEHE

OALDYIIiAR PAADMTYEET

KSLQ

patent US 6835536 from patent US 6835536 peptide orecursor

(TAP)

Triehoiongk BI ri! 135520jsp!P80070!TCBi TRiLO AGFAAOAAASLAPVAAOOL 2864

Trichoiongm BI and ΒΠ

Tricholon°;½ B1I TricholonEin BIl AGF A AO AAA SLAPV ATOOL 2865

Uncharacterized Uncharacterized protein, linocin CFP29 MT NLHRELAPiASAAWEQIEEE 2866 protein, homolog VARTF RSVAGRRVVDVEGPK iinocb/CFP29 GPALSAVGTGHLRDVBAPREQ homolqg VSARLREVRA1VELTVPFELSRD

A1DSVERGARDADWQPAKDAA

QRLAFAEI⁾HAiFI⁾GYAAAGilGi

REGS SNRRLTLPDD VGA YPDAI

SDALEALRLAG V DGP YS VLLGA

DAYTALSEARDOGYPVIDHIKRI

VSGEIIWAPAISGGCVL8TRGGD

YELHLGEDVSICYTSHTDKVVR

LYLRETFTFLMLTSEA

Uncharacterized Uncharacterized protein., linocin/CFP29 MNNLHRELAPISSAAWEOiEEE 2867 protein, honioiog VARTF RSVAGRRWDVEGPA iinoem/CFP29 GPELSAVGTGHLLDVAAPRELV homolog NARLREVRTIVELTVPFELSRDA

iDSVERGARDADWOPAKEAAO

RLAFAEDNAIFDGYPAAGIVGIR

EGTS RRLTLPADVGAYPDAIS

DALEALRLAO\T3GPYSVVLGS

DAYTALSEARDOGYPVLGHIKR

iVSGEilWAPAISGGCVLSTRGG

DYELHLGEDVSiGYTSHTDKGV

RLYLRETFTFLMLTSEA unnamed protein unnamed protein product M AGGRGRGGGGGGG VAGGGN 2868 product LRP WEC SPKCAGRC SNTO YKK

ACLTFCMKCCAKCLCVPPGTYG N GACPCYNNWKTKEGGPKCP

unnamed protein unnamed orotein product MA SRNK AAA LLLCFLFLA AV A. 2869 product ASAAEMIAGSGTGDGEGEELDK

GGGGGGGHHKHEGY N DGK GNLKPSOCGGECRRRCSKTHH

KKPCLFFC KCCAKCLCVPPGT YGNKETCPCY NWKTKKGGPK CP

unnamed protein unnamed protein product ME SKSP W SLRLLICCAAMV ALA 2870

LLPOOGGOAACFVPTPGPAPAP

PGSSATNTNASS w PRPAKPSA

FPPPMYGGVTPGTGSLOPHECG

GRCAERCSATAYOKPCLFFCRK

CCAACLCVPPGTYGNK TCPC

Y WKTKRGGP CP

unnamed protein unnamed orotein product SLDKRACNFOSCWATCOAOFISI 2871 product YFRRAFCDRSOCKCVFVRG unnamed protein unnamed prote n product KLAKLA XLAKLAKGK KKKG 2872 product KLGK RDP

unnamed protein unnamed protein product KLAKLAKKIAKLAKKHLKKHL 2873 product KKI-ILK

unnamed protein unnamed protein product VKRGLKLKLAKLA KLAKLA 2874 product

unnamed protein [21439788]unnarned protein product MAISKSTVWVTLCFILIOELGTY 2875 product [Glycine [Glycine max] GEDPHMDAAKKIDCGGKCNSR max] CSKA ROKMCiRAC SCCKKC

RCVPPGTSG RDLCPCYARLTT HGGKLKCP

unnamed protein [21439790]unnamed protein product MALRELLMMGILLLVCLAKVSS 2876 product [Glycine [Glycine max] DVNMOKEEDEELRFPNHPLiVR max] DGNRRLMQDIDCGGLCKTRCS

AHSRPNVCNRACGTCCVRCKC VPPGTSGNRELCGTCYTDMITH GNKTKCP

unnamed protein, [21439786]unnamed protein product MKLVFGTLLLCSLLLSFSFLEPV 2877 product [Glycine [ Glycine max] ί AYED S S YC SNKC A DR.C S S AGV max] KDRCVKYCGICCAECKCVPSGT

YGNKHECPCYR.DKLN GKP CP

unnamed protein [21439780 junnamed protein product MKVAFAAVLLICLVL8SSLFEVS 2878 product [Glycine [Glycine max] MAGSAFCSS CSKRCSRAGMK max] DRCMKFCG1CCS C CVPSGTY

GNKHECPCYRDMKN SKGKAKC

£

unnamed protein [21439778 junnamed protein product MKVAFVAVLLTCLVLSSSLFEVS 2879 product [Glycine [ Glycine max] MAGSAFCSSKCAKRCSRAGMK max] DRCTRFCGICCSKCRCVPSGTY

GNKHECPCYRDMKNS GKPK.C £

unnamed protein [21439310]unnamed protein product MLLLLVENHAEiVVSTVEASAP 2880 product [Glycine [Glycine max] OPHK TTHTLSHAPAPOPHKNT max] KSPVPNLOHGITEGSLKPOECGP

RCTARCSNTOYK PCLFFCOKC

CAKCLCVPPGTYGNKOVCPCY

NNWKTKRGGP CP

Uflerrn-2,7 Uperin-2.7 GHD1AKKLVGGIRTWLGI 2881

Varv peptide A Varv peptide A GLPVCGETCVGGTCNTPGCSCS 2882

WPVCTRN

Van' peptide E Varv peptide E GLP1CGETCVGGTCNTPGCSCS 2883

WPVCTRN

Varv peptide F Varv peptide F GVPICGETCTLGTCYTAGCSCS 2884

WPVCTRN

Vaso stati -1 Vasostatm- 1 LPVTSfSPMNKGDTEVM ClVEVI 2.885

SDTLSKP SPMPVSKE CFETLRG

DERILSILRHONLLKELODLALO

GAKERTHOO

Vespid cbemotactic gi[ 11027891 iisp!POCiMi jCRBLE VESMG FLPilAKLLGGLL 2886 peptide 5e Vespid chemotactic peptide 5e

Vespid chemotactic gil l ! 0278919isp|P0ClM2|CRBLF VESMG FLPIPRPILLGLL 2887 peptide 5f Vespid chemotactic peptide 5f

Vespid chemotactic gijl i0278920ispiP0C 3 M3pRBLG VESMG FLiiRRPlVLGLL 2888 peptide 5 Vespid chemotactic peptide 5g

Vespid chemotactic Vespid chemotactic peptide 5h FI.PIIGKI.L SGI.L 2889 peptide 5h

Vicilm-like Vicilin-like antimicrobial peptides 2-1 RORDPOOOYEOCOKHCORRET 2890 antimicrobial precursor ( AMP2 ) EPRI-IMOTCOORCERRYEKE R peptides 2-1 OOKRYEEOOREDEEKYEERM precursor KEED

i^'MiAMP2 i

Vicin-like Vicin-like antimicrobial peptide 2a ESEFDROEYEECKROCMOLETS 289 ! antimicrobial GOMRRCVSOCDKRFEEDIDWS peptide 2a KYDNOD

Vicin-like Vicin-like antimicrobial peotide 2a OCMOLETSGOMRRCVSOCD R 2892 antimicrobial FEEDIDWSKYDNOE

peptide 2a

Vicin-like Vicin-like antimicrobial peptide 2b DPOTDCOOCO RCROOESGPR 2893 antimicrobial OOOYCORRCKEICEEEEEYN

peptide 2b

Vicin-like Vicin-like antimicrobial peptide 2b DPOTECOOCORRCROOESDPRO 2894 antimicrobial OOYCORR C E1CEEEEE Y

peptide 2b

Vicin-like Vicin-like antimicrobial peptide 2c- 1 RORDPOOOYEOCOERCORHET 2895 antimicrobial EPRHMOTCOORCERRYEKEKR peptide 2c- 1 KQQ

Vicin-like Vicin-like antimicrobial peptide 2c- 3 RORDPOOOYEOCOKRCORRET 2896 antimicrobial EPRHMOICOORCERRYEKEKRK peptide 2c- 1 QQ

Vicin-like Vicin-like antimicrobial peptide 2c-2 RORDPOOOYEOCOERCORHET 2897 antimicrobial EPRHMOTCOORCERRYEKEKR peptide 2c-2 EQiMi

Vicin-like Vicin-like antimicrobial peptide 2c-2 RORDPOOOYEOCOKRCORRET 2898 antimicrobial EPRHMOICOORCERRYEKEKRK peptide 2c-2 OQKR

Vicin-like Vicin-like antimicrobial peptide 2c-3 RORDPOOOYEOCOERCORHET 2899 antimicrobial EPRHMOTCOORCERRYEKEKR peptide 2c- 3 KOOKRYEEOOREDEEKYEERM

KEEP

Vicin-like Vicin-like antimicrobial peptide 2c-3 RORDPOOOYEOCOKRCORRET 2900 antimicrobial EPRHMOICOORCERRYEKEKRK peptide 2c-3 OOKRYEEOOREDEEKYEERMK

EGD

Vicin-like Vicin-like antimicrobial peptide 2d KRDPOOREYEDCRRHCEOOEP 2901 antimicrobial RLOYOCORRCOEOO

peptide 2d

Vicin-like Vicin-like antimicrobial peptide 2d KRDPOOREYEDCRRRCEOOEPR 2902 antimicrobial OOYOCORRCREOO

peptide 2d WAMP-la Antimicrobial peptide !b; Short=WA P-lb; AORCGDOARGAKCPNCLCCGK 2.903

AliName: Antimicrobial oeptide H l ;Tk- YGFCGSGDAYCGAGSCOSOCR

AMP-H 1 : Contains: GC

WAMP- l a.

Winter flounder 1 Winter flounder 1 GKGRWLERiGKAGGfliGGALD 2904

HL

Winter flounder la Winter flounder 1 a WLRRIGKGVKIIGGAALDHL 2905

Winter flounder Winter flounder l al GRRKRKWLRRlGKGVKIiGGAA 2906 l al LDHL

Winter flounder 3 Winter flounder 3 FLGALIKGAIHGGRFIHGMIONH 2907

H

Winter flounder 4 Winter flounder 4 GWGSIF HGRHAA HIGHAAV 2908

HYL

Winter flounder Y Winter flounder Y FFRLI.FHGVi-IHGGGYI.NAA 2909

Winter flounder Z Winter flounder Z FFRLLFHGVHHVGKi PRA 2910

Witch flounder Witch flounder GC3.84 GWKKWLRKGAKHLGOAAIK 291 1 GC3.8-t

Witch flounder Witch flounder GcSc4B7 GFWGKLFKLGLHGIGLLHLHL 2912 GcSc4B7

Witch flounder Witch flounder GcSc4C5 AGW'GSlFKHiFKAGKFIHGAIOA 2913 GcSc4C5 HND

Xenopsin precursor ai! 148228030|refl P 001 079056. l !i 3482280 GWASKIGOTLGKTAKVGLKE.LT 2914 fragment ( PF ) 30 jxenopsin precursor protein [Xenopus QPK

laevis]

Zeamatin Zeamatin AAWTW OCPFTVWAASVPV 2915

GGGROLNRGESWRITAPAGTTA

ARTWARTGCKFDASGRGSCRTG CGGVLOCTGYGRAPNTLAEY

ALKOFN LDFFDTSLTDGFNVPM

SFLPDGGSGCSRGPRCAVDVNA

RCPAELRODGVCNNACPVFKK

DEYCCVGSAANDCHPTNYSRY

FKGOCPDAYSYPKDDATSTFTC

PAGT YKWFCP

Claims

s claimed is:

A pharmaceutical composition comprising:

i) an effective amount of a synthetic messenger ribonucleic acid (mR A) encoding an anti-microbial polypeptide (AMP); and ii) a pharmaceutically acceptable carrier,

wherein the synthetic mRNA comprises at least one nucleoside modification, and wherem the anti-microbial polypeptide is about 6 to about 100 amino acids in length.

The pharmaceutical composition of claim 1, wherein the anti-microbial polypeptide is about 6 to about 75 amino acids in length.

The pharmaceutical composition of claim 1, wherein the anti-microbial polypeptide is about 6 to about 50 amino acids in length.

The pharmaceutical composition of claim 1 , wherein the anti-microbial polypeptide is about 15 to about 45 amino acids in length,

The pharmaceutical composition of claim 1, wherein the anti-microbial polypeptide is substantially cationic and amphipathic,

The pharmaceutical composition of claim 1 , wherem the anti-microbial polypeptide is cytostatic or cytotoxic to a Gram-positive bacterium.

The pharmaceutical composition of claim 1, wherein the an ti-microbial polypeptide is cytostatic or cytotoxic to a Gram-negative bacterium.

The pharmaceutical composition of claim 1, wherein the at least one nucleoside modification is selected from the group consisting of pyridin-4-one ribonucleoside, 5- aza-uridine, 2-thio-5-aza-uridine, 2-thiouridine, 4-thio-pseudouridine, 2-thio- pseudouridine, 5-hydroxyuridine, 3-methyluridine, 5-earboxymethyl-uridine, 1-

[[77]]249 carboxymethyl-pseudouridme, 5-propynyl-uridme, 1 -propynyl-pseudouridme, 5- taurmomethyluridme, 1 -taurmomethyj-pseudouridine, 5-taurinometh.yl-2-tb.io-uridine, 1 - taurinomethyl-4-thio-uridine, 5 -methyl- uridine, 1 -methyl-pseudouridme, 4-thio- 1- methyl-pseudouridme, 2-thio- 1 -niethyl-pseudouridiiie, 1 -methyl- 1 -deaza-pseudouridme, 2-thio-l -methyl- 1-deaza-pseudouridine, dihydrouridine, dihydropseudouridine, 2-thio- dihydrouridine, 2-thio-dihydropseudouridme, 2-methoxyuridme, 2-memoxy-4-thio- uridine, 4-meihoxy-pseudouridine, 4-met oxy-2-thio-pseudouridme, 5-aza-cytidine, pseudoisocytidine, 3-methyl-cytidine, N4-acetylcytidine, 5-formyleytidine. N4- methylcytidine, 5-hydroxymethylcytidine, l-methyl-pseudoisocytidme, pyrrolo-cytidme, pyrrolo-pseudoisocytidine, 2-ihio-cytidine, 2-thio-5-methyl-cytidine, 4-thio- pseudoisocytidine, 4-thio- 1 -methyl-pseudoisocytidme, 4-thio- 1 -methyl- 1 -deaza- pseudoisocytidine, l-methyM-deaza-pseudotsocytidme, zebulartne, 5-aza-zebularine, 5- methyl-zebularine, 5-aza-2-lhio-zebularine, 2-tbio-zebuIariiie, 2-msthoxy-cytidme, 2- methoxy-5-methyl-cytidine, 4-methoxy-pseudoi.socytidme, 4-m.ethoxy- l-methyl- pseudoisocytidine, 2-aminopurme, 2, 6-diaminopurine, 7-deaza-adenine, 7-deaza-8-aza- adenine, 7~deaza-2-aminopurine, 7-deaza-8-aza-2-aminopurine, 7-deaza-2,6- diammopurine, 7-deaza-8-aza-2, 6-diaminopurine, 1 -methyladenosine, N6- methyladenosine, N6~isopentenyladenosme, N6-(cis-hydroxyisopentenyl)adenosine, 2- methylthio-N6-(cis-hydroxyisopentenyl) adenosine, N6-glycinylcarbamoyladenosine, N6-threonylcarbamoyiadenosine, 2-methylibio-N6-threonyl carbamoyiadenosine, Νό,Νό- dimethyladenosine, 7-methyladenine, 2-methylthio-adenine, 2-methoxy-adenine, inosine, 1-methyl-inosine, wyosine, wybutosine, 7-deaza-guanosine, 7-deaza-8-aza-guanosine, 6- thio-guanosine, 6-thio-7-deaza-guanosine, 6-thio-7-deaza-8-aza-guanosine, 7-methyi- guanosine, 6-thio-7-methyl-guanosine, 7-methylinosine, 6-niethoxy-guanosine, 1- methyiguanosme, N2-methylguanosme, N2,N2-dimeihylguanosine, 8-oxo-guanosine, 7- methyl-8-oxo-guanosine, 1 -methyl-6-thio-guanosine, N2-methyl-6-thio-guanosine, and N2,N2-dimethyl-6-thio-guanosine.

9. The pharmaceutical composition of claim 1 , wherein the composition is suitable for

administration selected from the group consisting of, systemic, local, intravenous, topical, oral, administration via a dressing, administration via a bandage, rectal, vaginal

[[7811250 intramusciiiar, transarterial, intraperitoneal, mtranasally, subcutaneously, endoscopically, transdermally and intrathecal!}',

10. The pharmaceutical composition of claim 9, wherein the administration is intravenous,

11. The pharmaceutical composition of claim 9, wherein the administration is repeated at least once.

12. The pharmaceutical composition of claim 1 , wherein the anti-microbial polypeptide is a secreted polypeptide.

13. The pharmaceutical composition of claim 1 , wherein the anti-mici biai polypeptide is selected from the group consisting of SEQ ID NOs: 1-2915.

1 . The phamiaceu lical composition of claim 1 , wherein the anti-microbial polypeptide is hBD-2 (SEQ ID NO: 191 or 192), LL-37 (SEQ ID NO: 6), or RNAse-7 (SEQ ID

NO:262).

15. The pharmaceutical composition of claim 1 , further comprising a lipid-based transfection reagent.

16. A. method to treat a microbial infection, comprising administering to a subject the

pharmaceutical composition of claim 1 ,

17. The method of claim 16, wherein the subject is human.

18. The method of claim 16, wherein the subject is a livestock animal.

19. The method of claim 16, wherein the pharmaceutical composition is administered by a route selected from the group consisting of systemic, local, intravenous, topical, oral, administration via a dressing, administration via a bandage, rectal, vaginal, intramuscular,

[[79]]25i transarterial, intraperitoneal, intranasally, subcutaneously, endoscopically, transdermally and intrathecally,

20. The method of claim 19, wherein the route is intravenous,

21. The method of claim 19, wherei the administration is repeated at least once,

22. The method of claim 16, further comprising administering an effective amount of a small molecule anti-microbial compound to the subject at the same time or at a different time from the administration of the pharmaceutical composition.

23. A kit comprising the pharmaceutical composition of claim 1 , packaging and instructions for use thereof,

[[8011252