ZA200109110B - Long lasting fusion peptide inhibitors or viral infection. - Google Patents
Long lasting fusion peptide inhibitors or viral infection. Download PDFInfo
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- ZA200109110B ZA200109110B ZA200109110A ZA200109110A ZA200109110B ZA 200109110 B ZA200109110 B ZA 200109110B ZA 200109110 A ZA200109110 A ZA 200109110A ZA 200109110 A ZA200109110 A ZA 200109110A ZA 200109110 B ZA200109110 B ZA 200109110B
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- South Africa
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- 239000000969 carrier Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 210000003850 cellular structure Anatomy 0.000 description 1
- 125000003636 chemical group Chemical group 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 201000010549 croup Diseases 0.000 description 1
- 125000000753 cycloalkyl group Chemical group 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
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- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- CEIPQQODRKXDSB-UHFFFAOYSA-N ethyl 3-(6-hydroxynaphthalen-2-yl)-1H-indazole-5-carboximidate dihydrochloride Chemical compound Cl.Cl.C1=C(O)C=CC2=CC(C3=NNC4=CC=C(C=C43)C(=N)OCC)=CC=C21 CEIPQQODRKXDSB-UHFFFAOYSA-N 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 125000005519 fluorenylmethyloxycarbonyl group Chemical group 0.000 description 1
- 230000000799 fusogenic effect Effects 0.000 description 1
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 description 1
- 150000002463 imidates Chemical class 0.000 description 1
- 102000018358 immunoglobulin Human genes 0.000 description 1
- 229940072221 immunoglobulins Drugs 0.000 description 1
- 230000001506 immunosuppresive effect Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
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- 230000006525 intracellular process Effects 0.000 description 1
- 229960000310 isoleucine Drugs 0.000 description 1
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 210000004324 lymphatic system Anatomy 0.000 description 1
- 125000005439 maleimidyl group Chemical group C1(C=CC(N1*)=O)=O 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
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- 238000000034 method Methods 0.000 description 1
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- 244000052769 pathogen Species 0.000 description 1
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- 150000002989 phenols Chemical class 0.000 description 1
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 1
- UYWQUFXKFGHYNT-UHFFFAOYSA-N phenylmethyl ester of formic acid Natural products O=COCC1=CC=CC=C1 UYWQUFXKFGHYNT-UHFFFAOYSA-N 0.000 description 1
- 150000003014 phosphoric acid esters Chemical class 0.000 description 1
- 125000003367 polycyclic group Chemical group 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
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- 125000006850 spacer group Chemical group 0.000 description 1
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Classifications
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Description
LONG LASTING FUSION PEPTIDE INHIBITORS OF VIRAL
INFECTION
: This invention relates to modified peptides that are inhibitors of viral activity and/or exhibit antifusogenic properties. In particular, this invention relates to modified peptide inhibitors of human immunodeficiency virus (HIV), respiratory syncytial virus (RSV), human parainfluenza virus (HPV), measles virus (MeV), and simian immunodeficiency virus (SIV) with long duration of action for the treatment of the respective viral infections. The invention also relates to conjugates of the modified peptides and endogenous carriers, particularly conjugates of the modified peptides and various mobile blood components, particularly mobile endogenous proteins.
Membrane fusion events, while commonplace in normal cell biological processes, are also involved in a variety of disease states, including, for example the entry of enveloped viruses into cells. Peptides are known that inhibit or otherwise disrupt membrane fusion-associated events, including, for example, inhibiting retroviral transmission to uninfected cells. As an example, the synthetic peptides DP-107 and DP-178 derived from separate domains within the human immunodeficiency virus type 1 (“HIV-1") transmembrane (“TM”) glycoprotein gp41, are potent inhibitors of HIV-1 infection and HIV induced cell-cell fusion.
Lambert, et al., “Peptides from Conserved Regions of Paramyxovirus
Fusion (F) Proteins are Potent Inhibitors of Viral Fusion,” Proc. Natl. Acad.
Science U.S.A., March 5, 1996, Vol. 93 (5), pp. 2186-91, discloses that the synthetic peptides DP-107 and DP-178 (T-20), derived from separate domains within the human immunodeficiency virus type 1 (HIV-1) transmembrane (TM) protein, gp4l, are potent inhibitors of HIV-1 infection and fusion. Using a computer searching strategy (computerized antiviral searching technology, :
C.A.S.T.) based on the predicted secondary structure of DP-107 and DP-178 (T- 20), Lambert, et al. identified conserved heptad repeat domains analogous to the
DP-107 and DP-178 regions of HIV-1 gp41 within the glycoproteins of other fusogenic viruses. Antiviral peptides derived from three representative paramyxoviruses, respiratory syncytial virus (RSV), human parainfluenza virus type 3 (HPIV-3), and measles virus (MV) blocked homologous virus-mediated syncytium formation and exhibited EC, values in the range 0.015-0.250 uM. - Moreover, these peptides were highly selective for the virus of origin. :
U.S. Patent Nos. 6,013,263, 6,017,536 and 6,020,459 incorporated herein in their entirety, likewise disclose that the 36 amino acid peptide DP178 corresponding to amino acids 638 to 673 of gp41 from the HIV-1 isolate LAI (HIV-1.,)), and the 38 amino acid peptide DP107 corresponding to amino acids 558-595 of gp41 from the HIV-1,,,, both exhibit potent anti-HIV-1 activity.
While many of the anti-viral or anti-fusogenic peptides described in the art exhibit potent anti-viral and/or anti-fusogenic activity, these peptides suffer from short plasma half-lifes in vivo, primarily due to rapid serum clearance and peptidase and protease activity. This in turn greatly reduces the effective anti-viral activity of the peptides. There is therefore a need for a method of prolonging the half-life of existing anti-viral and/or anti-fusogenic peptides and providing for longer duration of action of these peptides in vivo.
The present invention meets these and other needs and is directed to modified peptides having anti-viral activity and/or anti-fusogenic activity. These modified peptides provide for an increased stability in vivo and a reduced susceptibility to peptidase or protease degradation. These modified peptides thereby minimize, e.g., the need for more frequent, or even continual,
administration of the peptides. The products of varying embodiments of the present invention can be used, e.g., as a prophylactic against and/or treatment for infection of a number of viruses, including human immunodeficiency virus (HIV), human respiratory syncytial virus (RSV), human parainfluenza virus (HPV), measles virus (MeV) and simian immunodeficiency virus (SIV). Modification of : other peptides involved in viral transfection (e.g., Hepatitis, Epstein Barr and other related viruses) is also within the scope of the invention.
This invention relates to chemically reactive modifications of peptides exhibiting anti-viral and/or anti-fusogenic activity such that the modified peptides can react with available functionalities on blood components to form stable covalent bonds. In one embodiment of the invention, the modified peptides - comprise a reactive group which is reactive with amino groups, hydroxyl groups, or thiol groups on blood components to form stable covalent bonds. In another embodiment of the invention, the reactive group can be a maleimide which is reactive with a thiol group on a blood protein, including a mobile blood protein such as albumin.
In particular, the invention relates to such chemically reactive modifications of DP107 and DP178 peptides and analogs thereof, including peptides comprised of amino acid sequences from other (non-HIV) viruses that correspond to the gp41 region of HIV from which DP107 and DP178 are derived ] and that exhibit anti-viral or anti-fusogenic activity. More particularly, these peptides can exhibit anti-viral activity against, among others, human respiratory syncytial virus (RSV), human parainfluenza virus (HPV), measles virus (MeV) and simian immunodeficiency virus (SIV). The invention also relates to such chemically reactive modifications of the peptides of SEQ ID NO:1 to SEQ ID
NO:86.
The invention also relates to compositions for use in the prevention and/or treatment of viral infection comprising a peptide that exhibits anti-viral activity modified with a reactive group as described. More particularly, the invention relates to such compositions for use in the prevention and/or treatement of AIDS,
-4- on ? human respiratory syncytial virus (RSV), human parainfluenza virus (HPV), measles virus (MeV) and simian immunodeficiency virus (SIV).
The invention will be better understood by reference to the Tables, in which:
Table 1 lists the commonly occurring amino acids together with their one letter and three letter abbreviations, and common protecting groups.
Table 2 shows DP178 carboxy truncations.
Table 3 shows DP178 amino truncations.
Table 4 shows DP107 carboxy truncations.
Table 5 shows DP107 amino truncations.
Table 6 shows HIV-2,;,, DP178 analog carboxy truncations.
Table 7 shows HIV-2,,,,, DP178 analog amino truncations.
Table 8 shows RSV F2 region DP107 analog carboxy truncations.
Table 9 shows RSV F2 region DP107 analog amino truncations.
Table 10 shows RSV F1 region DP178 analog carboxy truncations.
Table 11 shows RSV F1 region DP178 analog amino truncations.
Table 12 shows HPV3 F1 region DP 178 analog carboxy truncations.
Table 13 shows HPV3 F1 region DP 178 analog amino truncations. .
Table 14 shows HPV3 F1 region DP107 analog carboxy truncations.
Table 15 shows HPV3 F1 region DP107 analog amino truncations. )
Table 16 shows representative anti-RSV peptides.
Table 17 shows representative anti-HPV3 peptides.
Table 18 shows representative anti-SIV peptides.
Table 19 shows representative anti-MeV peptides.
The invention will be better understood by reference to the Sequence
Listing, in which:
v
SEQ ID NO:1 shows the peptide sequence of DP178.
SEQ ID NO:2 shows the peptide sequence of DP107
SEQ ID NO:3-9 show peptide sequences of certain DP178 analogs.
SEQ ID NO:10-30 show the peptide sequences of RSV F1 region and F2 region corresponding to DP178 and DP107, and representtive anti-RSV peptides;
SEQ ID NO:31-62 show the peptide sequences of HPIV3 F1 region corresponding to DP178 and DP107, and representative anti-HPIV3 peptides;
SEQ ID NO:63-73 show peptide sequences of SIV corresponding to DP178 and representative anti-SIV peptides; and
SEQ ID NO:74-78 show peptide sequences of MeV corresponding to
DP178 and representative anti-MeV peptides.
To ensure a complete understanding of the invention the following definitions are provided:
Anti-viral peptides: As used herein, anti-viral peptides shall refer to peptides that inhibit viral infection of cells, by, for example, inhibiting cell-cell fusion or free virus infection. The route of infection may involve membrane fusion, as occurs in the case of enveloped viruses, or some other fusion event involving viral and cellular structures. Peptides that inhibit viral infection by a particular virus may be referenced with respect to that particular virus, e.g., anti-
HIV peptide, anti-RSV peptide, etc.
Antifusogenic peptides: Antifusogenic peptides are peptides demonstrating an ability to inhibit or reduce the level of membrane fusion events between two or more entities, €.g., virus-cell or cell-cell, relative to the level of membrane fusion that occurs in the absence of the peptide.
v
HIV and anti-HIV peptides: The human immunodeficiency virus (HIV), which is responsible for acquired immune deficiency syndrome (AIDS), is a member of the lentivirus family of retroviruses. There are two prevalent types of
HIV, HIV-1 and HIV-2, with various strain of each having been identified. HIV targets CD-4+ cells, and viral entry depends on binding of the HIV protein gp41 to
CD-4+ cell surface receptors. Anti-HIV peptides refer to peptides that exhibit anti- viral activity against HIV, including inhibiting CD-4+ cell infection by free virus and/or inhibiting HIV-induced syncytia formation between infected and uninfected
CD-4+ cells.
SIV and anti-SIV peptides: Simian immunodeficiency viruses (SIV) are lentiviruses that cause acquired immunodeficiency syndrome (AIDS)-like illnesses in susceptible monkeys. Anti-SIV peptides are peptides that exhibit anti-viral activity against SIV, including inhibiting of infection of cells by the SIV virus and inhibiting syncytia formation between infected and uninfected cells.
RSV and anti-RSV peptides: Respiratory syncytial virus (RSV) is a respiratory pathogen, especially dangerous in infants and small children where it can cause bronchiolitis (inflammation of the small air passages) and pneumonia.
RSVs are negative sense, single stranded RNA viruses and are members of the
Paramyxoviridae family of viruses. The route of infection of RSV is typically through the mucous membranes by the respiratory tract, i.e., nose, throat, windpipe and bronchi and bronchioles. Anti-RSV peptides are peptides that exhibit anti- viral activity against RSV, including inhibiting mucous membrane cell infection by free RSV virus and syncytia formation between infection and uninfected cells.
HPV and anti-HPV peptides: Human parainfluenza virus (HPIV or
HPV), like RSV, is another leading cause of respiratory tract disease, and like
RSVs, are negative sense, single stranded RNA viruses that are members of the
Paramyxoviridae family of viruses. There are four recognized serotypes of
Kl
HPIV -- HPIV-1, HPIV-2, HPIV-3 and HPIV-4. HPIV-1 is the leading cause of croup in children, and both HPIV-1 and HPIV-2 cause upper and lower respiratory tract illnesses. HPIV-3 is more often associated with bronchiolitis and pneumonia.
Anti-HPV peptides are peptides that exhibit anti-viral activity against HPV, including inhibiting infection by free HPV virus and syncytia formation between infected and uninfected cells. : "MeV and anti-Mev peptides: Measles virus (VM or MeV) is an enveloped negative, single-stranded RNA virus belonging to the Paramyxoviridae family of viruses. Like RSV and HPV, MeV causes respiratory disease, and also produces an immuno-suppression responsible for additional, opportunistic infections. In some cases, MeV can establish infection of the brain leading to severe neurlogical complications. Anti-MeV peptides are peptides that exhibit anti-viral activity against MeV, including inhibiting infection by free MeV virus 15 . and syncytia formation between infected and uninfected cells. : :
DP-178 and DP178 analogs: Unless otherwise indicated explicitly or by context, DP-178 means the 36 amino acid DP-178 peptide corresponding to amino acid residues 638-673 of the gp41 glycoprotein of HIV-1 isolate LAI (HIV, ,,) and having the sequence:
YTSLIHSLIEESQNQQEKNEQELLELDKWASLWNWEF (SEQ ID NO:1) as well as truncations, deletions and/or insertions thereof. Truncations of the
DP178 peptide may comprise peptides of between 3-36 amino acids. Deletions consist of the removal of one or more amino acid residues from the DP178 peptide, and may involve the removal of a single contigaous portion of the peptide sequence or multiple portions. Insertions may comprise single amino acid residues or stretches of residues and may be made at the carboxy or amino terminal end of the DP178 peptide or at a position internal to the peptide.
y
DP178 peptide analogs are peptides whose amino acid sequences are comprised of the amino acid sequences of peptide regions of viruses other than
HIV-1, ,, that correspond to the gp41 region from which DP178 was derived, as . 5 well as an truncations, deletions or insertions thereof. Such other viruses may include, but are not limited to, other HIV isolates such as HIV-2,,,, respiratory : syncytial virus (RSV), human parainfluenza virus (HPV), simian immunodeficiency virus (SIV), and measles virus (MeV). DP178 analogs also refer to those peptide sequences identified or recognized by the ALLMOTIS, 107x178x4 and PLZIP search motifs described in U.S. Patent Nos. 6,013,263, : : 6,017,536 and 6,020,459 and incorporated herein, having structural and/or amino acid motif similarity to DP178. DP178 analogs further refer to peptides described : as "DP178-like" as that term is defined in U.S. Patent Nos. 6,013,263, 6,017,536 and 6,020,459. 156. . ;
DP-107 and DP107 analogs: Unless otherwise indicated explicitly or by context, DP-107 means the 38 amino acid DP-107 peptide corresponding to amino acid residues 558-595 of the gp41 protein of HIV-1 isolate LAI (HIV, ,,) and - having the sequence: }
NNLLRAIEAQQHLLQLTVWQIKQLQARILAVERYLKDQ (SEQ ID NO:2) as well as truncations, deletions and/or insertions thereof. Truncations of the :
DP107 peptide may comprise peptides of between 3-38 amino acids. Deletions consist of the removal of one or more amino acid residues from the DP107 peptide, and may involve the removal of a single contiguous portion of the peptide sequence or multiple portions. Insertions may comprise single amino acid residues or stretches of residues and may be made at the carboxy or amino terminal end of the DP107 peptide or at a position internal to the peptide.
DP107 peptide analogs are peptides whose amino acid sequences are comprised of the amino acid sequences of peptide regions of viruses other than
HIV-1, ,, that correspond to the gp41 region from which DP107 was derived, as well as truncations, deletions and/or insertions thereof. Such other viruses may include, but are not limited to, other HIV isolates such as HIV-2,,,, respiratory syncytial virus (RSV), human parainfluenza virus (HPV), simian immunodeficiency virus (SIV), and measles virus (MeV). DP107 analogs also refer to those peptide sequences identified or recognized by the ALLMOTIS, 107x178x4 and PLZIP search motifs described in U.S. Patent Nos. 6,013,263, 6,017,536 and 6,020,459 and incorporated herein, having structural and/or amino acid motif similarity to DP107. DP107 analogs further refer to peptides described as "DP107-like" as that term is defined in U.S. Patent Nos. 6,013,263, 6,017,536 and 6,020,459.
Reactive Groups: Reactive groups are chemical groups capable of forming a covalent bond. Such reactive groups are coupled or bonded to a DP-107 or DP-178 peptide or analogs thereof or other anti-viral or anti-fusogenic peptide of interest. Reactive groups will generally be stable in an aqueous environment and will usually be carboxy, phosphoryl, or convenient acyl group, either as an ester or a mixed anhydride, or an imidate, thereby capable of forming a covalent } bond with functionalities such as an amino group, a hydroxy or a thiol at the target site on mobile blood components. For the most part, the esters will involve i phenolic compounds, or be thiol esters, alkyl esters, phosphate esters, or the like.
Functionalities: Functionalities are groups on blood components to which reactive groups on modified anti-viral peptides react to form covalent bonds.
Functionalities include hydroxyl groups for bonding to ester reactive entities; thiol groups for bonding to maleimides, imidates and thioester groups; amino groups for bonding to carboxy, phosphoryl or acyl groups and carboxyl groups for bonding to amino groups.
Blood Components: Blood components may be either fixed or mobile.
Fixed blood components are non-mobile blood components and include tissues, membrane receptors, interstitial proteins, fibrin proteins, collagens, platelets, endothelial cells, epithelial cells and their associated membrane and membraneous receptors, somatic body cells, skeletal and smooth muscle cells, neuronal components, osteocytes and osteoclasts and all body tissues especially those associated with the circulatory and lymphatic systems. Mobile blood components are blood components that do not have a fixed situs for any extended period of time, generally not exceeding 5, more usually one minute. These blood : components are not. membrane-associated and are present in the blood for extended periods of time and are present in a minimum concentration of at least 0.1 pg/ml.
Mobile blood components include serum albumin, transferrin, ferritin and immunoglobulins such as [gM and IgG. The half-life of mobile blood components \ 15 is at least about 12 hours. .
Protective Groups: Protective groups are chemical moieties utilized to protect peptide derivatives from reacting with themselves. Various protective groups are disclosed herein and in U.S. 5,493,007, which is hereby incorporated by reference. Such protective groups include acetyl, fluorenylmethyloxycarbonyl : (Fmoc), t-butyloxycarbonyl (Boc), benzyloxycarbonyl (CBZ), and the like. The | Lo specific protected amino acids are depicted in Table 1.
TABLE 1
NATURAL AMINO ACIDS AND THEIR ABBREVIATIONS
3-Letter 1-Letter Modified Amino Acids
Name Abbreviation Abbreviation
Fmoc-Ala-OH
Arginine | Arg | = R | Fmoc-Arg(Pbf)-OH
Asparagine | Asn | = N | Fmoc-Asn(Trt)-OH
Asparticacid | Asp | ~~ D | Asp(tBu)-OH
Fmoc-Cys(Trt)
Glutamicacid | Gu | ~~ E [| Fmoc-Glu(tBu)-OH
Glutamine | Gn | ~~ Q | Fmoc-Gin(Trt)-OH
Fmoc-Gly-OH
Fmoc-His(Trt)-OH
Isoleucine | We | 1 | Fmoc-le-OH
Fmoc-Leu-OH
Boc-Lys(Aloc)-OH
Fmoc-Lys(Aloc)-OH
Fmoc-Lys(Mtt)-OH __Methionine | Met | ~~ M | Fmoc-Met-OH
Phenylalanine Fmoc-Phe-OH
Proline - | Po | ~~ P | Fmoc-Pro-OH
Fmoc-Ser(tBu)-OH
Fmoc-Thr(tBu)-OH
Tryptophan Fmoc-Trp(Boc)-OH
Boc-Tyr(tBu)-OH
Fmoc-Val-OH
Linking Groups: Linking (spacer) groups are chemical moieties that link - 5 or connect reactive entities to antiviral or antifusogenic peptides. Linking groups may comprise one or more alkyl moeities, alkoxy moeity, alkenyl moeity, alkynyl moeity or amino moeity substituted by alkyl moeities, cycloalkyl moeity, polycyclic moeity, aryl moeity, polyaryl moeities, substituted aryl moeities, heterocyclic moeities, and substituted heterocyclic moeities. Linking groups may also comprise poly ethoxy amino acids, such as AEA ((2-amino) ethoxy acetic acid) or a preferred linking group AEEA ([2-(2-amino) ethoxy)] ethoxy acetic acid.
Sensitive Functional Groups — A sensitive functional group is a group of atoms that represents a potential reaction site on an antiviral and/or antifusogenic peptide. If present, a sensitive functional group may be chosen as the attachment : point for the linker-reactive group modification. Sensitive functional groups include but are not limited to carboxyl, amino, thiol, and hydroxyl groups.
Modified Peptides — A modified peptide is an antiviral and/or : antifusogenic peptide that has been modified by attaching a reactive group. The reactive group may be attached to the peptide either via a linking group, or optionally without using a linking group. It is also contemplated that one or more additional amino acids may be added to the peptide to facilitate the attachment of the reactive entity. Modified peptides may be administered in vivo such that : conjugation with blood components occurs in vivo, or they may be first conjugated to blood components in vitro and the resulting conjugated peptide (as defined below) administered in vivo.
Conjugated Peptides — A conjugated peptide is a modified peptide that has been conjugated to a blood component via a covalent bond formed between the reactive group of the modified peptide and the functionalities of the blood component, with or without a linking group. As used throughout this application, the term “conjugated peptide” can be made more specific to refer to particular . conjugated peptides, for example “conjugated DP178” or “conjugated DP107.”
Taking into account these definitions, the present invention takes advantage of the properties of existing anti-viral and antifusogenic peptides. The viruses that may be inhibited by the peptides include, but are not limited to all strains of viruses listed, e.g., in U.S. Patent Nos. 6,013,263, 6,017,536 and 6,020,459 at
Tables V-VII and IX-XIV therein. These viruses include, e.g., human retroviruses, including HIV-1, HIV-2, and human T-lympocyte viruses (HTLV-I and HTLV-II), and non-human retroviruses, including bovine leukosis virus, feline sarcoma virus,
feline leukemia virus, simian immunodeficiency virus (SIV), simian sarcoma virus, simian leukemia, and sheep progress pneumonia virus. Non-retroviral viruses may also be inhibited by the peptides of the present invention, including human respiratory syncytial virus (RSV), canine distemper virus, Newcastle
Disease virus, human parainfluenza virus (HPIV), influenza viruses, measles . viruses (MeV), Epstein-Barr viruses, hepatitis B viruses, and simian Mason-Pfizer viruses. Non-enveloped viruses may also be inhibited by the peptides of the present invention, and include, but are not limited to, picornaviruses such as polio viruses, hepatitis A virus, enteroviruses, echoviruses, coxsackie viruses, papovaviruses such as papilloma virus, parvoviruses, adenoviruses, and reoviruses.
As an example, the mechanism of action of HIV fusion peptides has been described as discussed in the background section of this application and antiviral and antifusogenic properties of the peptides have been well established. A synthetic peptide corresponding to the carboxyl-terminal ectodomain sequence (for instance, amino acid residues 643-678 of HIV-1 class B, of the LAI strain or - residues 638-673 from similar strain as well as residues 558-595) has been shown to inhibit virus-mediated cell-cell fusion completely at low concentration. The fusion peptide competes with the leucine zipper region of the native viral gp41 thus resulting in the interference of the fusion/infection of the virus into the cell.
The focus of the present invention is to modify a selected anti-viral and/or antifusogenic peptide with the DAC (Drug Activity Complex) technology to confer to this peptide improved bio-availability, extended half-life and better distribution through selective conjugation of the peptide onto a protein carrier but without modifying the peptide's anti-viral properties. The carrier of choice (but not limited to) for this invention would be albumin conjugated through its free thiol by an anti-viral and/or antifusogenic peptide modified with a maleimide moiety.
Several peptide sequences have been described in the literature as highly potent for the prevention of HIV-1 fusion/infection. As examples, peptide DP178 binds to a conformation of gp41 that is relevant for fusion. Thus in one embodiment of the invention, DP178 and DP178-like peptides are modified.
Likewise, other embodiments of the invention include modification of DP107 and
DP107-like peptide for use against HIV, as well as peptides analagous to DP107 : and DP178 that are found in RSV, HPV, MeV and SIV viruses. 1. DP178 and DP107
A. DP178 Peptides :
The DP178 peptide corresponds to amino acid residues 638 to 673 of the transmembrane protein gp41 from the HIV-1,,, isolate, and has the 36 amino acid sequence (reading from amino to carboxy terminus):
NH,-YTSLIHSLIEESQNQQEKNEQELLELDKWASLWNWF-COOH (SEQ :
ID NO:1)
In addition to the full-length DP178 36-mer, the peptides of this invention include truncations of the DP178 peptide comprising peptides of between 3 and 36 amino acid residues (i.e., peptides ranging in size from a tripeptide to a 36-mer polypeptide), These truncated peptides are shown in Tables 2 and 3. :
In addition amino acid substitutions of the DP178 peptide are also within the scope of the invention. HIV-1 and HIV-2 enveloped proteins are structurally : distinct, but there exists a striking amino acid conservation within the DP178- corresponding regions of HIV-1 and HIV-2. The amino acid conservation is of a periodic nature, suggesting some conservation of structure and/or function.
Therefore, one possible class of amino acid substitutions would include those amino acid changes which are predicted to stabilize the structure of the DP178 peptides of the invention. Utilizing the DP178 and DP178 analog sequences described herein, the skilled artisan can readily compile DP178 consensus sequences and ascertain from these, conserved amino acid residues which would represent preferred amino acid substitutions.
The amino acid substitutions may be of a conserved or non-conserved nature. Conserved amino acid substitutions consist of replacing one or more amino acids of the DP178 peptide sequence with amino acids of similar charge, size, and/or hydrophobicity characteristics, such as, for example, a glutamic acid (E) to aspartic acid (D) amino acid substitution. Non-conserved substitutions consist of replacing one or more amino acids of the DP178 peptide sequence with amino acids possessing dissimilar charge, size, and/or hydrophobicity : characteristics, such as, for example, a glutamic acid (E) to valine (V) substitution.
Amino acid insertions of DP178 may consist of single amino acid residues or stretches of residues. The insertions may be made at the carboxy or amino terminal end of the DP178 or DP178 truncated peptides, as well as at a position internal to the peptide.
Such insertions will generally range from 2 to 15 amino acids in length. It is contemplated that insertions made at either the carboxy or amino terminus of the peptide of interest may be of a broader size range, with about 2 to about 50 amino acids being preferred. One or more such insertions may be introduced into DP178 ) or DP178 truncations, as long as such insertions result in peptides which may still be recognized by the 107x178x4, ALLMOTIS or PLZIP search motifs described ’ above.
Preferred amino or carboxy terminal insertions are peptides ranging from about 2 to about 50 amino acid residues in length, corresponding to gp41 protein regions either amino to or carboxy to the actual DP178 gp41 amino acid sequence, respectively. Thus, a preferred amino terminal or carboxy terminal amino acid insertion would contain gp41 amino acid sequences found immediately amino to or carboxy to the DP178 region of the gp41 protein.
Deletions of DP178 or DP178 truncations are also within the scope of this invention. Such deletions consist of the removal of one or more amino acids from the DP178 or DP178-like peptide sequence, with the lower limit length of the : 5 resulting peptide sequence being 4 to 6 amino acids. -
Such deletions may involve a single contiguous or greater than one discrete portion of the peptide sequences. One or more such deletions may be introduced into DP178 or DP178 truncations, as long as such deletions result in peptides which may still be recognized by the 107x178x4, ALLMOTIS or PLZIP search motifs described above.
B. DP107 Peptides
DP107 is a 38 amino acid peptide which exhibits potent antiviral activity, and corresponds to residues 558 to 595 of HIV-1, ,, isolate transmembrane (TM) gp41 glycoprotein, as shown here:
NH,-NNLLRAIEAQQHLLQLTVWQIKQLQARILAVERYLKDQ-COOH (SEQIDNO:2)
In addition to the full-length DP107 38-mer, the DP107 peptides include truncations of the DP107 peptide comprising peptides of between 3 and 38 amino acid residues (i.e., peptides ranging in size from a tripeptide to a 38-mer - polypeptide), These peptides are shown in Tables 4 and 5, below. :
In addition, amino acid substitutions of the DP178 peptide are also within the scope of the invention. As for DP178, there also exists a striking amino acid conservation within the DP107-corresponding regions of HIV-1 and HIV-2, again of a periodic nature, suggesting conservation of structure and/or function.
Therefore, one possible class of amino acid substitutions includes those amino acid changes predicted to stabilize the structure of the DP107 peptides of the invention.
Utilizing the DP107 and DP107 analog sequences described herein, the skilled artisan can readily compile DP107 consensus sequences and ascertain from these, conserved amino acid residues which would represent preferred amino acid substitutions.
The amino acid substitutions may be of a conserved or non-conserved nature. Conserved amino acid substitutions consist of replacing one or more amino acids of the DP107 peptide sequence with amino acids of similar charge, size, and/or hydrophobicity characteristics, such as, for example, a glutamic acid (E) to aspartic acid (D) amino acid substitution. Non-conserved substitutions consist of replacing one or more amino acids of the DP107 peptide sequence with amino acids possessing dissimilar charge, size, and/or hydrophobicity characteristics, such as, for example, a glutamic acid (E) to valine (V) substitution. . 16
Amino acid insertions may consist of single amino acid residues or stretches of residues. The insertions may be made at the carboxy or amino terminal end of the DP107 or DP107 truncated peptides, as well as at a position internal to the peptide.
Such insertions will generally range from 2 to 15 amino acids in length. It is contemplated that insertions made at either the carboxy or amino terminus of the peptide of interest may be of a broader size range, with about 2 to about 50 amino acids being preferred. One or more such insertions may be introduced into DP107 or DP107 truncations, as long as such insertions result in peptides which may still be recognized by the 107x178x4, ALLMOTIS or PLZIP search motifs described : above.
Preferred amino or carboxy terminal insertions are peptides ranging from about 2 to about 50 amino acid residues in length, corresponding to gp41 protein regions either amino to or carboxy to the actual DP107 gp41 amino acid sequence, respectively. Thus, a preferred amino terminal or carboxy terminal amino acid insertion would contain gp41 amino acid sequences found immediately amino to or carboxy to the DP107 region of the gp41 protein.
Deletions of DP107 or DP107 truncations are also within the scope of this invention. Such deletions consist of the removal of one or more amino acids from the DP107 or DP107-like peptide sequence, with the lower limit length of the resulting peptide sequence being 4 to 6 amino acids.
Such deletions may involve a single contiguous or greater than one discrete portion of the peptide sequences. One or more such deletions may be introduced into DP107 or DP107 truncations, as long as such deletions result in peptides which may still be recognized by the 107x178x4, ALLMOTIS or PLZIP search 15 . motifs. . | .
DP107 and DP107 truncations are more fully described in U.S. Patent No. 5,656,480, which is incorporated herein by reference in its entirety Lo 2. DP107 and DP178 Analogs
Peptides corresponding to analogs of the DP178, DP178 truncations, .
DP107 and DP107 truncation sequences of the invention, described, above, may be found in other viruses, including, for example, non-HIV-1 enveloped viruses, non- enveloped viruses and other non-viral organisms.
Such DP178 and DP107 analogs may, for example, correspond to peptide sequences present in transmembrane ("TM") proteins of enveloped viruses and may, correspond to peptide sequences present in non enveloped and nonviral organisms. Such peptides may exhibit antifusogenic activity, antiviral activity, most particularly antiviral activity which is specific to the virus in which their native sequences are found, or may exhibit an ability to modulate intracellular processes involving coiled-coil peptide structures.
A. DP178 analogs
DP178 analogs are peptides whose amino acid sequences are comprised of the amino acid sequences of peptide regions of, for example, other (i.c., other than
HIV-1) viruses that correspond to the gp41 peptide region from which DP178 was derived. Such viruses may include, but are not limited to, other HIV-1 isolates and
HIV-2 isolates.
DP178 analogs derived from the corresponding gp41 peptide region of other (i.e., non HIV-1LAI) HIV-1 isolates may include, for example, peptide sequences as shown below.
NH2-YTNTIYTLLEESQNQQEKNEQELLELDKWASLWNWF-COOH (SEQ
ID NO:3)
NH2-YTGII'YNLLEESQNQQEKNEQELLELDKWANLWNWEF-COOH (SEQ
ID NO:4)
NH2-YTSLIYSLLEKSQIQQEKNEQELLELDKWASLWNWF-COOH(SEQ ID
NO:5)
The peptides of SEQ ID NO:3, SEQ ID NO:4 and SEQ ID NO:S are derived from HIV-1gg,, HIV-1gg, and HIV-1,,, respectively. Other DP178 analogs include those derived from HIV-2, including the peptides of SEQ ID NO:6 and
SEQ ID NO:7, which are derived from HIV-2,,, and HIV-2,,,, respectively. Still other useful analogs include the peptides of SEQ ID NO:8 and SEQ ID NO:9, which have been demonstrated to exhibit anti-viral activity.
In the present invention, it is preferred that the DP178 analogs represent peptides whose amino acid sequences correspond to the DP178 region of the gp41 protein, it is also contemplated that the peptides disclosed herein may, additionally, include amino sequences, ranging from about 2 to about 50 amino ’ acid residues in length, corresponding to gp41 protein regions either amino to or carboxy to the actual DP178 amino acid sequence.
Table 6 and Table 7 show some possible truncations of the HIV-2,p,,
DP178 analog, which may comprise peptides of between 3 and 36 amino acid residues (i.e., peptides ranging in size from a tripeptide to a 36-mer polypeptide).
Peptide sequences in these tables are listed from amino (left) to carboxy (right) terminus.
B. Additional DP178 Analogs and DP107 Analogs
DP178 and DP107 analogs are recognized or identified, for example, by : utilizing one or more of the 107x178x4, ALLMOTIS or PLZIP computer-assisted search strategies described above. The search strategy identifies additional peptide regions which are predicted to have structural and/or amino acid sequence features similar to those of DP107 and/or DP178.
The search strategies are described fully in the example presented in
Section 9 of US Patent Nos. 6,013,263, 6,017,536 and 6,020,459. While this : search strategy is based, in part, on a primary amino acid motif deduced from ~
DP107 and DP178, it is not based solely on searching for primary amino acid - sequence homologies, as such protein sequence homologies exist within, but not between major groups of viruses. For example, primary amino acid sequence : homology is high within the TM protein of different strains of HIV-1 or within the : :
TM protein of different isolates of simian immunodeficiency virus (SIV).
The computer search strategy disclosed in US Patent Nos. 6,013,263, 6,017,536 and 6,020,459 successfully identified regions of proteins similar to
Claims (30)
1. A modified anti-viral peptide comprising: © a peptide that exhibits anti-viral activity, and a reactive group which is reactive with amino groups, hydroxyl groups, or thiol groups on blood components to form stable covalent bonds.
2. The modified peptide of claim 1 wherein said reactive group is a succinimidyl or a maleimido group. :
3. The modified peptide of claim 1 wherein said reactive group is a maleimido group which is reactive with a thiol group on a blood protein.
4. The modified peptide of claim 1 wherein said peptide is DP178 or DP107 or analogs thereof. .
5. The modified peptide of claim 1 wherein said peptide exhibits anti- viral activity against human immunodeficiency virus (HIV).
6. The modified peptide of claim 5 wherein said peptide is selected from the group consisting of SEQ ID NO:1 to SEQ ID NO:9. :
7. The modified peptide of claim 5 wherein said peptide is DP 178 or DP 107.
8. The modified peptide of claim 1 wherein said peptide exhibits anti- viral activity against human respiratory syncytial virus (RSV).
9. The modified peptide of claim 8 wherein said peptide is selected from the group consisting of SEQ ID NO:10 to SEQ ID NO:30.
10. The modified peptide of claim 8 wherein said peptide is selected from the group consisting of SEQ ID NO:14 to SEQ ID NO:17 and SEQ ID NO:29.
11. The modified peptide of claim 1 wherein said peptide exhibits anti- viral activity against human parainfluenza virus (HPIV).
12. The modified peptide of claim 11 wherein said peptide is selected from the group consisting of SEQ ID NO:31 to SEQ ID NO:62.
13. The modified peptide of claim 11 wherein said peptide is selected : from the group consisting of SEQ ID NO: 35, SEQ ID NO:38 to SEQ ID NO:42, SEQ ID NO:52 and SEQ ID NO:58.
14. The modified peptide of claim 1 wherein said peptide exhibits anti- viral activity against measles virus (MeV).
+15. The modified peptide of claim 14 wherein said peptide is selected from the group consisting of SEQ ID NO:74 to SEQ ID NO:86.
16. The modified peptide of claim 14 wherein said peptide is selected from the group consisting of SEQ ID NO:77, SEQ ID NO:79, SEQ ID NO:81 and SEQID NO:84.
17. The modified peptide of claim 1 wherein said peptide exhibits anti- viral activity against simian immunodeficiency virus (SIV).
18. The modified peptide of claim 17 wherein said peptide is selected from the group consisting of SEQ ID NO:63 to SEQ ID NO:73.
19. A composition for use in the prevention and/or treatment of acquired immune deficiency syndrome (AIDS) comprising a peptide that exhibits : anti-viral activity against human immunodeficiency virus (HIV), modified with a reactive group which is reactive with amino groups, hydroxy! groups, or thiol : groups on blood components to form stable covalent bonds. :
20. The composition of claim 19 wherein said reactive group is a maleimido group which is reactive with a thiol group on a blood protein. :
21. The composition of claim 20 wherein said peptide is DP178 or Co DP107 or analogs thereof.
22. A composition for use in the prevention and/or treatment of human
15. respiratory syncytial virus (RSV) infection comprising a peptide that exhibits anti- viral activity against RSV, modified with a reactive group which is reactive with amino groups, hydroxyl groups, or thiol groups on blood components to form : stable covalent bonds.
23. The composition of claim 22 wherein said reactive group is a : maleimido group which is reactive with a thiol group on a blood protein.
24. The composition of claim 23 wherein said peptide is selected from the group consisting of SEQ ID NO:14 to SEQ ID NO:17 and SEQ ID NO:29.
25. A composition for use in the prevention and/or treatment of human parainfluenza virus (HPIV) infection comprising a peptide that exhibits anti-viral activity against human parainfluenza (HPIV), modified with a reactive group which is reactive with amino groups, hydroxyl groups, or thiol groups on blood components to form stable covalent bonds.
26. The composition of claim 25 wherein said reactive group is a maleimido group which is reactive with a thiol group on a blood protein.
27. The composition of claim 26 wherein said peptide is selected from the group consisting of SEQ ID NO: 35, SEQ ID NO:38 to SEQ ID NO:42, SEQ ID NO:52 and SEQ ID NO:58.
28. A composition for use in the prevention and/or treatment of measles virus (MeV) infection comprising a peptide that exhibits anti-viral activity against measles virus (MeV), modified with a reactive group which is reactive with amino groups, hydroxyl groups, or thiol groups on blood components to form stable covalent bonds.
29. The composition of claim 28 wherein said reactive group is a maleimido group which is reactive with a thiol group on a blood protein.
30. The composition of claim 29 wherein said peptide is selected from the group consisting of SEQ ID NO:77, SEQ ID NO:79, SEQ ID NO:81 and SEQ ID NO:84.
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US7575750B2 (en) | 2002-09-24 | 2009-08-18 | Frontiers Biotechnologies Col, Ltd. | Human immunodeficiency virus (HIV) gp41 peptide derivatives with enhanced solubility and antiviral activity |
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TWI300414B (en) | 2008-09-01 |
SM200000031B (en) | 2001-11-21 |
WO2000070665A3 (en) | 2001-04-19 |
CA2373252A1 (en) | 2000-11-23 |
WO2000070665A2 (en) | 2000-11-23 |
CN101289500A (en) | 2008-10-22 |
ZA200106676B (en) | 2002-07-19 |
CA2373252C (en) | 2007-08-07 |
AU4774800A (en) | 2000-12-05 |
JP4209086B2 (en) | 2009-01-14 |
AU764103B2 (en) | 2003-08-07 |
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JP2009143941A (en) | 2009-07-02 |
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