WO2008070083A2 - Milieu de filtration utilisant des produits antimicrobiens à base de peptide - Google Patents

Milieu de filtration utilisant des produits antimicrobiens à base de peptide Download PDF

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Publication number
WO2008070083A2
WO2008070083A2 PCT/US2007/024849 US2007024849W WO2008070083A2 WO 2008070083 A2 WO2008070083 A2 WO 2008070083A2 US 2007024849 W US2007024849 W US 2007024849W WO 2008070083 A2 WO2008070083 A2 WO 2008070083A2
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Prior art keywords
seq
seqidno
filter device
peptide
filter
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PCT/US2007/024849
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English (en)
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WO2008070083A3 (fr
Inventor
Robert C. Dixon
Robert S. Fatora
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Keybay Pharma, Inc.
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Publication of WO2008070083A2 publication Critical patent/WO2008070083A2/fr
Publication of WO2008070083A3 publication Critical patent/WO2008070083A3/fr

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    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D69/00—Semi-permeable membranes for separation processes or apparatus characterised by their form, structure or properties; Manufacturing processes specially adapted therefor
    • B01D69/02—Semi-permeable membranes for separation processes or apparatus characterised by their form, structure or properties; Manufacturing processes specially adapted therefor characterised by their properties
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N25/00—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests
    • A01N25/34—Shaped forms, e.g. sheets, not provided for in any other sub-group of this main group
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D67/00—Processes specially adapted for manufacturing semi-permeable membranes for separation processes or apparatus
    • B01D67/0081—After-treatment of organic or inorganic membranes
    • B01D67/0093—Chemical modification
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01D—SEPARATION
    • B01D2325/00—Details relating to properties of membranes
    • B01D2325/48—Antimicrobial properties

Definitions

  • a filter for removing, killing, and/deactivating bacteria in a fluid stream may include a substrate.
  • a portion of a substrate may include a therapeutically effective or bactericidally effective amount of an antimicrobial peptide.
  • the antimicrobial peptide may be immobilized or temporarily attached to the surface of a filter device.
  • the antimicrobial peptides are linear and alpha-helical and contain hydrophobic residues, positively charged residues, a high degree of cationicity and amphipathicity or hydrophobic moment.
  • the amphipathic alpha-helices of the immobilized antimicrobial peptides disclosed and claimed herein possess a high hydrophobic moment and net positive charge, and may be considered membrane-associated or surface-seeking peptide sequences.
  • the number of residues can be from about six to about forty-eight residues.
  • the antimicrobial peptides are selected from lentivirus lytic peptides (LLPs), lytic base unit peptides (LBUs) and engineered cationic antimicrobial peptides (eCAPs).
  • a method for immobilizing antimicrobial peptides on a substrate of a filter device may include providing a filter device substrate, and applying a linking layer to at least a portion of a surface of the substrate, followed by reacting a C- or N- terminus end of an antimicrobial peptide to the linking layer.
  • a C- or N- terminus end of an antimicrobial peptide may be bonded directly to the surface of the substrate without an intermediate linking layer.
  • a method of preventing or inhibiting infection in a subject including providing a filter device where at least a portion of a surface of a substrate of the filter device includes a therapeutically effective amount of an antimicrobial peptide, and filtering the subject's blood or blood products to kill any bacteria, and returning the blood or blood products to the subject is provided.
  • the antimicrobial peptide may be immobilized or semi-immobilized on the surface of the filter device substrate.
  • the antimicrobial peptides are linear and alpha helical, and contain hydrophobic and positively charged residues. More preferably, the antimicrobial peptides are selected from LLPs, LBUs and eCAPs.
  • a filter medium may include a sorptive material and a therapeutically and/or bactericidally effective amount of a substantially linear and substantially alpha-helical antimicrobial peptide immobilized on at least a portion of the surface, wherein the substantially linear and substantially alpha-helical antimicrobial peptide comprises hydrophobicity and cationicity.
  • the sorptive material of the filter medium may have a surface area from about 5 m 2 /g to about 2,500 m 2 /g.
  • the sorptive medium may have a surface of about 300 m 2 /g to about 2000 m 2 /g.
  • the surface area of the sorptive may be about 100 m 2 /g to about 300 m 2 /g.
  • the sorptive material of the filter medium may include a high surface area adsorbent selected from the group consisting of activated carbon, carbon nanotubes, activated alumina, pumicite, zeolite, diatomaceous earth, wood cellulose, and mixtures thereof.
  • the antimicrobial peptides that may be in contact with the sorptive material includes a surface coating on at least a portion of the sorptive material.
  • the surface coating may be covalently bonded to the sorptive material.
  • the surface coating may be bonded to a linking layer on at least a portion of the sorptive material.
  • Another embodiment may include a plurality of solid antimicrobial particles interspersed with the sorptive material. Further embodiments may include having the antimicrobial peptides immobilized within the filter device.
  • the antimicrobial peptides that may be in contact with the sorptive material include a surface coating on at least a portion of the sorptive material and a plurality of solid antimicrobial particles
  • An exemplary embodiment of a filter medium may further include an outer case, where the outer case substantially surrounds the sorptive material and the therapeutically and/or bactericidally effective amount of an antimicrobial peptide, where the outer case may further include an inlet and an outlet, and wherein the inlet and outlet are positioned so that a liquid contacts the therapeutically and/or bactericidally effective amount of an antimicrobial peptide during a filtering process.
  • Figure 1 schematically depicts an exemplary embodiment of a linear, hydrophobic, positively charged antibacterial peptide covalently bonded to a substrate through an organosilane linking group.
  • administering when used in conjunction with a therapeutic means to administer a therapeutic directly into or onto a target tissue or to administer a therapeutic to a patient whereby the therapeutic positively impacts the tissue to which it is targeted.
  • administering' when used in conjunction with antimicrobial peptides, can include, but is not limited to, providing antimicrobial peptide into or onto the target bacteria from a filter device that includes a substrate coated with antimicrobial peptide, and providing antimicrobial peptides to a subject by attaching them to components of a filter device.
  • antimicrobial refers to the ability of the peptides of the invention to prevent, inhibit or destroy the growth of microbes such as bacteria, fungi, protozoa and viruses.
  • bacteria As used herein the term "bactericidally effective” refers to the ability of an antimicrobial peptide to kill or deactivate microbes such as bacteria, fungi, protozoa and viruses.
  • filter device includes any device that is used to attract, kill or deactivate, and remove microbes such as bacteria, fungi, protozoa and viruses in a flowing fluid stream.
  • the filter device in embodiments herein may kill or deactivate the microbes while another filter or filters may remove the bacteria.
  • the filter device may be included in an article, including a component part, or accessory which is intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, in man or other animals, or intended to affect the structure or any function of the body of man or other animals.
  • the filter device may also include an article that is used bactericidally outside of the human body in a flowing fluid stream.
  • a filter device could be used to attract, kill, and remove microbes such as bacteria, fungi, protozoa and viruses, in a blood filter external to a subject's body, where the filtered sanitized blood is returned to the subject.
  • the filter device may be used in blood banks.
  • blood received at a blood bank could be filtered through a filter device of embodiments herein to prevent microbial infection of a subject that receives a transfusion of blood from the blood bank.
  • the blood may be stored under conditions known to a person of ordinary skill in the art after it is removed from a subject and streamed through a filter.
  • the filtered blood may be returned to the first subject or transfused into a compatible second subject.
  • the filter device may be used to attract, remove, kill and/or deactivate microbes such as bacteria, fungi, protozoa and viruses in an air stream, such as but not limited to, a heating and air conditioning system of a high-risk ward of a hospital or an operating room, any health care facility in general, a public or private meeting place, or in a private residence.
  • air filter devices embodied herein are envisioned for use in compartmentalized spaces, such as but not limited to air craft cabins, and other spaces where the flow of fresh air is restricted.
  • Embodiments of antimicrobial filters disclosed herein are envisioned to be used in any situation wherein it is desirable to attract, remove, kill and/or deactivate microbes that are present in a fluid stream, such as a gas, for example but not limited to air, or a liquid, such as but not limited to water.
  • a fluid stream such as a gas, for example but not limited to air, or a liquid, such as but not limited to water.
  • An exemplary use of a filter device of the instant invention would be a filter attached to an endotracheal tube or a filter in a lung ventilator system to prevent and/or inhibit microbes from entering the lungs of a patient.
  • filter device substrate may include any material to which an antimicrobial peptide could be bound or immobilized.
  • Non- limiting examples of embodiments may include metal, plastic, ceramic, composites or other materials coated, at least partially, with antimicrobial peptides, where the coated material is arranged in a fashion in which a fluid stream containing microbes is directed through the antimicrobial coated material so that the immobilized antimicrobial proteins are positioned to attract, remove, kill, and/or deactivate microbes in the stream.
  • the coated materials may be fibrous or tubule. The fibers or tubules may be intermingled, woven, in the form of a matrix or a lattice.
  • the fibers or tubules may be arranged parallel, perpendicular, off- angle, or a mixture of orientations with respect to the flow of the microbe containing fluid.
  • the antimicrobial filter device substrates may include coated particles, a fluid bed of coated particles, and the like.
  • the precise dimensional and geometrical interrelationship of filter device substrates with respect to each other is only limited so that the coated substrates act therapeutically and/or bactericidally to effectively attract, remove, kill, and/or deactivate microbes that pass through or over the coated substrates.
  • the therapeutically and/or bactericidally effective dimensional and geometrical relationships of the coated filter substrates can be determined by one of ordinary skill in the art without undue experimentation.
  • the term "improves" is used to convey that the present invention changes either the appearance, form, characteristics and/or the physical attributes of the tissue, fluid stream, or bodily fluid to which it is being provided, applied or administered.
  • the change in form may be demonstrated by any of the following alone or in combination: reduction of the incidence of bacterial and viral infections in a subject, and the reduction or elimination of active microbes in filtered fluid stream.
  • inhibiting includes the administration of a compound, or providing a device that includes a compound of the present invention to prevent the onset of the symptoms, alleviating the symptoms, or eliminating the disease, condition or disorder.
  • peptide refers to an oligomer of at least two contiguous amino acids, linked together by a peptide bond.
  • pharmaceutically acceptable it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • the term "therapeutic” means an agent utilized to treat, combat, ameliorate, prevent or improve an unwanted condition or disease of a patient.
  • embodiments of the present invention are directed to the prevention of infections associated with biomedical devices installed in a subject permanently or for a therapeutic time.
  • therapeutic means using an agent in a device to prevent, inhibit, or improve an unwanted condition or disease of a patient, where the device is installed in the environment of a patient, such as for example, but not limited to, in an air filter, a water filter, or an extracorporeal blood filter.
  • a "therapeutic time” as used herein, is a time required to effectively treat, combat, ameliorate, prevent or improve an unwanted condition or disease of a subject.
  • a "therapeutically effective amount" of an antibacterial peptide is a predetermined amount calculated to achieve the desired effect, i.e., to attract, remove, kill, and/or deactivate microbes in fluids when in the presence of an antimicrobial filtering device. It is recognized that the microbes may not be immediately killed or deactivated by the antimicrobial peptides of a filtering device, but that due to electrostatic or other interactions, discussed herein, between the antimicrobial peptides and the bacterial cell membrane the bacteria could be removed from the fluid and rendered ineffective in causing infections.
  • the effective amount of antibacterial peptide is the amount immobilized on a filter device substrate that substantially attracts, removes, kills, and/or deactivates the microbes passing through the filter device in the microbe infested fluid stream, thus inhibiting or preventing infection in a subject.
  • the specific dose of an antimicrobial peptide on a filter device substrate according to this invention to obtain therapeutic and/or prophylactic effects will, of course, be determined by the particular circumstances surrounding the case, including, for example, the peptide used, the nature of the filter device, and the contemplated microbe to be killed or deactivated.
  • ⁇ therapeutically effective amount of antimicrobial peptide of this invention is typically an amount such that when it is immobilized on an antimicrobial filter device, it is sufficient to achieve an effective killing, deactivating or removal of microbes in the filter device prior to the fluid stream exiting the filter device.
  • the filter device may attract, kill or deactivate, and remove microbes from a fluid stream passing through the filter.
  • a separate filter such as, but not limited to a particulate filter, may- be in place after the antimicrobial filter device to remove microbes from the fluid stream. Any combination of antimicrobial filter devices and particulate filters or other filters are encompassed in embodiments of this invention.
  • treat refers to both therapeutic treatment and prophylactic or preventative measures, wherein the object is to prevent or slow down (lessen) a bacterial infection, or to obtain beneficial or desired clinical results, such as, but not limited to removal of microbes from blood, blood products, liquids, and gases and mixtures of gasses including but not limited to air.
  • beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of the extent of the condition, disorder or disease; stabilization (i.e , not worsening) of the state of the condition, disorder or disease; delay in onset or slowing of the progression of the condition, disorder or disease; amelioration of the condition, disorder or disease state; and remission (whether partial or total), whether detectable or undetectable, or enhancement or improvement of the condition, disorder or disease.
  • Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment. Treatment also includes killing or deactivating of microbes in a fluid stream.
  • tissue refers to any aggregation of similarly specialized cells which are united in the performance of a particular function.
  • Embodiments of the present invention are directed to filter devices containing substrates that are at least partially coated with or result in an immobilization or permanent or semi-permanent fixation of antimicrobial peptides.
  • the filter devices may be permanently or semi-permanently introduced into the body of a subject, preferably a human, and include for example an implanted blood filter.
  • the filter devices may be used as a blood or blood product (collectively referred to as '"blood”) antimicrobial filter that sanitizes blood that is removed from the patient and subsequently returned in a sanitized condition.
  • the antimicrobial peptides include linear peptides with an alpha-helical secondary conformation, including those containing hydrophobic regions and regions of positively charged residues.
  • Preferred antimicrobial peptides include substantially linear and substantially alpha-helical peptides of high amphipathicity with an overall positive charge or cationicity derived from cationic peptides.
  • an amphipathic alpha-helix one side of the helix contains mainly hydrophilic amino acids and the other side contains mainly hydrophobic amino acids.
  • An alpha-helix of the antimicrobial peptides of the instant invention has about 3.6 residues to make one turn of the alpha-helix. The distance between two turns is about 0.54 nm.
  • the hydrogen bonds stabilize the alpha helix.
  • the alpha-helices of the instant invention can be either right-handed or left-handed.
  • one side of the helix contains primarily hydrophobic residues while the other side contains primarily hydrophilic residues, which additionally have a net positive charge. This is depicted in FlG. 1 , which will be discussed further below.
  • the cationicity of the antimicrobial peptide used in filter devices disclosed herein results in an electrostatic attraction to the negatively charged membrane of bacteria and microbes.
  • the alpha- helix of the antimicrobial peptides is oriented away from the surface that they are bonded to (as depicted in FIG. 1 ), and it is suggested that they are able to electrostatically attract the bacteria and penetrate the bacteria cell membranes, resulting in a bactericidal effect.
  • the killed bacteria may remain bonded to the immobilized antimicrobial peptide until a fluid shear force or other force is capable of disrupting the bonding between the membrane of the killed bacterium and the immobilized antimicrobial peptide.
  • the antimicrobial peptide regains its efficacy after being saturated with bacteria, after the bacteria that have interacted with and saturated the antimicrobial peptides are removed from the immobilized antimicrobial peptides.
  • a preferred length of an antimicrobial peptide for some embodiments herein may include peptides containing about 6 to about 48 amino acid residues. Another preferred embodiment may include peptides that contain about 6 to about 36 amino acid residues. Still another preferred embodiment may include peptides that contain about 12 to about 36 amino acid residues. Effective immobilized antimicrobial peptides with numbers of residues outside of the ranges listed are also encompassed in embodiments of this invention.
  • FIG. 1 shows an antimicrobial peptide 22 immobilized to a surface of a substrate 24 of a filter device (not shown) through covalent bonding.
  • the antimicrobial peptide 22 depicts an eCAP, and specifically SEQ ID NO.183 containing 12 amino acid residues.
  • the eCAP in this exemplary embodiment is bonding to the surface of a filter device substrate 24 through an organosilane linking layer 34, also referred to as an organosilane coupling agent or coating.
  • organosilane linking layer 34 also referred to as an organosilane coupling agent or coating.
  • the specific organosilane coating or linking layer 34 in the non-limiting example of FIG. 1 is a carboxymethyl- silane.
  • the organosilane layer 34 may have been first applied to the substrate 24 using, for example, carboxymethyltriethoxy silane, employing procedures that are familiar to one of ordinary skill in the art.
  • the N-tcrminus 36 of the antimicrobial peptide 22 covalently bonds with the carboxyl group 38 of the linking layer 34.
  • the organosilane layer could be an aminosilane layer (not shown) in which the C- terminus of the antimicrobial group could react with the amine of the organosilane layer.
  • substrate surface functional groups that can react or strongly interact with the C-terminus 40 or N-terminus 36 of antimicrobial peptides of embodiments herein are encompassed in the scope of the instant invention, including those on alternative linking layers or on the surface of the filter device substrate itself.
  • Alternative methods of immobilizing antimicrobial peptides of the instant invention are presented hereinbelow.
  • Antimicrobial peptides that are useful in embodiments of the present invention include those derived from selected amino acid sequences in viral transmembrane proteins.
  • the peptides may be derived from lentiviruses, primarily human immunodeficiency virus (HIV), simian immunodeficiency virus (SIV), and equine infectious anemia virus (EIAV).
  • HIV human immunodeficiency virus
  • SIV simian immunodeficiency virus
  • EIAV equine infectious anemia virus
  • LLPs lytic peptides derived from lentiviruses and are designated by the term "LLPs”, as disclosed in U.S. Pat. No. 5,714,577, which is incorporated herein in its entirety.
  • LLPs are unique in that they are derived from naturally occurring sequences that are part of a larger folded protein.
  • the antimicrobial peptides are structural and functional analogs of the naturally occurring parent peptides which exhibit selective toxicity for microorganisms.
  • analog refers to a peptide which contains substitutions, rearrangements, deletions, additions and/or chemical modifications in the amino acid sequence of parent peptide, and retains the structural and functional properties of the parent peptide.
  • the antimicrobial peptides are structural and functional homologs of the naturally occurring parent peptides which exhibit selective toxicity for microorganisms.
  • homolog refers to a peptide, the sequence of which is at least 80% homologous to the amino acid sequence of a parent peptide, and retains the structural and functional properties of the parent peptide.
  • the amino acid sequences of the antimicrobial peptides of the invention correspond to or are analogous to or homologous to peptides LLPl and LLP2, which, in turn, correspond to residues 828-855 and 768-788 of the HlV-I TM protein (gp41) (strain HXB2R), respectively; peptides SLP-I , SLP-2A and SLP-2B (SLP2 region), which, in turn, correspond to residues 852-879, 771 -795 and 790-817 of the SIV TM protein (MM239 strain of SlV), respectively; and peptide ELP, which corresponds to residues 808-836 of EIAV (Wyoming strain).
  • the antimicrobial peptides of the invention are unique in their functional properties.
  • cytolytic peptides can be classified into two major functional types.
  • Antibacterial peptides magainins and cecropins, for example
  • Hemolytic peptides generally both kill bacteria and lyse red blood cells; melittin from bee venom is an example of such a peptide.
  • the antimicrobial peptides useful in the present invention are moderately hemolytic; they do lyse red blood cells, but only at high concentrations.
  • the unique structure of the antimicrobial peptides of the invention imparts high potency while maintaining selectivity.
  • the structural properties defining the antimicrobial peptides useful in embodiments of the present invention include, inter alia, a significant number of positively charged amino acid residues and the ability to form three-dimensional amphipathic helical structures.
  • Functional properties include, inter alia, a selective antimicrobial cytolytic activity, but minimal cytolytic activity toward mammalian cells.
  • Arg Arginine
  • Cys Cysteine
  • GIn Glutamine
  • Leu Leucine
  • VaI Valine.
  • a peptide analog or homolog within the scope of the present invention may be identified by the following criteria: (1) the parent peptide of the analog is an antimicrobial peptide having a sequence which corresponds to a vital TM protein, particularly a lentivirus TM protein; (2) the amino acid sequence of the peptide is capable of forming an amphipathic helix and contains a number of positively charged residues; (3) the peptide is selectively antimicrobial in its biological function and has minimal cytolytic activity toward mammalian cells.
  • the allowed amino acid interchanges which are contemplated include, inter alia, the substitution of an individual residue in the peptide with a residue that falls within the same chemical subset, e.g., a hydrophobic amino acid replaced by the same or a positively charged residue with the same. This degree of substitution allows for the construction of peptide analogs from the parent structure which retain the structural and functional properties of the parent peptide, without undue experimentation.
  • Analogs may also contain non-conservative amino acid interchanges provided that structural and functional properties are retained or enhanced.
  • a singular characteristic of the antimicrobial peptides useful in embodiments of the present invention is the presence of a significant number of positively charged residues, especially arginine.
  • Analogs and homologs include those that encompass substitutions which retain the overall charge characteristics of the peptides.
  • the peptides useful in embodiments of the present invention have a net charge of at least +3 at neutral pH. Net charge is calculated by adding the sum of the charge value of positively charged amino acids (arginine, lysine, histidine) (+1) and the charge value of the negatively charged amino acids (aspartic acid, glutamic acid) (-1).
  • the positively- charged arginines in the peptides may be substituted by histidine or lysine so as to retain positively charged residues.
  • Analogs may be designed which increase the number of positively charged amino acids so long as the antimicrobial activity of the peptide is not diminished, for example, the number of arginine residues may be increased.
  • An analog which increased the number of positive charges in an LLPl analog peptide has been shown to be more toxic to bacteria than the parent LLPl .
  • Additional analogs of the peptides useful in embodiments of the present invention can have an altered number of hydrophobic amino acids based on the parent peptide, producing peptides having altered specificity. For example, an increase in hydrophilic residues appears to reduce antimicrobial effectiveness. However, such changes appear to increase antimicrobial specificity by reducing undesired hemolytic activity. Therefore, based on the teachings and guidance herein, one skilled in the art can design analogs useful in embodiments of the invention which have a desired potency and selectivity.
  • amino acid changes which are contemplated include, inter alia, the replacement of amino acid residues in a parent peptide such that the homologous peptide retains the structural and functional properties of the parent peptide.
  • a primary common and recognizable feature of the antimicrobial peptides is their secondary structure, or more specifically, their potential to form amphipathic structures, which may be in the form of an alpha-helix or a beta conformation.
  • An alpha-helix motif for example, comprises residues arranged such that 3.5 amino acid residues complete 1 turn of the helix.
  • An estimate of amphipathicity may therefore be made by examination of the amino acid sequence; for example, peptides comprising amino acid residues arranged in a hydrophobic-hydrophobic- hydrophilic-hydrophilic repeating motif are highly likely to form an alpha-helix.
  • Amino acid residues arranged to alternate in a hydrophobic-hydrophilic-hydrophobic-hydrophilic repeating motif are likely to form a beta conformation.
  • Such "ideal" motifs are found in the antimicrobial peptides of the invention and as such may be used by those skilled in the art as a foundation for engineering additional amphipathic peptide analogs of the invention without great difficulty based on the teachings herein.
  • the antimicrobial peptides useful in embodiments of the invention may further contain proline or glycine, amino acid residues which can be tolerated within a general amphipathic structure and may indicate demarcations between different aniphipathic regions.
  • residues may impart a structure which enhances the activity and selectivity of a peptide because of a bend or kink between helices.
  • a solidly helical structure may be less selective (e.g. LLP2, SLP2A).
  • Homologs may also be engineered, using these structural considerations that are at least 80% homologous to the amino acid sequence of a parent peptide, and retain the structural and essential antimicrobial functional properties of the parent peptide.
  • Analogs and/or homologs of the invention preferably contain at least one cysteine which, by virtue of its capacity to form a disulfide bond, can confer high potency and a very high degree of bactericidal activity to a peptide containing such a residue.
  • a peptide preferably contains a single cysteine residue to ensure that any disulfide bond formed by the cysteine would be intermolecular and result in a disulfide-linked dimeric peptide (e.g. bis-LLPl).
  • the residue to be replaced by cysteine is preferably neither very hydrophobic nor basic and lies on the interface of the hydrophilic and hydrophobic faces of the amphipathic structure when modeled as such. Computer modeling programs such as "Helicalwheel" may be used to design such peptides.
  • the antimicrobial peptides of the invention generally comprise a positively charged C-terminus.
  • those peptides having this characteristic generally have some hemolytic activity, and analogs which optimize antimicrobial selectivity (i.e., decrease hemolytic activity) may be those which replace the positively charged C-terminus with negatively charged or hydrophobic residues. Since reduction of the basic character of the C-terminus may provide antimicrobial selectivity, analogs are provided in which the amino acids of the C-terminus region may be reversed in situ, or, alternatively, the N-terminus and C-terminus regions may be interchanged. The peptide is then comprised of a positively charged N-terminus and a hydrophobic C-terminus.
  • Analogs and homologs which are chimeras of particular antimicrobial peptides and/or other cytolytic peptides are within the scope of the present invention, provided that the structural and functional properties described herein are retained.
  • the use of D-amino acids in place of L- amino acids in the peptides may provide increased metabolic stability, since peptides containing D-amino acids are resistant to mammalian proteases, which generally cleave peptides composed of L-amino acids
  • Embodiments of the present invention may also include the use of peptide analogs and homologs which are truncated, i.e., shorter than the parent amino acid sequence or to truncated parent peptide fragments.
  • a minimal length required to effectuate ion-channel formation in membranes is believed to be a peptide of about 6-12 amino acid residues in length, but shorter lengths, if shown to be effective in embodiments of the instant invention are within the scope of this invention. It has been suggested that the antimicrobial peptides may dimerize so as to comprise the approximately 20 amino acid length believed to be required to transverse a membrane.
  • cysteine residue in an antimicrobial peptide is of importance in facilitating the formation of intramolecular or intermolecular disulfide bonds which can stabilize a dimeric peptide.
  • a 2 l-amino acid segment of LLPl was capable of pore formation in planar lipid bilayers in vitro, although it was not tested for antimicrobial activity.
  • the design of analogs of minimal length can optimize potency of the peptides in terms of effectiveness per mass.
  • the antimicrobial peptides useful in the present invention have the following structural formula:
  • Peptides may be derived from proteins of any lentivirus or any DNA or RNA virus including, but not limited to, HIV-I , HIV-2, SIV, EIAV, feline immunodeficiency virus (FIV), bovine immunodeficiency virus (BIV), visna virus and all classes, subclasses and isolates thereof.
  • antimicrobial peptides which are derived from, and are analogs of, the LLPl peptide parent sequence corresponding to amino acids 828- 856 of the HIV-I viral isolate HXB2R Env and include SA-5 (SEQ ID NO. 1), LSA-5 (SEQ ID NO. 2) and WLSA-5 (SEQ ID NO. 3) (see Table 1 below) are useful to coat filter devices.
  • SA-5 SEQ ID NO. 1
  • LSA-5 SEQ ID NO. 2
  • WLSA-5 SEQ ID NO. 3
  • the antimicrobial activity of other LLPl peptide analogues has been previously described (see Tencza et al., 1999, Journal of Antimicrobial Chemotherapy 44:33-41 , U.S. Pat. No. 5,714,577 of Montelaro et al. and U.S. Pat. No.
  • Antimicrobial peptides useful in this invention include those disclosed in U.S. Pat. No. 6,887,847, which is incorporated herein in its entirety.
  • the antimicrobial peptides are LLPl analogs having modifications based on the following principles: (i) optimizing amphipathicity, (ii) substituting arginine (Arg) on the charged face and/or valine (VaI) or tryptophan (Tip) on the hydrophobic face with another amino acid, and (iii) increasing peptide length (referred to collectively herein as Lytic Base Unit peptides (LBU peptides), e.g.
  • LBU peptides Lytic Base Unit peptides
  • LBU-2 SEQ ID NO. 174; LBU-3, SEQ ID NO. 175; LBU-3.5, SEQ ID NO. 176; LBU-4, SEQ ID NO. 177; WLBU-I , SEQ ID NO. 178, WLBU-2, SEQ ID NO. 179, WLBU-3, SEQ ID NO. 180; and WLBU-4, SEQ ID NO. 181 ; see Table 2).
  • the LBU peptides deviate greatly from the parent LLPI, for example, LBU-2 and LBU-3 deviate from the parent LLPl sequence by greater than 90%.
  • the LLPl analogue peptides and the LBU peptides (collectively referred to herein as "engineered LLPs" (eLLPs)) useful in embodiments of the present invention have a broader spectrum of activity (i.e., the ability to kill highly resistant bacteria) and increased potency (i.e., lowering the molar concentration required to kill bacteria) when compared with previously described LLPl analogs.
  • the eLLPs of the present invention are highly inhibitory to microorganisms under physiologic salt concentrations, function in the presence of synovial fluid, and demonstrate only minimal toxicity in animal models. As a result, the eLLPs may be defined as selective antimicrobial agents.
  • the peptides useful in embodiments of the present invention function by disrupting bacterial membranes and are active when bound to a solid phase. The ability of these peptides to maintain activity when bound to a solid phase is a significant advantage over conventional antibiotics.
  • the antimicrobial peptides useful in embodiments of the present invention exhibit antimicrobial activity against diverse microorganisms, and are analogs of the LLPl peptide corresponding to amino acids 828-856 of the HIV-I viral isolate HXB2R Env TM.
  • the eLLPs comprise Arg-rich sequences, which, when modeled for secondary structure, display high amphipathicity and hydrophobic moment.
  • the eLLPs are highly inhibitory to microorganisms, but significantly less toxic to mammalian cells. As a result, these peptides can be characterized as selective antimicrobial agents.
  • eLLPs of the present invention include LLPl peptide analogs comprising modifications based on the following principles: (i) optimizing amphipathicity, (ii) substituting Arg on the charged face and/or VaI or Trp on the hydrophobic face, and (iii) increasing peptide length, collectively referred to herein as LBU peptides.
  • engineered cationic antimicrobial peptides may be useful in embodiments of the present invention.
  • eCAP engineered cationic antimicrobial peptides
  • one embodiment of the present invention provides a filter device comprising a filter device coated with an antimicrobial peptide.
  • the antimicrobial peptide is selected from LLPs, LBUs and eCAPs.
  • the antimicrobial peptide is selected from SEQ ID NO. 1 through SEQ ID NO. 185.
  • the antimicrobial peptide may be immobilized or temporarily attached to the surface of the substrate of the filter device.
  • the antimicrobial peptides are present on the filter device in a therapeutically effective amount; in another preferred embodiment the antimicrobial peptides are present on the filter device in a bactericidally effective amount.
  • the antimicrobial peptide is coated on the substrate of the filter device such that the antimicrobial peptides substantially cover the entire surface of the substrate of the filter device.
  • the antimicrobial peptide is coated on the surface of the substrate of the filter device such that the antimicrobial peptide covers a partial surface or portion of the surface of the substrate of the filter device.
  • the antimicrobial peptide may be immobilized or temporarily attached to the surface of the substrate of the filter device.
  • the antimicrobial peptide is coated on the surface of the substrate of the filter device and further includes a second therapeutic agent.
  • the antimicrobial peptides useful in the present invention have the following structural formula: SEQ ID NO. 4, SEQ ID NO. 5. SEQ ID NO. 8. SEQ ID NO. 9, SEQ ID NO. 173 through SEQ ID NO. 185. [0083
  • Another embodiment of the instant invention includes antimicrobial peptides selected from SEQ ID NO. 1 through SEQ ID NO. 185.
  • Preferred antimicrobial peptides to be used as antimicrobial coatings on components of a filter device include but are not limited to, LLPs, LBUs and eCAPs, as presented above, including preferably, SEQ ID NO. 4, SEQ ID NO. 5, SEQ ID NO. 8, SEQ ID NO. 9, SEQ ID NO. 173 through SEQ ID NO. 185.
  • Embodiments herein include a uniform antimicrobial coating, as disclosed hereinabove, for a surface of a substrate of a filter device.
  • the antimicrobial coating substantially covers the entire surface of the substrate of a filter device.
  • Still other embodiments include a partial antimicrobial coating for a substrate of a filter device.
  • the coating may only cover a portion of the surface of a substrate of a filter device.
  • Still further embodiments of the present invention include a filter device that has a substrate that is coated with a therapeutically effective amount of antimicrobial peptide. The antimicrobial peptide may be immobilized or temporarily attached to the surface of the substrate or portions thereof.
  • Another embodiment of the present invention includes methods to coat a surface of a substrate of a filter device with antimicrobial peptides.
  • Preferred methods for coating a surface of a substrate of a filter device with antimicrobial peptides are disclosed in more detail hereinbelow.
  • a biocompatible material (or biomaterial) should be used for the surface of the substrate and other components of the filter device.
  • a biocompatible material is a synthetic or natural material used to replace part of a living system or to function in intimate contact with living tissue and cells.
  • Biocompatible materials may include for example synthetic and natural polymers, such as but not limited to acrylic, polyethylene terephthalate (PET), polymethyl methacrylate (PMMA), polypropylene resins cellulose and collagen.
  • PET polyethylene terephthalate
  • PMMA polymethyl methacrylate
  • Metals with high strength, low modulus and body fluid resistance, such as, but not limited to titanium and titanium alloys are considered biocompatible materials.
  • the antimicrobial peptides may be bonded directly to at least a portion of a surface of a filter devise substrate, or alternatively may be bonded to linking groups that are bonded to at least a portion of the surface of a filter devise substrate.
  • covalent bond formation between the surface and the peptide; or between the surface, the linking group, and the peptide is preferred.
  • Other types of bonding including, but not limited to acid-base interactions, ionic bonding, hydrogen bonding, dispersion forces, and van der Waals interactions are included in the scope of embodiments herein.
  • immobilized refers to antibacterial peptides that remain bonded to the surface of a filter devise substrate, and maintain efficacy for at least a therapeutic time period, or for a predetermined time period, when the filter device may be replaced or rejuvenated.
  • the surface of the filter device substrate may be cleaned or activated to increase the polarity of the surface, or to provide functional groups on the surface, to promote chemical reaction of the peptide and the surface.
  • Cleaning, passivating, or activating a surface may include chemical processes such as, but not limited to, repetitive acid or alkaline washing followed by rinsing with distilled or deionized water.
  • Cleaning, passivating, or activating a surface may also include physical processes such as for example corona discharge. Any cleaning and/or activating process known now or hereafter to one of ordinary skill in the art is within the scope of embodiments herein.
  • a linking group also known as a linker, a coupling agent, a primer, and a tie layer, is used to bond an antimicrobial peptide to a filter device substrate surface is a form of chemical surface functionalization.
  • One end of the linking group readily forms bonds that are stable under physiological conditions with the filter device substrate surface.
  • the linking group may then be capable of forming hydrolytically and physiologically stable bonds with a terminal end of an antimicrobial peptide.
  • the linking group may be further treated to create reactive sites on the linking group.
  • Such treatments may include corona discharge, plasma processes, flame treatments, or other processes known now or hereafter to one of ordinary skill in the art to create polar and/or reactive groups, such as for example, hydroxyl, carboxyl, and carbonyl groups.
  • polar and/or reactive groups such as for example, hydroxyl, carboxyl, and carbonyl groups.
  • silanization may be used to functionalize the surface of a filter device substrate.
  • the device substrate surface 24 is silanized using an organosilane 34 which has an organic group that may be used to couple other molecules to the device surface.
  • the organic group may include but is not limited to one or more amine groups, epoxides, carboxylic acids, thiols, or vinyl groups.
  • the reaction of organosilanes with material surface is known to one of ordinary skill in the art and need not be further developed herein. As describe above, in the example of FIG.
  • a carboxyl surface group is shown to react with the amine group of an antimicrobial peptide.
  • a photoactivatable group such as for example, benzophenone can be used.
  • an organosilane with a hydrophobic side group such as, for example octadecyltrimethoxysilane may be used.
  • a material such as a block copolymer may be used to functionalize a surface of a substrate of a filter device with antimicrobial proteins.
  • a hydrophobic block of a copolymer may interact with a hydrophobic substrate surface.
  • a hydrophilic block of the copolymer may extend away from the surface, and can have functional groups that can react with the antimicrobial peptide.
  • a parylene coating may be initially applied to the filter device substrate surface.
  • Parylene is the tradename for a variety of polyxylylene polymers marketed by Para Tech Coating, Inc., Aliso Viejo, CA.
  • Parylene C is a polymer manufactured from di-p-xylene, a dimer of p-xylene.
  • Di-p-xylene, more properly known as [2.2]paracyclophane is made from p-xylene in several steps involving bromination, amination and elimination. Heating [2.2]paracyclophane in a partial vacuum gives rise to a diradical species, which polymerizes when deposited on a surface.
  • a biomedical device with a parylene coating can then be further treated to produce polar reactive groups at the surface, so that antimicrobial peptides can chemically react with the modified parylene coated surface.
  • Methods to produce polar reactive groups on plastic and metallic materials are known in the art, and may include for example ozone treatments, corona discharge, flame treatments, plasma processing, acid etching, ultraviolet light irradiation, gamma ray irradiation, and electron beam irradiation. It is recognized that these surface modification techniques can be used on most polymeric surfaces to produce reactive groups to which the antimicrobial peptides can form covalent bonds and become immobilized on the filter device substrate surface.
  • Embodiments of using the antimicrobial peptides disclosed and claimed herein include making composite coatings of polymers with the antimicrobial peptides.
  • a rubber surface can be modified by photochemical immobilization of an antimicrobial peptide.
  • a photochemically reactive compound can be made to react with a surface using the appropriate wavelength of light.
  • Antimicrobial peptides can then be reacted with the photochemical reactive compound, and thus immobilizing the peptide on the filter device substrate surface.
  • United States Patent Publication 2003/0228410 discloses a photochemical process to immobilize biomolecules on a surface using a photochemical reaction of l -fluoro-2-nitro-4-azidobenzene with the polymer surface.
  • any polymer having a carbon-hydrogen bond can be photochemically activated.
  • the antimicrobial peptides disclosed and claimed herein can the react with the photochemically activated surface.
  • Other methods of photochemically immobilizing biomolecules known now or hereafter to one of ordinary skill in the art are within the scope of embodiments disclosed and claimed herein.
  • a charged surface active agent may react with the surface and act as an anchor for chemically reacting with the antimicrobial peptides.
  • TDMAC tri decyl methyl ammonium chloride
  • TDMAC has a quaternary ammonium compound with three long hydrophobic chains and a positively charged nitrogen.
  • a negatively charged end of an antimicrobial peptide zwitterion of those disclosed and claimed in this invention could ionically bond with the positively charged nitrogen, and thus be anchored or immobilized on the filter device substrate surface.
  • Entrapment of antimicrobial peptides in a polymer matrix that forms a filter device substrate or is coated on a surface of a substrate of a filter device is another means of preparing an antimicrobial filter device in embodiments of the present invention.
  • Polymer matrices with antimicrobial peptides could be used to construct a filter device substrate or applied as a coating on a device.
  • the antimicrobial peptides may not be chemically reacted with the polymer matrix. The peptides may then slowly diffuse out of the matrix and work as a bactericide in the vicinity of the surface. A sustained release of the antimicrobial peptides is possible, resulting in longer term bactericidal protection.
  • An exemplary, but not limiting, polymer matrix is one of polyurethane.
  • antimicrobial peptides may be desirable for antimicrobial peptides to both be covalently bonded to the surface of a medical device and to exhibit a sustained release or elution from the substrate surface of a filter device. In such scenarios, the total of the eluting phase and the covalently bonded phase provides prolonged bactericidal protection.
  • PVD plasma vapor deposition
  • CVD chemical vapor deposition
  • graft polymerization Other means of treating surfaces or depositing coatings on surfaces such as plasma vapor deposition (PVD), chemical vapor deposition (CVD), graft polymerization are also techniques that can be used to immobilize antimicrobial peptides on a filter device substrate surface. Any surface modification technique that is known now or hereafter to one or ordinary skill in the art, which can be used to enable covalent bonding or other method of immobilization of antimicrobial peptides on a filter device substrate surface are within the scope of this invention.
  • the antimicrobial peptides of the present invention are peptides which exhibit antimicrobial activity against diverse microorganisms.
  • the antimicrobial peptides are alpha-helical, more preferably the antimicrobial peptides are selected from groups designated herein as LLPs, LBUs, and eCAPs.
  • the LLPs, LBUs, and eCAPs classes of peptides are further disclosed and described below.
  • the peptides correspond to amino acid sequences in the transmembrane (TM) proteins of lentiviruses, in particular, HIV and SlV.
  • the antimicrobial peptides comprise arginine-rich sequences, which, when modeled for secondary structure, display high amphipathicity and hydrophobic moment.
  • the antimicrobial peptides are highly inhibitory to microorganisms but significantly less toxic to red blood cells and other normal mammalian cells. As a result, these peptides can be characterized as selective antimicrobial agents.
  • the antimicrobial peptides may retain antibacterial activity after a filter device coated with the antimicrobial peptide is sterilized. It is reported below that the WLBU-2 peptide coated on a substrate retained antimicrobial activity after ethylene oxide sterilization.

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Abstract

L'invention concerne un appareil de filtration antimicrobien et un procédé de filtration d'un fluide avec utilisation de l'appareil. L'appareil de filtration peut inclure un substrat, le substrat ayant une surface. Une quantité thérapeutiquement efficace d'un peptide antimicrobien linéaire et alpha-hélicoïdal peut être immobilisée sur au moins une partie de la surface. Le peptide antimicrobien linéaire et alpha-hélicoïdal possède des régions hydrophobes et cationiques. Les microbes et/ou les substances pathogènes sont retirés, tués, et/ou désactivés lors du passage du courant de liquide contenant les microbes et/ou les agents pathogènes à travers l'appareil de filtration antimicrobien.
PCT/US2007/024849 2006-12-04 2007-12-04 Milieu de filtration utilisant des produits antimicrobiens à base de peptide WO2008070083A2 (fr)

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Cited By (7)

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Publication number Priority date Publication date Assignee Title
EP2168592A1 (fr) * 2008-09-24 2010-03-31 Helmholtz Zentrum München Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH) Peptides antimicrobiens
US8071540B2 (en) * 2007-07-13 2011-12-06 University of Pittsburgh—of the Commonwealth System of Higher Education Virus derived antimicrobial peptides
CN102558308A (zh) * 2010-12-31 2012-07-11 天津药物研究院 一种用于形成药物复合物的载体多肽、制备方法及其用途
WO2012154959A1 (fr) * 2011-05-11 2012-11-15 Elixir Institute Of Regenerative Medicine Inhibiteurs d'un peptide tyrosinase et leurs utilisations
EP3000523A1 (fr) * 2014-09-01 2016-03-30 Korea Institute Of Machinery & Materials Structure de filtration de liquide
CN110396474A (zh) * 2019-07-23 2019-11-01 中国人民解放军陆军军医大学第一附属医院 一种干细胞过滤分离器
US11951151B2 (en) 2019-11-08 2024-04-09 University of Pittsburgh—of the Commonwealth System of Higher Education Compositions comprising antimicrobial peptides

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US5714577A (en) * 1996-01-26 1998-02-03 University Of Pittsburgh Antimicrobial peptides
US20030228410A1 (en) * 2002-06-10 2003-12-11 Pradip Nahar Process for photochemical activation of polymer surface and immobilization of biomolecules onto the activated surface
US6887847B2 (en) * 2001-02-16 2005-05-03 University Of Pittsburgh Virus derived antimicrobial peptides

Patent Citations (3)

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Publication number Priority date Publication date Assignee Title
US5714577A (en) * 1996-01-26 1998-02-03 University Of Pittsburgh Antimicrobial peptides
US6887847B2 (en) * 2001-02-16 2005-05-03 University Of Pittsburgh Virus derived antimicrobial peptides
US20030228410A1 (en) * 2002-06-10 2003-12-11 Pradip Nahar Process for photochemical activation of polymer surface and immobilization of biomolecules onto the activated surface

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8071540B2 (en) * 2007-07-13 2011-12-06 University of Pittsburgh—of the Commonwealth System of Higher Education Virus derived antimicrobial peptides
EP3327142A1 (fr) * 2007-07-13 2018-05-30 University of Pittsburgh- Of the Commonwealth System of Higher Education Peptides antimicrobiens dérivés de virus
EP2168592A1 (fr) * 2008-09-24 2010-03-31 Helmholtz Zentrum München Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH) Peptides antimicrobiens
WO2010034787A1 (fr) * 2008-09-24 2010-04-01 Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH) Peptides antimicrobiens
CN102558308A (zh) * 2010-12-31 2012-07-11 天津药物研究院 一种用于形成药物复合物的载体多肽、制备方法及其用途
WO2012154959A1 (fr) * 2011-05-11 2012-11-15 Elixir Institute Of Regenerative Medicine Inhibiteurs d'un peptide tyrosinase et leurs utilisations
EP3000523A1 (fr) * 2014-09-01 2016-03-30 Korea Institute Of Machinery & Materials Structure de filtration de liquide
CN110396474A (zh) * 2019-07-23 2019-11-01 中国人民解放军陆军军医大学第一附属医院 一种干细胞过滤分离器
US11951151B2 (en) 2019-11-08 2024-04-09 University of Pittsburgh—of the Commonwealth System of Higher Education Compositions comprising antimicrobial peptides
US11998586B2 (en) 2019-11-08 2024-06-04 University of Pittsburgh—of the Commonwealth System of Higher Education Compositions comprising antimicrobial peptides

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