Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
  • A61L27/14—Macromolecular materials
  • A61L27/22—Polypeptides or derivatives thereof, e.g. degradation products
  • A61L27/227—Other specific proteins or polypeptides not covered by A61L27/222, A61L27/225 or A61L27/24
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
  • A61L27/28—Materials for coating prostheses
  • A61L27/34—Macromolecular materials
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
  • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
  • A61L27/54—Biologically active materials, e.g. therapeutic substances
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P19/00—Drugs for skeletal disorders
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • C07K14/001—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof by chemical synthesis
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
  • C07K7/04—Linear peptides containing only normal peptide links
  • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
  • A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
  • A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
  • A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
  • A61L2300/606—Coatings

Definitions

• the present invention provides materials and methods for coating surfaces with a coating that reduces adsorption by, and/or biochemically interacts with, biological cells, viruses and/or macromolecules.
• the present invention finds use in providing improved medical implants, catheters, and similar items.
• Pathogenic bacterial biofilms form on both outer and inner walls of catheters and may be detected on catheter surfaces within twenty four hours of catheter insertion.
• Bacteria in these biofilms are thickly embedded in a mostly polysaccharide substance known simply as “matrix” which protects the bacteria from administered antibiotics as well as the immune system.
• matrix a mostly polysaccharide substance known simply as “matrix” which protects the bacteria from administered antibiotics as well as the immune system.
• These biofilms also provide an environment in which bacteria can exchange drug-resistance genes. The selective pressures on bacteria in these environments give rise to bacteria which are resistant not only to commonly-used antibiotics but also to drugs which are treatments of “last resort.”
• urinary catheters which are typically used with incontinent elderly patients and are typically made of silicone and latex. Unfortunately, virtually all patients who have urinary catheters in place for 28 days or more develop urinary tract infections (Donlan (2001) Emerg. Infect. Dis. 7: 277-281). Nearly all hospital-acquired systemic infections that are not associated with central line catheters are associated with urinary catheters (Maki & Tambyah (2001) Emerg. Infect. Dis. 7: 342-347). Treatment of urinary catheter-associated infections alone costs an estimated $1.8 billion annually (Platt et al. (1982) N. Engl. J. Med. 307: 637-642).
• Polymer surfaces can also be “fouled” and their usefulness negated by the adherence of non-bacterial cells and/or protein.
• receptacles that are used for collecting and storing blood for use in transfusion can be “fouled” and destroy the blood stored in them unless they deter the natural tendency of various blood components to clot and to adhere to surfaces.
• receptacles that are used for storing proteins of interest are often made from synthetic polymers such as, for example, plastic tubes, syringes, etc. Once proteins begin to adhere to a receptacle wall, the process often continues until no protein remains in solution. Thus, these receptacles should ideally prevent adhesion of the proteins to the receptacle surface in order to preserve the quality of the proteins stored in them.
• biofilm “life cycle” from the adhesion of bacteria to a surface to the maturation of a biofilm and subsequent release of cells has been the focus of many recent basic research studies.
• genes required for biofilm formation and maturation have been identified in a broad range of Gram-positive and Gram-negative microbes. While similar themes have been elucidated among microbes in terms of biofilm development (i.e., a role for surface adhesion and quorum sensing), no universal “biofilm genes” have yet been identified that are conserved among the many opportunistic pathogens.
• Biofilm formation is-regulated via the exchange of chemical signals between cells in a process called quorum sensing.
• Staphylococci bacteria which are a common cause of nosocomial infections related to biofilm formation on implanted catheters, use two peptide-based quorum sensing systems.
• the first system is composed of the autoinducer RNA-III activating protein (RAP) and its target receptor TRAP (target of RNA-III activating protein).
• RAP autoinducer RNA-III activating protein
• TRAP target of RNA-III activating protein
• the agr system controls toxin production (Balaban et al.
• S. aureus virulence can be inhibited by the heptapeptide YSPWTNF, which is called RIP (RNA-III inhibiting peptide).
• RIP is a competitive inhibitor of RAP binding to TRAP, and thus inhibits TRAP phosphorylation, leading to reduced expression of the agr system, which leads in turn to suppression of the virulence phenotype (Gov et al. (2001) Peptides 22: 1609-1620; Vieira-da-Motta et al. (2001) Peptides 22: 1621-1627).
• AHLs N-acyl-homoserine lactone signaling molecules
• LuxI-type signal synthetases N-acyl-homoserine lactone signaling molecules
• LuxR-type signal receptors N-acyl-homoserine lactone signaling molecules
• the AHL-dependent sensing system mediates the regulation of a number of genes, including those involved in biofilm formation and production of virulence factors (Eberl (1999) Syst. Appl. Microbiol. 22(4): 493-506).
• impregnating catheters with antibiotics may help prevent colonization by killing organisms when they come in close proximity to the surface, before they can establish a biofilm.
• chlorhexidine-impregnated catheters showed limited efficacy in preventing infections, they are also believed to cause hypersensitivity reactions (Knight et al. (2001) Intern. Med. J. 31: 436-437).
• impregnating catheters with antibiotics may be counter-productive because as the concentration of antibiotics released from the catheter inevitably falls, bacteria are exposed to sublethal levels of antibiotics, a condition that promotes the development of antibiotic resistance (Rachid et al. (2000) J. Bacteriol.
• Another alternative for preventing biofilm formation is the development of a coating that prevents adherence of bacterial cells to the catheter surface.
• Such coatings could be used alone or in combination with antibacterial impregnation of the catheter to further prevent biofilm formation.
• the most commonly used coatings to prevent biological fouling on surfaces include those generated using plasma treatment, biotin-avidin conjugation strategies, phospholipids, self-assembled monolayers on transition metal coatings, and chemically grafted poly(ethylene glycol) (Kingshott et al. (1999) Anal. Biochem. 273(2): 156-62; Ratner (1993) J. Biomed. Mater. Res. 27: 837-50).
• Hubbell et al. have described a method to suppress the interaction, adsorption or attachment of proteins or cells to a biomaterial surface through a polymer coating comprised of a polyionic backbone with poly(ethylene glycol) (PEG) or poly(ethylene oxide) (PEO) side chains (U.S. Patent Application No. 20020128234).
• Still another non-covalent means of associating PEG with metal surfaces includes linkage to mussel adhesive protein (Dalsin et al.
• the present invention provides materials and compositions for an improved coating for surfaces of medical devices, including implants and catheters.
• the coating is an interfacial biomaterial (“IFBM”) which comprises at least one binding module that specifically binds to a surface (“surface-binding module”) and at least one binding module that performs another function (“affector module”).
• the affector module can: inhibit binding to the polymer surface by an organism, cell, or protein (“adhesion-resistance module”); modify the behavior of cells and/or organisms which bind to it (“behavior modification module”); and/or bind to a moiety which is a compound or molecule of interest (“moiety-binding module”).
• the modules are connected by a linker.
• the affector module inhibits biofilm formation.
• the compositions and methods of the invention improve the performance of medical devices, for example, by preventing unwanted adsorption and/or growth of bacterial cells on the surface of the device.
• the present invention provides compositions for an improved coating for medical devices and methods of coating medical devices using those compositions.
• the term “medical device” as used herein refers to any article used as an implant in the body of a patient (including both human and non-human patients), any article used as a conduit (e.g., a catheter) related to medical treatment or for biological materials, or any container used as a storage device for biological materials, for example, for proteins or solutions containing cells. Medical devices may be made of any material, including metal and/or polymers.
• the coating of the invention is an interfacial biomaterial (“IFBM”) which comprises at least one binding module that specifically binds to a surface of a medical device (“surface-binding module”) and at least one binding module that performs another function (“affector module”).
• IFBM interfacial biomaterial
• the binding modules are connected by a linker.
• the affector module acts to inhibit formation of a biofilm by any suitable mechanism.
• the affector module may inhibit formation of a biofilm by inhibiting binding of an organism, cell, or compound (e.g., a protein) to the surface of the medical device (“adhesion-resistance module”).
• the affector module inhibit formation of a biofilm by modifying the behavior of cells and/or organisms which come into contact with it or bind to it (“behavior modification module”); and/or it may function to specifically bind to a moiety which is a compound or molecule of interest (“moiety-binding module”).
• any affector module is suitable for use in an IFBM of the invention so long as an IFBM comprising it acts to inhibit formation of a biofilm.
• Affector modules may have more than one function; thus, for example, a single affector module may have both adhesion-resistance function and behavior modification function.
• Any affector module may be used in an IFBM of the invention so long as it accomplishes the objective of the invention to inhibit biofilm formation.
• at least one binding module i.e., surface-binding module or affector module
• Exemplary binding modules are set forth in SEQ ID NOs: 1-10, 39-43, 95-96, and 97-558.
• compositions and methods of the invention improve the performance of medical devices including those made from polymeric materials.
• polymer or “polymeric material” as used herein refers to any of numerous natural and synthetic compounds of usually high molecular weight consisting of up to millions of repeated linked units, each a relatively simple molecule.
• microbial growth, attachment, and biofilm formation are particularly problematic.
• said microbial organisms include non-pathogenic microbes that are ordinarily present in non-sterile areas as well as pathogenic microbes that are present as a result of extant disease or due to accidental introduction during the insertion of the device.
• the IFBM coatings of the invention are useful for improving the performance of medical devices such as, for example, implants, catheters, and endotracheal tubes. In some embodiments, these coatings prevent unwanted adsorption of and/or growth of bacterial cells to the surface of the device.
• the surface-binding module of the IFBM of the invention is selected to specifically bind to the material of which the surface of the medical device is made. Typically, this binding is non-covalent.
• the affector module of the IFBM of the invention is chosen so as to confer to an IFBM-coated surface a desired property such as, for example, resistance to adhesion of bacteria.
• the IFBMs of the invention comprise at least one surface-binding module and at least one affector module which are connected by a linker.
• a linker may be chosen for particular properties, such as a specific susceptibility to modification and/or to allow affector modules flexibility of orientation at a distance from the binding modules so linked.
• the linker itself may also have activities similar to those of the binding module or affector module; that is, the linker may act to enhance binding to a particular surface or to have anti-adhesive properties such as inhibiting cell attachment, etc.
• an IFBM comprising a poly (ethylene glycol) (“PEG”) linker to join the surface-binding module to the affector module may help to prevent non-specific protein and/or cell adherence to the surface of the medical device coated with that IFBM.
• PEG poly (ethylene glycol)
• the affector module inhibits biofilm formation. In some embodiments, an affector module inhibits biofilm formation due to its anti-adhesive properties; that is, the affector module is a molecule or moiety that does not bind to biomolecules and/or biomolecular constituents of cells. In some embodiments, an affector module inhibits biofilm formation by damaging cells so that they do not adhere to the surface or by affecting a regulatory mechanism of cells that is involved in biofilm formation. Any combination of affector modules may be linked to any combination of surface-binding modules to create an IFBM of the invention so long as the IFBM comprises at least one affector module and at least one surface-binding module.
• a surface-binding module is a peptide that binds to the surface of a medical device.
• a surface-binding module may bind to any material which is used to make a medical device, including a metal, a metal oxide, a non-metal oxide, a ceramic, a polymer, such as, for example, a synthetic polymer such as a polyurethane, a rubber, a plastic, an acrylic, a silicone, and combinations thereof. Suitable materials are known in the art.
• Binding modules i.e., surface-binding modules and/or affector modules
• Binding modules which are peptides may comprise sequences disclosed in this application or known in the art, such as the peptides described in pending U.S. patent application Ser. No. 10/300,694, filed Nov. 20, 2002 and published on Oct. 2, 2003 as publication number 20030185870. Binding modules can also be identified using the methods described in pending U.S. patent application Ser. No. 10/300,694 and/or other methods known in the art. In some embodiments, binding modules may be identified by screening phage display libraries for affinity to materials such as titanium, stainless steel, cobalt-chrome alloy, polyurethane, polyethylene, acrylic, latex or silicone.
• binding modules which are peptides which exhibit specific binding to particular materials are set forth in SEQ ID NOs: 1-10 (showing specific binding to titanium), 39-43 (showing specific binding to stainless steel), 95-96 (showing specific binding to Teflon), and 97-558.
• binding specifically or “specific binding” is intended that a binding module binds to a selected surface, material, or composition.
• a binding module that binds specifically to a particular surface, material or composition binds at least 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, 300%, 400%, 500%, or a higher percentage more than the binding module binds to an appropriate control such as, for example, a different material or surface, or a protein typically used for such comparisons such as bovine serum albumin.
• an antibody useful as a binding module encompasses single chain antibodies.
• an antibody useful as a binding module may be a single chain variable fragment antibody (scFv).
• a single chain antibody is an antibody comprising a variable heavy and a variable light chain that are joined together, either directly or via a peptide linker, to form a continuous polypeptide.
• the term “single chain antibody” as used herein encompasses an immunoglobulin protein or a functional portion thereof, including but not limited to a monoclonal antibody, a chimeric antibody, a hybrid antibody, a mutagenized antibody, a humanized antibody, and antibody fragments that comprise an antigen binding site (e.g., Fab and Fv antibody fragments).
• the IFBM comprises an affector module that is an anti-adhesive or that binds to a protein which is an anti-adhesive.
• the surface-binding module of the IFBM binds to the surface of the device and the anti-adhesive forms a dense structure that prevents the adsorption of biological cells, viruses and macromolecules onto that surface.
• Suitable anti-adhesives are “non-interactive” polymer and/or functional groups that resist adhesion to protein and/or to cells.
• non-interactive as used herein with regard to coating polymer articles means a polymer that reduces the amount of non-specific adsorption of molecules to a coated surface, such as, for example, inorganic ions, peptides, proteins, saccharides and cells such as mammalian cells, bacteria and fungi.
• an IFBM may comprise an affector module which is a non-interactive polymer or an IFBM may comprise an affector module which binds to a non-interactive polymer.
• Suitable non-interactive polymers which have adhesion-resistant function are known in the art and include, for example: albumin, poly(ethylene glycol) (PEG) (see, e.g., Wagner et al. (2004) Biomaterials 25: 2247-2263; Harris et al.
• mixed polyalkylene oxides having a solubility of at least one gram/liter in aqueous solutions such as some poloxamer nonionic surfactants; neutral water-soluble polysaccharides; poly(vinyl alcohol); poly(N-vinyl pyrrolidone); non-cationic polymethacrylates such as poly(methacrylic acid); many neutral polysaccharides, including dextran, FicollTM, and derivatized celluloses; non-cationic polyacrylates such as poly(acrylic acid); and esters, amides, and hydroxyalkyl amides thereof, and combinations thereof.
• an IFBM can comprise an affector module that binds human serum albumin, a native protein present in the blood of people and animals which is known to reduce bacterial adherence to coated surfaces (see, e.g., Keogh and Eaton (1994) J. Lab. Clin. Med. 124: 537-545; U.S. Pat. No. 5,073,171; Sato et al. (2002) Biotechnol. Prog. 18: 182-192).
• IFBMs comprising an affector module which has affinity for albumin can be coated onto polymer surfaces such as catheters or containers for blood, serum or other tissue, or solutions containing bacteria; albumin present in physiological solutions will then bind to the affector module, effectively providing a coating of albumin to the polymer surface, e.g., of the catheter or container.
• the IFBM comprises an affector module that has anti-microbial activity.
• the affector module can be a peptide which has anti-microbial activity such as, for example, cationic antimicrobial peptides such as a magainin, defensin, bacteriocin, or microcin, all of which are known in the art (see, e.g., Lin et al. (2001) Medical Device Technology , October 2001 issue; Zasloff (2002) Nature 415: 389-395). Lactoferrin is also known to inhibit biofilm formation and is therefore useful as an affector module.
• the mechanism of action for many anti-microbial peptides is through disruption of the integrity of the bacterial membrane; most of these peptides do not affect the membranes of plant or animal cells. Because this disruption is mechanical in nature, it is unlikely that bacteria would develop resistance to these peptides (Zasloff (2002) Nature 415: 389-395).
• an affector module has biofilm inhibitor activity due to its interference with a regulatory mechanism of cells that is involved in their establishment of or participation in a biofilm.
• Suitable biofilm inhibitors for use as an affector module include compounds that are known in the art to interfere with bacterial quorum sensing such as RNA III inhibiting peptide (RIP), RIP analogs, antagonists of TRAP (Target for RNA III Activating Peptide), antagonists of N-acyl-homoserine lactone-based signaling, and furanone analogs.
• the IFBMs of the invention can be coated onto a medical device and implanted into the body.
• the linkers used in such IFBMs can be, for example, a PEG linker which joins the binding module to the affector module and also may prevent non-specific protein and/or cell adherence to the surface of the medical device.
• the affector module which has affinity for albumin will bind endogenous serum albumin, thereby specifically coating the surface of the medical device with albumin.
• a medical device coated with such IFBMs may also be coated with albumin by contacting the device with albumin-containing solutions in vitro prior to implantation of the device in a patient (see, e.g., Wagner et al. (2004) Biomaterials 25: 2247-2263; Harris et al. (2004) Biomaterials 25: 4135-4148).
• Phage display technology is well-known in the art and can be used to identify additional peptides for use as binding modules in IFBMs of the invention.
• a library of diverse peptides can be presented to a target substrate, and peptides that specifically bind to the substrate can be selected for use as binding modules. Multiple serial rounds of selection, called “panning,” may be used.
• any one of a variety of libraries and panning methods can be employed to identify a binding module that is useful in the methods of the invention.
• libraries of antibodies or antibody fragments may be used to identify antibodies or fragments that bind to particular cell populations or to viruses (see, e.g., U.S. Pat. Nos.
• Panning methods can include, for example, solution phase screening, solid phase screening, or cell-based screening. Once a candidate binding module is identified, directed or random mutagenesis of the sequence may be used to optimize the binding properties of the binding module.
• bacteria and “phage” are synonymous and are used herein interchangeably.
• the term “bacteriophage” is defined as a bacterial virus containing a nucleic acid core and a protective shell built up by the aggregation of a number of different protein molecules.
• a library can comprise a random collection of molecules.
• a library can comprise a collection of molecules having a bias for a particular sequence, structure, or conformation. See, e.g., U.S. Pat. Nos. 5,264,563 and 5,824,483.
• Methods for preparing libraries containing diverse populations of various types of molecules are known in the art, and numerous libraries are also commercially available. Methods for preparing phage libraries can be found, for example, in Kay et al. (1996) Phage Display of Peptides and Proteins (San Diego, Academic Press); Barbas (2001) Phage Display: A Laboratory Manual (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y.).
• a binding module that is a peptide comprises about 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 50, 60, 70, 80, 90, 100, 200, or up to 300 amino acids.
• Exemplary binding modules that are peptides are set forth in SEQ ID NOs: 1-10, 39-43, and 95-558.
• Peptides that are useful as binding modules in IFBMs of the invention may differ from these exemplary peptides so long as the desired property of the binding module is retained.
• Peptides useful as a binding module can be linear, branched, or cyclic, and can include non-peptidyl moieties.
• peptide broadly refers to an amino acid chain that includes naturally occurring amino acids, synthetic amino acids, genetically encoded amino acids, non-genetically encoded amino acids, and combinations thereof. Peptides can include both L-form and D-form amino acids.
• a peptide of the present invention can be subject to various changes, substitutions, insertions, and deletions where such changes provide for certain advantages in its use.
• the term “peptide” encompasses any of a variety of forms of peptide derivatives including, for example, amides, conjugates with proteins, cyclone peptides, polymerized peptides, conservatively substituted variants, analogs, fragments, chemically modified peptides, and peptide mimetics. Any peptide that has desired binding characteristics can be used in the practice of the present invention.
• Non-genetically encoded amino acids include but are not limited to 2-aminoadipic acid; 3-aminoadipic acid; ⁇ -aminopropionic acid; 2-aminobutyric acid; 4-aminobutyric acid (piperidinic acid); 6-aminocaproic acid; 2-aminoheptanoic acid; 2-aminoisobutyric acid; 3-aminoisobutyric acid; 2-aminopimelic acid; 2,4-diaminobutyric acid; desmosine; 2,2′-diaminopimelic acid; 2,3-diaminopropionic acid; N-ethylglycine; N-ethylasparagine; hydroxylysine; allo-hydroxylysine; 3-hydroxyproline; 4-hydroxyproline; isodesmosine; allo-isoleucine; N-methylglycine (sarcosine); N-methylisoleucine; N-methylvaline; norvaline; norleucine; and
• Representative derivatized amino acids include, for example, those molecules in which free amino groups have been derivatized to form amine hydrochlorides, p-toluene sulfonyl groups, carbobenzoxy groups, t-butyloxycarbonyl groups, chloroacetyl groups or formyl groups.
• Free carboxyl groups can be derivatized to form salts, methyl and ethyl esters or other types of esters or hydrazides.
• Free hydroxyl groups can be derivatized to form O-acyl or O-alkyl derivatives.
• the imidazole nitrogen of histidine can be derivatized to form N-im-benzylhistidine.
• a conservatively substituted variant refers to a peptide having an amino acid residue sequence substantially identical to a sequence of an exemplary peptide in which one or more residues have been conservatively substituted with a functionally similar residue such that the “conservatively substituted variant” will bind to the same binding partner with substantially the same affinity as the parental variant and will prevent binding of the parental variant.
• a conservatively substituted variant displays a similar binding specificity when compared to the exemplary reference peptide.
• the phrase “conservatively substituted variant” also includes peptides wherein a residue is replaced with a chemically derivatized residue.
• conservative substitutions include the substitution of one non-polar (hydrophobic) residue such as isoleucine, valine, leucine or methionine for another; the substitution of one aromatic residue such as tryptophan, tyrosine, or phenylalanine for another; the substitution of one polar (hydrophilic) residue for another such as between arginine and lysine, between glutamine and asparagine, between glycine and serine; the substitution of one basic residue such as lysine, arginine or histidine for another; or the substitution of one acidic residue such as aspartic acid or glutamic acid for another.
• one non-polar (hydrophobic) residue such as isoleucine, valine, leucine or methionine for another
• the substitution of one aromatic residue such as tryptophan, tyrosine, or phenylalanine for another
• the substitution of one polar (hydrophilic) residue for another such as between arginine and lysine, between
• binding modules of the present invention also include peptides having one or more substitutions, additions and/or deletions of residues relative to the sequence of an exemplary peptide sequence as disclosed herein, so long as the binding properties of the original exemplary peptide are retained.
• binding modules of the invention include peptides that differ from the exemplary sequences disclosed herein by about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 amino acids but that retain the ability of the corresponding exemplary sequence to bind to a particular material or to act as an affector module.
• binding module of the invention that differs from an exemplary sequence disclosed herein will retain at least 25%, 50%, 75%, or 100% of the activity of a binding module comprising an entire exemplary sequence disclosed herein as measured using an appropriate assay. That is, binding modules of the invention include peptides that share sequence identity with the exemplary sequences disclosed herein of at least 70%, 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or greater sequence identity.
• Sequence identity may be calculated manually or it may be calculated using a computer implementation of a mathematical algorithm, for example, GAP, BESTFIT, BLAST, FASTA, and TFASTA in the Wisconsin Genetics Software Package of Genetics Computer Group, Version 10 (available from Accelrys, 9685 Scranton Road, San Diego, Calif., 92121, USA).
• the scoring matrix used in Version 10 of the Wisconsin Genetics Software Package is BLOSUM62 (see Henikoff and Henikoff (1989) Proc. Natl. Acad. Sci. USA 89: 10915). Alignments using these programs can be performed using the default parameters.
• a peptide can be modified, for example, by terminal-NH 2 acylation (e.g., acetylation, or thioglycolic acid amidation) or by terminal-carboxylamidation (e.g., with ammonia or methylamine). Terminal modifications are useful to reduce susceptibility by proteinase digestion, and to therefore prolong a half-life of peptides in solutions, particularly in biological fluids where proteases can be present. Peptide cyclization is also a useful modification because of the stable structures formed by cyclization and in view of the biological activities observed for such cyclic peptides. Methods for cyclizing peptides are described, for example, by Schneider & Eberle (1993) Peptides. 1992: Proceedings of the Twenty - Second European Peptide Symposium, Sep. 13-19, 1992 , Interlaken, Switzerland , Escom, Leiden, The Netherlands.
• a binding module peptide can comprise one or more amino acids that have been modified to contain one or more halogens, such as fluorine, bromine, or iodine, to facilitate linking to a linker molecule.
• the term “peptide” also encompasses a peptide wherein one or more of the peptide bonds are replaced by pseudopeptide bonds including but not limited to a carba bond (CH 2 —CH 2 ), a depsi bond (CO—O), a hydroxyethylene bond (CHOH—CH 2 ), a ketomethylene bond (CO—CH 2 ), a methylene-oxy bond (CH 2 —O), a reduced bond (CH 2 —NH), a thiomethylene bond (CH 2 —S), an N-modified bond (—NRCO—), and a thiopeptide bond (CS—NH).
• IFBMs of the invention comprise binding modules which comprise peptides that specifically bind to materials used in medical implants, such as peptides having an amino acid sequence as set forth in SEQ ID NOs:1-10, 39-43, and 95-558. While these exemplary peptide sequences are disclosed herein, one of skill will appreciate that the binding properties conferred by those sequences may be attributable to only some of the amino acids comprised by the sequences.
• a peptide which comprises only a portion of an exemplary amino acid sequence disclosed herein may have substantially the same binding properties as a peptide comprising the full-length exemplary sequence; thus, also useful as binding modules in IFBMs of the present invention are peptides that comprise only 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 of the amino acids in a particular exemplary sequence provided herein. Such amino acids may be contiguous or non-contiguous so long as the desired property of the binding module is retained as determined by an appropriate assay.
• Such amino acids may be concentrated at the amino-terminal end of the exemplary peptide (for example, 4 amino acids may be concentrated in the first 4, 5, 6, 7, 8, 9, 10, 11, or 12 amino acids of the peptide) or they may be dispersed throughout the exemplary peptide.
• Binding modules of the present invention that are peptides can be synthesized by any of the techniques that are known to those skilled in the art of peptide synthesis. Representative techniques can be found, for example, in Stewart & Young (1969) Solid Phase Peptide Synthesis , (Freeman, San Francisco, Calif.); Merrifield (1969) Adv. Enzymol. Relat. Areas Mol. Biol. 32:221-296; Fields & Noble (1990) Int. J. Pept. Protein Res. 35:161-214; and Bodanszky (1993) Principles of Peptide Synthesis, 2nd Rev. Ed. (Springer-Verlag, Berlin). Representative solid phase synthesis techniques can be found in Andersson et al.
• peptides having a specified amino acid sequence can be purchased from commercial sources (e.g., Biopeptide Co., LLC of San Diego, Calif., and PeptidoGenics of Livermore, Calif.).
• the linker that joins the binding module to at least one other module to form an IFBM can be any suitable linker.
• Linkers may be peptides or non-peptides. Suitable linkers are known in the art and can comprise, for example, a polymer, including a synthetic polymer or a natural polymer.
• an IFBM is synthesized as a single continuous peptide comprising sequences originally identified as separate binding modules; in such embodiments, the linker is simply one of the bonds in the peptide.
• Representative synthetic polymers include but are not limited to polyethers (e.g., poly(ethylene glycol) (“PEG”)), polyesters (e.g., polylactic acid (PLA) and polyglycolic acid (PGA)), polyamines, polyamides (e.g., nylon), polymethacrylates (e.g., polymethylmethacrylate; PMMA), polyacrylic acids, polyurethanes, polystyrenes, flexible chelators such as EDTA, EGTA and other synthetic polymers having a molecular weight of about 200 daltons to about 1000 kilodaltons.
• PEG poly(ethylene glycol)
• polyesters e.g., polylactic acid (PLA) and polyglycolic acid (PGA)
• Pamines e.g., polyamides (e.g., nylon)
• polymethacrylates e.g., polymethylmethacrylate; PMMA
• polyacrylic acids e.g., polyurethanes, polyst
• Natural polymers include but are not limited to hyaluronic acid, alginate, chondroitin sulfate, fibrinogen, fibronectin, albumin, collagen, calmodulin EF-hand domains and other natural polymers having a molecular weight of about 200 daltons to about 20,000 kilodaltons.
• Polymeric linkers can comprise a diblock polymer, a multi-block copolymer, a comb polymer, a star polymer, a dendritic polymer, a hybrid linear-dendritic polymer, or a random copolymer.
• a linker can also comprise a mercapto(amido)carboxylic acid, an acrylamidocarboxylic acid, an acrlyamido-amidotriethylene glycolic acid, and derivatives thereof. See, for example, U.S. Pat. No. 6,280,760.
• Linkers are known in the art and include linkers that can be cleaved and linkers that can be made reactive toward other molecular moieties or toward themselves, for cross-linking purposes. Fluorescent linkers are also known in the art.
• Methods for linking a linker molecule to a ligand, binding module, or to a non-binding domain will vary according to the reactive groups present on each molecule. Protocols for linking using reactive groups and molecules are known to one of skill in the art. See, e.g., Goldman et al. (1997) Cancer Res. 57: 1447-1451; Cheng (1996) Hum. Gene Therapy 7: 275-282; Neri et al. (1997) Nat. Biotechnol. 19: 958-961; Nabel (1997) Current Protocols in Human Genetics , vol. on CD-ROM (John Wiley & Sons, New York); Park et al. (1997) Adv. Pharmacol. 40: 399-435; Pasqualini et al. (1997) Nat.
• compositions and methods of the invention find particular use in coating any implantable or insertable medical device that is susceptible to microbial growth on and around the surfaces of the device.
• Implantable medical devices that can be improved with the compositions and methods of the invention include those adapted to remain implanted for a relatively long-term, i.e., for period of from about 30 days to about 12 months or greater, such as, for example, orthopedic implants. However, devices intended to remain implanted for about 30 days or less such as, for example, certain catheters, are also included within the scope of the present invention.
• “Medical device” as used herein refers to devices used in human patients as well as to devices used in non-human animals.
• Examples of medical devices that are conduits and vessels made of polymers or that have polymeric surfaces include but are not limited to: medical conduits for insertion into a human or animal body, such as catheters and endotrachial tubes; vessels such as blood collection tubes, specimen containers and storage jars; vessels and conduits for the storage and transport of biochemical reagents in biomedical research or manufacturing; and tubing and containers for waste, water or combinations thereof.
• the polymer may be any suitable kind, including for example a synthetic polymer such as a plastic, rubber, a silicone material and combinations thereof. Suitable materials are known in the art and include polyurethane, polyethylene, polyvinylchloride, acrylic and latex.
• implantable medical devices include but are not limited to: prosthetic joints, plates, screws, pins, nails, rivets, bone fixation implants and artificial ligaments and tendons.
• Medical devices may be made of any suitable material, including for example a synthetic polymer, a plastic, a metal (such as titanium, stainless steel, or cobalt-chrome alloy), a metal oxide, a non-metal oxide, a silicone material, a ceramic material, and combinations thereof. Suitable materials are known in the art and include polyurethane, polyethylene, and silicone.
• Medical devices that are coated with IFBMs of the invention will exhibit at least one superior property in comparison to an appropriate control, such as a similar medical device that is not coated with at least one IFBM; for example, a medical device coated with IFBMs of the invention will exhibit reduced formation of bacterial biofilms or show resistance to adhesion of protein or cells.
• an IFBM is considered to act to inhibit formation of a biofilm if a surface coated with that IFBM exhibits a detectable decrease in the tendency for a biofilm to form on that surface when compared to a suitable control surface or if a surface coated with that IFBM shows a detectable increase in resistance to adhesion of protein or cells when compared to a suitable control surface.
• An IFBM also acts to inhibit formation of a biofilm if a surface coated with that IFBM becomes coated with a biofilm which exhibits a detectable reduction in any of the characteristics of a biofilm. That is, an IFBM acts to inhibit formation of a biofilm if it decreases the frequency of biofilm formation or if it reduces a characteristic of a biofilm or resists adhesion of protein or cells by at least 5%, 10%, 15%, 20%, 30%, 40%, 50%, 100% when a surface coated with that IFBM is compared to a surface that is uncoated or that is not coated with that IFBM.
• a medical device which is coated with at least one IFBM has a superior property where that medical device has a measurable characteristic which differs in a statistically significant way from the same characteristic of an appropriate control medical device (such as, for example, a medical device that is not coated with at least one IFBM).
• an appropriate control medical device such as, for example, a medical device that is not coated with at least one IFBM.
• a property of a medical device which is coated with at least one IFBM will have a property which is superior to a property of an appropriate control medical device by at least 5%, 10%, 15%, 20%, 30%, 40%, 50%, 100%, or more.
• Such a property may result from the performance of the IFBM or of its component modules.
• One of skill in the art is familiar with techniques that can be used to compare the performance of coated and uncoated medical devices or materials.
• a medical device which is coated with at least one IFBM will inhibit biofilm formation by at least 5% when compared to a comparable uncoated medical device.
• a medical device that is coated with at least one IFBM is coated by any suitable method, for example, by dipping or spraying the IFBM onto the device.
• the coating may be stabilized, for example, by air drying or by lyophilization.
• these treatments are not exclusive, and other coating and stabilization methods may be employed; one of skill in the art will be able to select the compositions and methods used to fit the needs of the particular device and purpose.

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