Collagen peptide-based pharmaceutical composition and its use

Abstract

The present invention pertains to the fields of medicinal chemistry, biotechnology, and pharmaceuticals. The present invention provides a composition comprising one or more collagen mimetic peptides optionally conjugated to one or more therapeutic compounds or one or more contrast compounds, methods of using such compositions in treating, preventing, ameliorating, curing, and / or diagnosing specific diseases and physical disorders in humans and veterinary animals, including anterior segment diseases and physical disorders, including corneal and scleral diseases, disorders or conditions such as myopia, presbyopia, keratoconus, etc. The present invention also provides for the use of such compositions in treating, preventing, ameliorating, curing, and / or diagnosing diseases, disorders, and conditions in various other tissues, organs, and organ systems. The present invention also provides methods for manufacturing such collagen mimetic peptides and compositions. The present invention also provides a medical device comprising one or more of such compositions of the present invention.

Description

Technical Field

[0001] Cross - Reference to Related Applications and Incorporation by Reference This application claims the benefit of the filing date of U.S. Provisional Patent Application No. 63 / 367,080, filed on June 27, 2022, entitled "Collagen Peptide - Based Medicament Compositions and Uses Thereof", with inventors Robert O. Baratta, Richard E. Schlumpf, Brian J. Del Buono, and David J. Calkins, and is hereby incorporated by reference in its entirety.

[0002] Description of Research and Development Funded by the Federal Government Not applicable.

[0003] Names of Parties to a Joint Research Agreement Not applicable.

[0004] Reference to an Electronically Submitted Sequence Listing Not applicable.

[0005] The present invention relates to the fields of pharmaceutical chemistry, biotechnology, pharmaceuticals and medical devices, as well as the use of pharmaceutical compounds and medical devices for the treatment, prevention and improvement of diseases, disorders and physical ailments in humans and veterinary animals, particularly certain eye diseases and disorders including corneal and scleral diseases and disorders such as myopia, keratoconus, episcleritis, superior episcleritis and presbyopia.

Background Art

[0006] Collagen is the most abundant protein in vertebrates and is a basic structural protein of vertebrate tissues. It occurs in virtually all tissues, including skin and other epithelial tissues (including the inner surfaces of most luminal organs such as the gastrointestinal tract), tendons, bones, blood vessels, cartilage, ligaments, and teeth. In humans, collagen constitutes approximately one-third of the total protein and about three-fourths of the dry weight of the skin (see Shoulders, M.D., and Raines, R.T., Ann. Rev. Biochem. 78:929-958 (2009), Gelse, K., et al., Adv. Drug Deliv. Rev. 55:1531-1546 (2003)).

[0007] Collagen is generally a fibrous protein composed of a triple helix consisting of two identical chains and a third chain with slightly different chemical composition. Mammals produce at least 46 different collagen polypeptide chains, which combine to form variants or "types" of collagen. To date, 28 types of collagen have been reported. Collagen types are broadly classified, according to their structural forms, into fibrous (types I, II, III, V, and XI), which account for about 90% of all collagen proteins found in mammals, and non-fibrous (basement membrane or type IV, and other non-fibrous collagen types with interrupted helical structures) (see the same reference). The five most common types of collagen and their tissue distributions are as follows:

[0008] Type I: Skin, tendon, organs, bone, vascular connective tissue,

[0009] Type II: Cartilage,

[0010] Type III: Reticular connective tissue, often associated with type I collagen,

[0011] Type IV: Basement membrane of epithelial tissues and certain solid tumors, and

[0012] Type V: Hair, placenta, outer cell membrane.

[0013] In each of these variants, the polypeptide chains of collagen have a structure in which the amino acids proline (Pro), 4(R)-hydroxyproline (Hyp), and glycine (Gly) are usually repeated approximately 300 times in the sequence X-Y-Gly, where X is often a Pro residue and Y is often a (Hyp) residue. In vertebrates, a typical repeat motif in collagen is ProProGly (see Hulmes, D.J.S., “Collagen Diversity, Synthesis and Assembly,” in: Collagen: Structure and Mechanics, P. Fratzl, Ed., New York: Springer, pp. 15-47 (2008)). Subsequently, in vivo, after collagen biosynthesis but before the chains begin to form a triple helix, the hydroxylation of Pro residues occurs enzymatically. Thus, the hydroxylation of at least one Pro residue in the ProProGly motif (typically forming ProHypGly) is thought to be important for both the proper folding and stability of the collagen triple helix, both of which are essential for the normal structure and function of collagen in vivo (see Shoulders, M.D., and Raines, R.T., Ann. Rev. Biochem. 78:929-958 (2009)). For example, (ProHypGly) 10 (SEQ ID NO: 396) has a triple helix melting temperature of 58°C, while that of (ProProGly) 10 (SEQ ID NO: 397) is only 24°C (Sakakibara et al., Biochim. Biophys. Acta, 303:198-202 (1973)), and the rate at which the chain of (ProHypGly) 10 (SEQ ID NO: 396) folds into a triple helix is significantly higher than the corresponding rate for the chain of (ProProGly) 10 (SEQ ID NO: 397) (Chopra and Ananthanarayanan, Proc. Natl. Acad. Sci. USA, 79:7180-7184 (1982)).

[0014] Type I collagen is the most abundant and most well-studied collagen. In humans and most other animals, it forms more than 90% of the organic mass of bone and is the major collagen in many interstitial connective tissues, with the exceptions of a few such as hyaline cartilage, brain, and vitreous humor, as well as tendons, skin, ligaments, and corneas. The triple helix of type I collagen is usually formed as a heterotrimer by two identical α1 chains and one α2 chain. The triple helix fibers are mainly incorporated in vivo into composite fibrils containing other types of collagen that vary depending on the tissue type and location as described above (Fleischmajer, E.D. et al., J. Struct. Biol. 105: 162-169 (1990), Niyibizi, C. and Eyre, D.R., Connect. Tissue Res. 20:247-250 (1989)). In most organs, especially tendons and fascia, type I collagen provides tensile stiffness, and in bone, it defines the biomechanical properties related to load-bearing, tensile strength, and torsional stiffness.

[0015] In connective tissues (such as bone, tendon, cartilage, ligament, skin, blood vessels, and teeth), individual collagen molecules are wound together as tight triple helices. These helices are organized into fibrils with high tensile strength through cross-linking of individual triple helix fibers (Lodish, H. et al., “Collagen: The Fibrous Proteins of the Matrix”, in: Molecular Cell Biology, 4th ed., Section 22.3, New York: W.H. Freeman (2000)), (Jones & Miller, J. Mol. Biol., 218:209-219 (1991)). By changing the arrangement and cross-linking of collagen fibrils, vertebrates can support stresses in one dimension (tendon), two dimensions (skin), or three dimensions (cartilage).

[0016] Collagen plays a major role in maintaining the structural integrity of tissues and organs in the body. In all parenchymal organs, collagen corresponds to the major component of the interstitial matrix and basement membrane, and in all connective tissues, especially bone and cartilage, collagen provides the major functional framework of the structure. However, in addition to these biomechanical aspects, collagen is also involved in a variety of additional functions. For example, specific cell surface receptors and intracellular receptors interact with collagen, and signal transduction by these receptors is involved in cell adhesion, differentiation, growth, and other cell activities, as well as cell survival both in vivo and in vitro (Vogel, W.F., Eur. J. Dermatol. 11:506-514 (2001), Gelse, K., et al., Adv. Drug Deliv. Rev. 55:1531-1546 (2003)). Collagen is also involved in the capture, local storage, and delivery of growth factors and cytokines in the various tissues where collagen is found. Through these receptor interactions and storage and delivery functions, collagen plays an important role in organ development, wound healing, and tissue repair (Chattopadhyay, S. and R. Raines, Biopolymers 101:821-833 (2014), Yamaguchi, Y. et al., Nature 346:281-284 (1990), Hay, E.D., J. Cell Biol. 91:205s-223s (1981), Bautista, C.M. et al., Metabolism 39:96-100 (1990), Zhu, Y. et al., J. Cell Biol. 144:1069-1080 (1998), Schlegel, K.A. et al., Biomaterials 25:5387-5393 (2004), Kumar, V.A., et al., Biomacromol. 15:1484-1490 (2014)).From these functions, collagen is also eligible as a candidate transport medium for delivering therapeutic compounds (see, for example, Chattopadhyay, S., et al., J. Tissue Eng. Regen. Med. 10: 1012-1020 (2012), Schuppan, D., et al., Gastroenterol. 114: 139-152 (1998), Frenkel, S. R., et al., J. Bone Jt. Surg. 79-B: 831-836 (1997), Albu, M. G., et al., “Collagen-Based Drug Delivery Systems for Tissue Engineering”, in: Biomaterials Applications for Nanomedicine, Pignatello, R. (Ed.), ISBN: 978-953-307-661-4, DOI: 10.5772 / 22981, Rijeka, Croatia: InTech (https: / / www.intechopen.com / books / biomaterials-applications-for-nanomedicine / collagen-based-drug-delivery-systems-for-tissue-engineering (2011))), and is also eligible for use in wound healing by directly promoting tissue repair or regeneration (Wakitani, S., et al., J. Bone Jt. Surg. 71-B: 74-80 (1989), Kumar, V. A., et al., Biomacromol. 15: 1484-1490 (2014)). Collagen (more specifically, disrupted collagen) has also been associated with tumor progression and metastasis in humans and other vertebrates (see the review of this issue by Fang, M., et al., Tumor Biol. 35: 2871-2882 (2014)).

[0017] However, in addition to intact collagen molecules, collagen fragments may also have therapeutic uses and, in fact, may function in a superior manner compared to native collagen. For example, non-collagenous fragments of type IV, XV, and XVIII collagen have been shown to promote blood vessel and tumor cell growth and to affect various other cellular activities (Ortega, N. and Werb, Z., J. Cell Sci. 115:4201-4214 (2002), Davis, G. E. et al., Am. J. Pathol. 156:1489-1498 (2000), O’Reilly, M. S. et al., Cell 88:277-285 (1997)). Similarly, as described in more detail below, fragments or composites of collagen-mimetic peptides (CMPs) of type I collagen have recently been studied for their usefulness in the treatment of diseases and medical disorders, both as the pharmaceutical active ingredient (API) itself and in the delivery of skin wound healing agents (see U.S. Patent Nos. 5,973,112, 7,122,521, 7,858,741, and U.S. Patent Publication No. US2007 / 0275897 A1. All of these disclosures are incorporated herein by reference in their entirety. See also, for example, Chattopadhyay, S. et al., J. Tissue Eng. Regen. Med. 10:1012-1020 (2012), Kumar, V. A. et al., Biomacromolecules 15:1484-1490 (2014)).

[0018] Collagen abnormalities are associated with a wide variety of human diseases, including eye diseases and disorders such as cataracts and glaucoma (Coudrillier, B., et al., PLoS ONE 10:e0131396 (2015), Huang, W. et al., Med. Sci. Monit. Basic Res. 19:237-240 (2013), Dua, H. S., et al., Br. J. Ophthalmol. 98:691-697 (2014)), arthritis, rheumatism, bone fragility, atherosclerosis, and cirrhosis. Collagen destruction is also associated with certain human and veterinary diseases, such as certain cancers (especially carcinomas of the luminal organs and certain sarcomas). See, for example, Lauer, J. L., and Fields, G. B., “Collagen in Cancer”, in The Tumor Microenvironment, New York: Springer, pp. 477-507 (2010). Collagen is also extremely important in wound healing and is known to be upregulated in epithelial wound areas where healing is taking place, including within the skin and within the cornea of the eye (see, for example, U.S. Patent Nos. 5,973,112 and 7,122,521, which are incorporated herein by reference in their entirety. Also see Chattopadhyay, S., et al., J. Tissue Eng. Regen. Med. 10:1012-1020 (2012), Chattopadhyay, S., et al., Org. Biomol. Chem. 10:5892-5897 (2012), Kumar, V. A., et al., Biomacromol. 15:1484-1490 (2014)). Indeed, collagen, collagen fragments, or specific mimetic peptides of native collagen have been reported to be promising in treating certain wounds and diseases in humans and animals, particularly skin wounds (see, for example, U.S. Patent Nos. 5,973,112, 7,122,521, 7,858,741, and U.S. Patent Publication No. US2007 / 0275897 A1. All of these are incorporated herein by reference in their entirety).See also Kumar, V.A. et al., Biomacromolecules 15:1484-1490 (2014). These collagen fragments or collagen-mimetic peptides are thought to be able to specifically target areas of collagen disruption associated with skin wounds by inserting into disrupted collagen and reforming the native type I collagen triple helix (see, for example, Chattopadhyay, S., et al., J. Tissue Eng. Regen. Med. 10:1012-1020 (2012), Chattopadhyay, S., et al., Org. Biomol. Chem. 10:5892-5897 (2012)). As a result, attempts have been made to use collagen as a vehicle for delivering specific drugs, with varying degrees of success (see, for example, B. An, et al., Adv. Drug Deliv. Rev. 97:69-84 (2016), V. Chak, et al., Intl. J. Pharm. Teaching and Practices 4:811 (2013)). Collagen-mimetic peptides have also been used for topical application to deliver a neuropeptide known as substance P, a conjugated therapeutic compound, to areas of skin wounds. Such CMP-substance P conjugates have been shown to accelerate wound healing in a mouse skin model (Chattopadhyay, S., et al., J. Tissue Eng. Regen. Med. 10:1012-1020 (2012)).Certain extracellular matrix (ECM) components containing collagen are also involved in maintaining the proper structure and function of the nervous system, particularly the peripheral nervous system, and disruption or damage to these ECM components often leads to neuronal disorders and / or death (see, for example, Koopmans G, Hasse B, Sinis N. The role of collagen in peripheral nerve repair (Chapter 19). International Review of Neurobiology. Volume 87: Academic Press, Elsevier; pp. 363-79 (2009), Gao X, et al., Rev. Neurosci. 24(4):443-53 (2013), Campbell IC et al., J. Biomech. Eng. 136(2):021005 (2014), Vecino E et al., J. Cytol. Histol. S3:007 (2015), Vecino E., and Kwok, J.C.F., “The Extracellular Matrix in the Nervous System: The Good and the Bad Aspects”, in Composition and Function of the Extracellular Matrix in the Human Body, F. Travascio, ed., Intech Open, ISBN 978-953-51-2416-0 (2016) (accessed November 8, 2019, http: / / dx.doi.org / 10.5772 / 62527)).

[0019] The treatment of diseases / disorders is expensive, difficult to deliver specifically, and can have adverse effects on sites distal to the intended site of action. For example, many pharmaceutical compositions, including antibiotics, small molecule therapeutics (e.g., anti-cancer compounds), and biologics (e.g., monoclonal antibody therapeutics), are administered parenterally in a non-targeted manner and must diffuse or otherwise reach the disease site before they can produce a therapeutic effect. This "shotgun approach" to such therapies necessarily requires higher dosages in human or veterinary animals than a therapeutic approach that enables controlled or programmable release at or near the disease site by delivering therapeutic compounds and compositions in a more targeted manner, resulting in longer treatment durations and potentially reduced patient compliance. In particular, eye diseases, disorders, and physical conditions, specifically those involving the cornea and / or sclera of the eye (referred to herein as "corneosclera"), have often proven difficult to treat and / or correct. For example, presbyopia is an eye disorder that is frequently associated with aging (Lafosse, E. et al., Cont. Lens Ant. Eye 43(2):103-114 (2020), Balgos, M. J. T. D et al., Taiwan J. Ophthalmol 8:121-140 (2018), Katz, J. A. et al., Clin. Ophthalmol. 15:2167-2178 (2021)) and is often treated by optical correction mechanically (e.g., with glasses or contact lenses) or by refractive surgery (e.g., by conductive keratoplasty, LASIK / LASEK surgery, laser refractive keratectomy, or lens implant).Myopia is an eye disorder found in all age groups, including both children (Hou, W. et al., Eye Contact Lens 44(4):248 - 259(2018), Lau, J.K. et al., Invest. Ophthalmol. 61(2):22(2020), Tideman, J.W.L. et al., Acta Ophthalmol. 96:301 - 309(2018)) and adults (Kim, H.K. et al., Int. J. Ophthalmol. 14(8):1231 - 1236(2021), Wang, B. et al., PLoS ONE 12(4):e0175913(2017), Pugazhendhi, S. et al., Clin. Ophthalmol. 14:853 - 873(2020)). It is treated with corrective lenses and / or pharmacologically, for example with atropine or pirenzepine (Gwiazda, J., Optom. Vis. Sci. 86(6):624 - 628(2009)) and other pharmacotherapeutic approaches (Wang, W.-Y. et al, Biomed. Pharmacother. 133:111092(2021)). Especially in children and the elderly, due to inconvenience and discomfort, etc., patient compliance with such corrective measures is often insufficient, and vision loss continues and may, in some cases, worsen.

[0020] In prior studies by some of the inventors herein, it has been demonstrated and / or suggested that certain CMP-containing formulations may be useful in the treatment of certain anterior segment eye diseases such as dry eye disease and other corneal diseases, disorders and injuries (see, e.g., U.S. Patent No. 10,632,168, Baratta, R.O. et al., Baratta et al., Front. Pharmacol. 12:705623 (2021), Baratta, R.O. et al., Surv. Ophthalmol. 67:60-67 (2022)), as well as certain posterior segment disorders and conditions such as glaucoma, macular degeneration, optic neuropathy, etc. (see, e.g., U.S. Patent No. 11,389,513, McGrady, N.R. et al., Front. Pharmacol. 12:764709 (2021), Ribeiro, M. et al., Int. J. Mol. Sci 23:2911 (2022), Ribeiro et al., Int. J. Mol. Sci. 23:7004 (2022)). The disclosure of each of these references is hereby incorporated herein by reference in its entirety. However, from this prior research, much remains unclear about the potential impact of CMP-containing formulations in the treatment and / or prevention of other eye diseases such as corneal-scleral disorders, diseases and conditions including, but not limited to, myopia, presbyopia and keratoconus. Most of these eye diseases require mechanical and / or surgical intervention, are often incomplete, uncomfortable or inconvenient for patients, and often require adjustment and / or re-intervention as the patient ages. SUMMARY OF THE INVENTION PROBLEM TO BE SOLVED BY THE INVENTION

[0021] Accordingly, there is a need in the art for formulations and methods of use that overcome many of the drawbacks in conventional treatments for certain eye diseases and disorders, particularly diseases, disorders and pathologies of the corneosclera, in human and veterinary animals. Such formulations and methods of use would enable the use of lower doses of drugs and more targeted delivery of drugs to the intended site of action, and would reduce treatment problems or delays resulting from patient non-compliance. Finally, there is a need in the art for methods of producing such compositions that meet the needs of the medical community and patient community in terms of reducing costs while maximizing treatment effectiveness.

Means for Solving the Problems

[0022] The inventors have inferred that conjugation of various therapeutic and / or diagnostic compounds with collagen or collagen-mimicking peptides would provide an elegant, rapid and reproducible approach that overcomes many of the above limitations in the treatment, diagnosis and drug delivery of specific physical diseases and disorders, since collagen breakdown is associated with various diseases and disorders in humans and other animals. Accordingly, the present invention provides compositions suitable for use in methods for the treatment and diagnosis of physical disorders and diseases, particularly diseases, disorders and pathologies of the corneosclera, and provides drug delivery systems, medical devices, and methods for their manufacture. Accordingly, the present invention meets the needs in the art as described above.

Effects of the Invention

[0023] In one aspect, the present invention provides a composition comprising one or more collagen mimetic peptides (CMPs), which in certain embodiments are conjugated to one or more therapeutic compounds and / or one or more diagnostic compounds, thereby forming CMP conjugates and compositions. Such CMPs and CMP conjugates, as well as compositions comprising such CMPs and / or CMP conjugates, are useful in the treatment, prevention, amelioration, and diagnosis of various diseases, disorders, and physical conditions in humans and veterinary animals. In certain embodiments of this aspect, the present invention provides therapeutic and diagnostic compositions useful for treating, preventing, ameliorating, or diagnosing specific diseases and disorders in humans and veterinary animals, comprising such CMPs and / or CMP conjugates, and one or more pharmaceutically acceptable carriers, excipients, or formulations, optionally comprising one or more additional therapeutic or diagnostic agents.

[0024] In another aspect, the present invention provides a method for treating, preventing, ameliorating, or diagnosing a disease or disorder in a human or veterinary animal suffering from or predisposed to a specific disease or disorder in humans and veterinary animals, by administering a conjugate and / or composition of the present invention. Diseases and disorders that are preferably treated, prevented, cured, ameliorated, or diagnosed in accordance with this aspect of the present invention include, but are not limited to, eye diseases or disorders, particularly corneal and scleral diseases, disorders, and conditions, including keratoconus, myopia, and presbyopia; skin diseases or disorders; cancer; gastrointestinal diseases or disorders; urogenital diseases or disorders; fibrotic diseases or disorders; cardiovascular diseases or disorders; bone diseases or disorders; and rheumatic diseases or disorders.

[0025] In yet another aspect, the present invention provides a medical device coated with or comprising one or more of the conjugates or compositions of the present invention. In a related aspect, the present invention provides a method of treating, curing, preventing, or ameliorating a disease or disorder in a human or veterinary animal, the method comprising implanting one or more of the medical devices of this aspect of the present invention into a human or veterinary animal under conditions such that the disease or disorder is treated, cured, prevented, or ameliorated.

[0026] In still other aspects, the present invention provides methods of manufacturing the compositions, conjugates, and medical devices of the present invention.

[0027] Other objects, advantages, and features of the present invention will be readily apparent to those skilled in the art upon consideration of the description, drawings, examples, and claims presented herein.

Brief Description of the Drawings

[0028]

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BEST MODE FOR CARRYING OUT THE INVENTION

[0029] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods and materials are described below.

[0030] According to a first aspect, the present invention provides a composition suitable for use as a medicament for treating or preventing such diseases, disorders, structural abnormalities or injuries in a human or veterinary animal in need of treatment or prevention of a disease, disorder, structural abnormality or injury. In certain embodiments, the composition provided by the present invention comprises (a) at least one CMP conjugated to at least one additional TC so as to form a conjugate of the collagen mimetic peptide (CMP) and the therapeutic compound (TC), and (b) one or more pharmaceutically suitable carriers. In a related aspect, the present invention provides a composition suitable for use in a diagnostic agent for performing in a human or veterinary animal in need thereof the diagnosis or detection of a disease, disorder, structural abnormality or injury. In certain embodiments, the composition provided by the present invention comprises (a) at least one CMP conjugated to at least one DC so as to form a conjugate of the collagen mimetic peptide (CMP) and the diagnostic compound or agent (DC), and (b) one or more pharmaceutically suitable carriers. In other related embodiments, the composition provided by the present invention comprises (a) at least one collagen mimetic peptide (CMP) and (b) at least one additional therapeutic compound, and the CMP and the at least one additional therapeutic compound are, optionally, mixed or "formulated" in a formulation together with one or more pharmaceutically suitable carriers. In similar embodiments, the composition provided by the present invention comprises (a) at least one collagen mimetic peptide (CMP) and (b) at least one diagnostic compound or agent (such as a compound or agent for labeling), and the CMP and the at least one diagnostic compound or agent are, optionally, mixed or "formulated" in a formulation together with one or more pharmaceutically suitable carriers for use in one or more diagnostic methods of the present invention.

[0031] In certain embodiments of the present invention, the collagen mimetic peptide has the sequence (Xaa - Yaa - Gly) nComprises, consists essentially of, or consists of an amino acid sequence that is a multiple repeat of a specific tripeptide having (SEQ ID NO: 417), wherein Xaa is independently selected from the group consisting of proline, 4S-hydroxyproline, fluoroproline, chloroproline, lysine, cysteine, and methionine, Yaa is independently selected from the group consisting of proline, 4R-hydroxyproline, fluoroproline, chloroproline, lysine, cysteine, and methionine, Gly is a glycine residue, and n is an integer in the range of 1 to 20, such as 3 to 15, 5 to 15, or 5 to 10, preferably 5, 6, 7, 8, 9, or 10.

[0032] In other embodiments, the present invention provides a collagen-mimetic peptide comprising, but not limited to, one or more alternative amino acids including alanine (Ala), glutamine (Gln), glutamic acid (Glu), asparagine (Asn), and aspartic acid (Asp) in place of at least one of the amino acids defined by the tripeptide shown in SEQ ID NO: 417.

[0033] In a particular embodiment of the present invention, the collagen-mimetic peptide is a 21-mer comprising the amino acid sequence of 7 repeats of the 3-amino acid sequence of proline-proline-glycine ((Pro-Pro-Gly)7), i.e., Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly (SEQ ID NO: 1), or comprises, consists essentially of, or consists of the corresponding amino acid sequence.

[0034] In certain other embodiments of the present invention, the collagen-mimicking peptide substitutes Pro1 of SEQ ID NO: 1 with hydroxyproline (Hyp), preferably a 4S-hydroxyproline residue, to form a 7-repeat sequence of 4S-hydroxyproline-proline-glycine ((Hyp-Pro-Gly)7), i.e., an amino acid sequence of Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly (SEQ ID NO: 2), and is a 21-mer containing 7 repeats of the 3-amino acid sequence, or contains an amino acid sequence corresponding thereto, or consists essentially of or consists of the same.

[0035] In certain other embodiments of the present invention, the collagen-mimicking peptide substitutes Pro2 of SEQ ID NO: 1 with Hyp, preferably a 4S-hydroxyproline residue, to form a 7-repeat sequence of 4S-hydroxyproline-proline-glycine ((Pro-Hyp-Gly)7), i.e., an amino acid sequence of Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly (SEQ ID NO: 3), and is a 21-mer containing 7 repeats of the 3-amino acid sequence, or contains an amino acid sequence corresponding thereto, or consists essentially of or consists of the same.

[0036] In certain other embodiments of the present invention, the collagen-mimicking peptide substitutes Pro1 of SEQ ID NO: 1 with fluoroproline (Flp) to form a 7-repeat sequence of fluoroproline-proline-glycine ((Flp-Pro-Gly)7), i.e., an amino acid sequence of Flp-Pro-Gly-Flp-Pro-Gly-Flp-Pro-Gly-Flp-Pro-Gly-Flp-Pro-Gly-Flp-Pro-Gly-Flp-Pro-Gly (SEQ ID NO: 4), and is a 21-mer containing 7 repeats of the 3-amino acid sequence, or contains an amino acid sequence corresponding thereto, or consists essentially of or consists of the same.

[0037] In certain other embodiments of the present invention, the collagen-mimicking peptide has the proline 2 of SEQ ID NO: 1 replaced with Flp, resulting in a 7-repeat sequence of proline-fluoroproline-glycine ((Pro-Flp-Gly)7), i.e., an amino acid sequence of Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly (SEQ ID NO: 5), and is a 21-mer containing 7 repeats of the 3-amino acid sequence, or contains an amino acid sequence corresponding thereto, or consists essentially of or consists of the same.

[0038] In certain other embodiments of the present invention, the collagen-mimicking peptide has the proline 1 of SEQ ID NO: 1 replaced with fluoroproline (Flp) and the proline 2 of SEQ ID NO: 1 replaced with Hyp, resulting in a 7-repeat sequence of fluoroproline-hydroxyproline-glycine ((Flp-Hyp-Gly)7), i.e., an amino acid sequence of Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly (SEQ ID NO: 6), and is a 21-mer containing 7 repeats of the 3-amino acid sequence, or contains an amino acid sequence corresponding thereto, or consists essentially of or consists of the same.

[0039] In the CMP containing Flp, the Flp moiety can be in the 4-cis or 4-trans configuration, preferably in the 4-cis configuration.

[0040] In certain other embodiments of the present invention, the collagen-mimicking peptide has the proline 1 of SEQ ID NO: 1 replaced with chloroproline (Clp) to have the sequence of a 7-repeat of chloroproline-proline-glycine ((Clp-Pro-Gly)7), i.e., the amino acid sequence of Clp-Pro-Gly-Clp-Pro-Gly-Clp-Pro-Gly-Clp-Pro-Gly-Clp-Pro-Gly-Clp-Pro-Gly-Clp-Pro-Gly (SEQ ID NO: 7), and is a 21-mer containing a 7-repeat of a 3-amino acid sequence, or can contain, consist of, or have an amino acid sequence corresponding thereto.

[0041] In certain other embodiments of the present invention, the collagen-mimicking peptide has the proline 2 of SEQ ID NO: 1 replaced with chloroproline (Clp) to have the sequence of a 7-repeat of proline-chloroproline-glycine ((Pro-Clp-Gly)7), i.e., the amino acid sequence of Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly (SEQ ID NO: 8), and is a 21-mer containing a 7-repeat of a 3-amino acid sequence, or can contain, consist of, or have an amino acid sequence corresponding thereto.

[0042] In certain other embodiments of the present invention, the collagen-mimicking peptide has the proline 1 of SEQ ID NO: 1 replaced with Clp and the proline 2 of SEQ ID NO: 1 replaced with Hyp to have the sequence of a 7-repeat of chloroproline-hydroxyproline-glycine ((Clp-Hyp-Gly)7), i.e., the amino acid sequence of Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Clp-Gly (SEQ ID NO: 9), and is a 21-mer containing a 7-repeat of a 3-amino acid sequence, or can contain, essentially consist of, or consist of an amino acid sequence corresponding thereto.

[0043] In the CMP containing Clp, the Clp moiety can be in a 4-cis or 4-trans configuration, preferably in a 4-cis configuration.

[0044] In certain other embodiments of the present invention, the collagen mimetic peptide, at any one of SEQ ID NOs: 1-9, substitutes at least one proline residue of SEQ ID NO: 1, at least one hydroxyproline residue of SEQ ID NOs: 2-3 and 6, at least one fluoroproline residue of SEQ ID NOs: 4-6, or at least one chloroproline residue of SEQ ID NOs: 7-9 with at least one cysteine (Cys) residue, and is, for example, a 21-mer having the following sequence or includes, consists of, or can have an amino acid sequence corresponding thereto:

[0045] Pro-Pro-Gly-Pro-Pro-Gly-Cys-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly (SEQ ID NO: 10),

[0046] Hyp-Pro-Gly-Hyp-Pro-Gly-Cys-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly (SEQ ID NO: 11),

[0047] Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Cys-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly (SEQ ID NO: 12),

[0048] Pro-Flp-Gly-Pro-Flp-Gly-Pro-Cys-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly (SEQ ID NO: 13),

[0049] Pro-Clp-Gly-Pro-Clp-Gly-Pro-Cys-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly (SEQ ID NO: 14),

[0050] Cys-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly (SEQ ID NO: 15),

[0051] Pro-Cys-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly (SEQ ID NO: 16),

[0052] Pro-Pro-Gly-Cys-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly (SEQ ID NO: 17),

[0053] Pro-Pro-Gly-Pro-Cys-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly (SEQ ID NO: 18),

[0054] Pro-Pro-Gly-Pro-Pro-Gly-Pro-Cys-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly (SEQ ID NO: 19),

[0055] Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Cys-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly (SEQ ID NO: 20),

[0056] Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Cys-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly (SEQ ID NO: 21),

[0057] Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Cys-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly (SEQ ID NO: 22),

[0058] Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Cys-Gly-Pro-Pro-Gly-Pro-Pro-Gly (SEQ ID NO: 23),

[0059] Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Cys-Pro-Gly-Pro-Pro-Gly (SEQ ID NO: 24),

[0060] Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Cys-Gly-Cys-Pro-Gly (SEQ ID NO: 25),

[0061] Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Cys-Pro-Gly (SEQ ID NO: 26),

[0062] Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Cys-Gly (SEQ ID NO: 27),

[0063] Cys-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly (SEQ ID NO: 28),

[0064] Hyp-Cys-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly (SEQ ID NO: 29),

[0065] Hyp-Pro-Gly-Cys-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly (SEQ ID NO: 30),

[0066] Hyp-Pro-Gly-Hyp-Cys-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly (SEQ ID NO: 31),

[0067] Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Cys-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly (SEQ ID NO: 32),

[0068] Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Cys-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly (SEQ ID NO: 33),

[0069] Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Cys-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly (SEQ ID NO: 34),

[0070] Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Cys-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly (SEQ ID NO: 35),

[0071] Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Cys-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly (SEQ ID NO: 36),

[0072] Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Cys-Pro-Gly-Hyp-Pro-Gly (SEQ ID NO: 37),

[0073] Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Cys-Gly-Hyp-Pro-Gly (SEQ ID NO: 38),

[0074] Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Cys-Pro-Gly (SEQ ID NO: 39),

[0075] Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Cys-Gly (SEQ ID NO: 40),

[0076] Cys-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly (SEQ ID NO: 41),

[0077] Pro-Cys-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly (SEQ ID NO: 42),

[0078] Pro-Hyp-Gly-Cys-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly (SEQ ID NO: 43),

[0079] Pro-Hyp-Gly-Pro-Cys-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly (SEQ ID NO: 44),

[0080] Pro-Hyp-Gly-Pro-Hyp-Gly-Cys-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly (SEQ ID NO: 45),

[0081] Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Cys-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly (SEQ ID NO: 46),

[0082] Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Cys-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly (SEQ ID NO: 47),

[0083] Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Cys-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly (SEQ ID NO: 48),

[0084] Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Cys-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly (SEQ ID NO: 49),

[0085] Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Cys-Hyp-Gly-Pro-Hyp-Gly (SEQ ID NO: 50),

[0086] Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Cys-Gly-Pro-Hyp-Gly (SEQ ID NO: 51),

[0087] Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Cys-Hyp-Gly (SEQ ID NO: 52),

[0088] Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Cys-Gly (SEQ ID NO: 53),

[0089] Cys-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly (SEQ ID NO: 54),

[0090] Pro-Cys-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly (SEQ ID NO: 55),

[0091] Pro-Flp-Gly-Cys-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly (SEQ ID NO: 56),

[0092] Pro-Flp-Gly-Pro-Cys-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly (SEQ ID NO: 57),

[0093] Pro-Flp-Gly-Pro-Flp-Gly-Cys-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly (SEQ ID NO: 58),

[0094] Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Cys-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly (SEQ ID NO: 59),

[0095] Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Cys-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly (SEQ ID NO: 60),

[0096] Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Cys-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly (SEQ ID NO: 61),

[0097] Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Cys-Gly-Pro-Flp-Gly-Pro-Flp-Gly (SEQ ID NO: 62),

[0098] Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Cys-Flp-Gly-Pro-Flp-Gly (SEQ ID NO: 63),

[0099] Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Cys-Gly-Pro-Flp-Gly (SEQ ID NO: 64),

[0100] Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Cys-Flp-Gly (SEQ ID NO: 65),

[0101] Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Cys-Gly (SEQ ID NO: 66),

[0102] Cys-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly (SEQ ID NO: 67),

[0103] Pro-Cys-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly (SEQ ID NO: 68),

[0104] Pro-Flp-Gly-Cys-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly (SEQ ID NO: 69),

[0105] Pro-Flp-Gly-Pro-Cys-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly (SEQ ID NO: 70),

[0106] Pro-Flp-Gly-Pro-Flp-Gly-Cys-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly (SEQ ID NO: 71),

[0107] Pro-Flp-Gly-Pro-Flp-Gly-Pro-Cys-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly (SEQ ID NO: 72),

[0108] Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Cys-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly (SEQ ID NO: 73),

[0109] Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Cys-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly (SEQ ID NO: 74),

[0110] Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Cys-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly (SEQ ID NO: 75),

[0111] Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Cys-Gly-Pro-Flp-Gly-Pro-Flp-Gly (SEQ ID NO: 76),

[0112] Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Cys-Flp-Gly-Pro-Flp-Gly (SEQ ID NO: 77),

[0113] Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Cys-Gly-Pro-Flp-Gly (SEQ ID NO: 78),

[0114] Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Cys-Flp-Gly (SEQ ID NO: 79),

[0115] Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Cys-Gly (SEQ ID NO: 80),

[0116] Cys-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly (SEQ ID NO: 81),

[0117] Flp-Cys-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly (SEQ ID NO: 82),

[0118] Flp-Hyp-Gly-Cys-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly (SEQ ID NO: 83),

[0119] Flp-Hyp-Gly-Flp-Cys-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly (SEQ ID NO: 84),

[0120] Flp-Hyp-Gly-Flp-Hyp-Gly-Cys-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly (SEQ ID NO: 85),

[0121] Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Cys-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly (SEQ ID NO: 86),

[0122] Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Cys-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly (SEQ ID NO: 87),

[0123] Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Cys-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly (SEQ ID NO: 88),

[0124] Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Cys-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly (SEQ ID NO: 89),

[0125] Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Cys-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly (SEQ ID NO: 90),

[0126] Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Cys-Hyp-Gly-Flp-Hyp-Gly (SEQ ID NO: 91),

[0127] Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Cys-Gly-Flp-Hyp-Gly (SEQ ID NO: 92),

[0128] Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Cys-Hyp-Gly (SEQ ID NO: 93),

[0129] Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Cys-Gly (SEQ ID NO: 94),

[0130] Cys-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly (SEQ ID NO: 95),

[0131] Pro-Cys-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly (SEQ ID NO: 96),

[0132] Pro-Clp-Gly-Cys-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly (SEQ ID NO: 97),

[0133] Pro-Clp-Gly-Pro-Cys-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly (SEQ ID NO: 98),

[0134] Pro-Clp-Gly-Pro-Clp-Gly-Cys-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly (SEQ ID NO: 99),

[0135] Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Cys-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly (SEQ ID NO: 100),

[0136] Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Cys-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly (SEQ ID NO: 101),

[0137] Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Cys-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly (SEQ ID NO: 102),

[0138] Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Cys-Gly-Pro-Clp-Gly-Pro-Clp-Gly (SEQ ID NO: 103),

[0139] Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Cys-Clp-Gly-Pro-Clp-Gly (SEQ ID NO: 104),

[0140] Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Cys-Gly-Pro-Clp-Gly (SEQ ID NO: 105),

[0141] Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Cys-Clp-Gly (SEQ ID NO: 106),

[0142] Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Cys-Gly (SEQ ID NO: 107),

[0143] Cys-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly (SEQ ID NO: 108),

[0144] Pro-Cys-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly (SEQ ID NO: 109),

[0145] Pro-Clp-Gly-Cys-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly (SEQ ID NO: 110),

[0146] Pro-Clp-Gly-Pro-Cys-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly (SEQ ID NO: 111),

[0147] Pro-Clp-Gly-Pro-Clp-Gly-Cys-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly (SEQ ID NO: 112),

[0148] Pro-Clp-Gly-Pro-Clp-Gly-Pro-Cys-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly (SEQ ID NO: 113),

[0149] Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Cys-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly (SEQ ID NO: 114),

[0150] Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Cys-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly (SEQ ID NO: 115),

[0151] Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Cys-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly (SEQ ID NO: 116),

[0152] Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Cys-Gly-Pro-Clp-Gly-Pro-Clp-Gly (SEQ ID NO: 117),

[0153] Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Cys-Clp-Gly-Pro-Clp-Gly (SEQ ID NO: 118),

[0154] Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Cys-Gly-Pro-Clp-Gly (SEQ ID NO: 119),

[0155] Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Cys-Clp-Gly (SEQ ID NO: 120),

[0156] Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Cys-Gly (SEQ ID NO: 121),

[0157] Cys-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly (SEQ ID NO: 122),

[0158] Clp-Cys-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly (SEQ ID NO: 123),

[0159] Clp-Hyp-Gly-Cys-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly (SEQ ID NO: 124),

[0160] Clp-Hyp-Gly-Clp-Cys-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly (SEQ ID NO: 125),

[0161] Clp-Hyp-Gly-Clp-Hyp-Gly-Cys-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly (SEQ ID NO: 126),

[0162] Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Cys-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly (SEQ ID NO: 127),

[0163] Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Cys-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly (SEQ ID NO: 128),

[0164] Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Cys-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly (SEQ ID NO: 129),

[0165] Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Cys-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly (SEQ ID NO: 130),

[0166] Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Cys-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly (SEQ ID NO: 131),

[0167] Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Cys-Hyp-Gly-Clp-Hyp-Gly (SEQ ID NO: 132),

[0168] Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Cys-Gly-Clp-Hyp-Gly (SEQ ID NO: 133),

[0169] Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Cys-Hyp-Gly (SEQ ID NO: 134), and

[0170] Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Cys-Gly (SEQ ID NO: 135).

[0171] In certain other embodiments of the present invention, the collagen-mimetic peptide, in any one of SEQ ID NOs: 1-9, has at least one proline residue of SEQ ID NO: 1, at least one hydroxyproline residue of SEQ ID NOs: 2-3 and 6, at least one fluoroproline residue of SEQ ID NOs: 4-6, or at least one chloroproline residue of SEQ ID NOs: 7-9 replaced with at least one methionine (Met) residue, for example, is a 21-mer having the following sequence or includes, consists of, or can have the corresponding amino acid sequence:

[0172] Pro-Pro-Gly-Pro-Pro-Gly-Met-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly (SEQ ID NO: 136),

[0173] Hyp-Pro-Gly-Hyp-Pro-Gly-Met-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly (SEQ ID NO: 137),

[0174] Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Met-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly (SEQ ID NO: 138),

[0175] Pro-Flp-Gly-Pro-Flp-Gly-Pro-Met-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly (SEQ ID NO: 139),

[0176] Pro-Clp-Gly-Pro-Clp-Gly-Pro-Met-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly (SEQ ID NO: 140),

[0177] Met-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly (SEQ ID NO: 141),

[0178] Pro-Met-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly (SEQ ID NO: 142),

[0179] Pro-Pro-Gly-Met-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly (SEQ ID NO: 143),

[0180] Pro-Pro-Gly-Pro-Met-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly (SEQ ID NO: 144),

[0181] Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Met-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly (SEQ ID NO: 145),

[0182] Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Met-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly (SEQ ID NO: 146),

[0183] Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Met-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly (SEQ ID NO: 147),

[0184] Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Met-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly (SEQ ID NO: 148),

[0185] Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Met-Gly-Pro-Pro-Gly-Pro-Pro-Gly (SEQ ID NO: 149),

[0186] Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Met-Pro-Gly-Pro-Pro-Gly (SEQ ID NO: 150),

[0187] Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Met-Gly-Pro-Pro-Gly (SEQ ID NO: 151),

[0188] Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Met-Pro-Gly (SEQ ID NO: 152),

[0189] Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Met-Gly (SEQ ID NO: 153),

[0190] Met-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly (SEQ ID NO: 154),

[0191] Hyp-Met-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly (SEQ ID NO: 155),

[0192] Hyp-Pro-Gly-Met-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly (SEQ ID NO: 156),

[0193] Hyp-Pro-Gly-Hyp-Met-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly (SEQ ID NO: 157),

[0194] Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Met-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly (SEQ ID NO: 158),

[0195] Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Met-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly (SEQ ID NO: 159),

[0196] Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Met-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly (SEQ ID NO: 160),

[0197] Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Met-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly (SEQ ID NO: 161),

[0198] Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Met-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly (SEQ ID NO: 162),

[0199] Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Met-Pro-Gly-Hyp-Pro-Gly (SEQ ID NO: 163),

[0200] Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Met-Gly-Hyp-Pro-Gly (SEQ ID NO: 164),

[0201] Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Met-Pro-Gly (SEQ ID NO: 165),

[0202] Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Met-Gly (SEQ ID NO: 166),

[0203] Met-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly (SEQ ID NO: 167),

[0204] Pro-Met-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly (SEQ ID NO: 168),

[0205] Pro-Hyp-Gly-Met-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly (SEQ ID NO: 169),

[0206] Pro-Hyp-Gly-Pro-Met-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly (SEQ ID NO: 170),

[0207] Pro-Hyp-Gly-Pro-Hyp-Gly-Met-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly (SEQ ID NO: 171),

[0208] Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Met-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly (SEQ ID NO: 172),

[0209] Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Met-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly (SEQ ID NO: 173),

[0210] Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Met-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly (SEQ ID NO: 174),

[0211] Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Met-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly (SEQ ID NO: 175),

[0212] Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Met-Hyp-Gly-Pro-Hyp-Gly (SEQ ID NO: 176),

[0213] Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Met-Gly-Pro-Hyp-Gly (SEQ ID NO: 177),

[0214] Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Met-Hyp-Gly (SEQ ID NO: 178),

[0215] Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Met-Gly (SEQ ID NO: 179),

[0216] Met-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly (SEQ ID NO: 180),

[0217] Pro-Met-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly (SEQ ID NO: 181),

[0218] Pro-Flp-Gly-Met-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly (SEQ ID NO: 182),

[0219] Pro-Flp-Gly-Pro-Met-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly (SEQ ID NO: 183),

[0220] Pro-Flp-Gly-Pro-Flp-Gly-Met-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly (SEQ ID NO: 184),

[0221] Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Met-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly (SEQ ID NO: 185),

[0222] Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Met-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly (SEQ ID NO: 186),

[0223] Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Met-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly (SEQ ID NO: 187),

[0224] Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Met-Gly-Pro-Flp-Gly-Pro-Flp-Gly (SEQ ID NO: 188),

[0225] Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Met-Flp-Gly-Pro-Flp-Gly (SEQ ID NO: 189),

[0226] Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Met-Gly-Pro-Flp-Gly (SEQ ID NO: 190),

[0227] Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Met-Flp-Gly (SEQ ID NO: 191),

[0228] Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Met-Gly (SEQ ID NO: 192),

[0229] Met-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly (SEQ ID NO: 193),

[0230] Pro-Met-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly (SEQ ID NO: 194),

[0231] Pro-Flp-Gly-Met-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly (SEQ ID NO: 195),

[0232] Pro-Flp-Gly-Pro-Met-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly (SEQ ID NO: 196),

[0233] Pro-Flp-Gly-Pro-Flp-Gly-Met-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly (SEQ ID NO: 197),

[0234] Pro-Flp-Gly-Pro-Flp-Gly-Pro-Met-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly (SEQ ID NO: 198),

[0235] Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Met-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly (SEQ ID NO: 199),

[0236] Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Met-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly (SEQ ID NO: 200),

[0237] Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Met-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly (SEQ ID NO: 201),

[0238] Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Met-Gly-Pro-Flp-Gly-Pro-Flp-Gly (SEQ ID NO: 202),

[0239] Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Met-Flp-Gly-Pro-Flp-Gly (SEQ ID NO: 203),

[0240] Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Met-Gly-Pro-Flp-Gly (SEQ ID NO: 204),

[0241] Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Met-Flp-Gly (SEQ ID NO: 205),

[0242] Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Met-Gly (SEQ ID NO: 206),

[0243] Met-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly (SEQ ID NO: 207),

[0244] Flp-Met-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly (SEQ ID NO: 208),

[0245] Flp-Hyp-Gly-Met-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly (SEQ ID NO: 209),

[0246] Flp-Hyp-Gly-Flp-Met-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly (SEQ ID NO: 210),

[0247] Flp-Hyp-Gly-Flp-Hyp-Gly-Met-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly (SEQ ID NO: 211),

[0248] Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Met-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly (SEQ ID NO: 212),

[0249] Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Met-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly (SEQ ID NO: 213),

[0250] Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Met-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly (SEQ ID NO: 214),

[0251] Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Met-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly (SEQ ID NO: 215),

[0252] Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Met-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly (SEQ ID NO: 216),

[0253] Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Met-Hyp-Gly-Flp-Hyp-Gly (SEQ ID NO: 217),

[0254] Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Met-Gly-Flp-Hyp-Gly (SEQ ID NO: 218),

[0255] Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Met-Hyp-Gly (SEQ ID NO: 219),

[0256] Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Met-Gly (SEQ ID NO: 220),

[0257] Met-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly (SEQ ID NO: 221),

[0258] Pro-Met-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly (SEQ ID NO: 222),

[0259] Pro-Clp-Gly-Met-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly (SEQ ID NO: 223),

[0260] Pro-Clp-Gly-Pro-Met-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly (SEQ ID NO: 224),

[0261] Pro-Clp-Gly-Pro-Clp-Gly-Met-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly (SEQ ID NO: 225),

[0262] Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Met-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly (SEQ ID NO: 226),

[0263] Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Met-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly (SEQ ID NO: 227),

[0264] Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Met-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly (SEQ ID NO: 228),

[0265] Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Met-Gly-Pro-Clp-Gly-Pro-Clp-Gly (SEQ ID NO: 229),

[0266] Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Met-Clp-Gly-Pro-Clp-Gly (SEQ ID NO: 230),

[0267] Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Met-Gly-Pro-Clp-Gly (SEQ ID NO: 231),

[0268] Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Met-Clp-Gly (SEQ ID NO: 232),

[0269] Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Met-Gly (SEQ ID NO: 233),

[0270] Met-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly (SEQ ID NO: 234),

[0271] Pro-Met-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly (SEQ ID NO: 235),

[0272] Pro-Clp-Gly-Met-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly (SEQ ID NO: 236),

[0273] Pro-Clp-Gly-Pro-Met-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly (SEQ ID NO: 237),

[0274] Pro-Clp-Gly-Pro-Clp-Gly-Met-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly (SEQ ID NO: 238),

[0275] Pro-Clp-Gly-Pro-Clp-Gly-Pro-Met-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly (SEQ ID NO: 239),

[0276] Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Met-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly (SEQ ID NO: 240),

[0277] Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Met-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly (SEQ ID NO: 241),

[0278] Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Met-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly (SEQ ID NO: 242),

[0279] Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Met-Gly-Pro-Clp-Gly-Pro-Clp-Gly (SEQ ID NO: 243),

[0280] Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Met-Clp-Gly-Pro-Clp-Gly (SEQ ID NO: 244),

[0281] Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Met-Gly-Pro-Clp-Gly (SEQ ID NO: 245),

[0282] Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Met-Clp-Gly (SEQ ID NO: 246),

[0283] Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Met-Gly (SEQ ID NO: 247),

[0284] Met-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly (SEQ ID NO: 248),

[0285] Clp-Met-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly (SEQ ID NO: 249),

[0286] Clp-Hyp-Gly-Met-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly (SEQ ID NO: 250),

[0287] Clp-Hyp-Gly-Clp-Met-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly (SEQ ID NO: 251),

[0288] Clp-Hyp-Gly-Clp-Hyp-Gly-Met-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly (SEQ ID NO: 252),

[0289] Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Met-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly (SEQ ID NO: 253),

[0290] Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Met-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly (SEQ ID NO: 254),

[0291] Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Met-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly (SEQ ID NO: 255),

[0292] Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Met-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly (SEQ ID NO: 256),

[0293] Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Met-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly (SEQ ID NO: 257),

[0294] Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Met-Hyp-Gly-Clp-Hyp-Gly (SEQ ID NO: 258),

[0295] Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Met-Gly-Clp-Hyp-Gly (SEQ ID NO: 259),

[0296] Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Met-Hyp-Gly (SEQ ID NO: 260), and

[0297] Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Met-Gly (SEQ ID NO: 261).

[0298] In certain other embodiments of the present invention, the collagen-mimetic peptide, in any one of SEQ ID NOs: 1-9, substitutes at least one proline residue of SEQ ID NO: 1, at least one hydroxyproline residue of SEQ ID NOs: 2-3 and 6, at least one fluoroproline residue of SEQ ID NOs: 4-6, or at least one chloroproline residue of SEQ ID NOs: 7-9 with at least one lysine (Lys) residue, for example, it can be a 21-mer having the following sequence or include, consist of, or have an amino acid sequence corresponding thereto:

[0299] Pro-Pro-Gly-Pro-Pro-Gly-Lys-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly (SEQ ID NO: 262),

[0300] Hyp-Pro-Gly-Hyp-Pro-Gly-Lys-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly (SEQ ID NO: 263),

[0301] Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Lys-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly (SEQ ID NO: 264),

[0302] Pro-Flp-Gly-Pro-Flp-Gly-Pro-Lys-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly (SEQ ID NO: 265),

[0303] Pro-Clp-Gly-Pro-Clp-Gly-Pro-Lys-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly (SEQ ID NO: 266),

[0304] Lys-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly (SEQ ID NO: 267),

[0305] Pro-Lys-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly (SEQ ID NO: 268),

[0306] Pro-Pro-Gly-Lys-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly (SEQ ID NO: 269),

[0307] Pro-Pro-Gly-Pro-Lys-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly (SEQ ID NO: 270),

[0308] Pro-Pro-Gly-Pro-Pro-Gly-Pro-Lys-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly (SEQ ID NO: 271),

[0309] Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Lys-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly (SEQ ID NO: 272),

[0310] Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Lys-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly (SEQ ID NO: 273),

[0311] Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Lys-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly (SEQ ID NO: 274),

[0312] Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Lys-Gly-Pro-Pro-Gly-Pro-Pro-Gly (SEQ ID NO: 275),

[0313] Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Lys-Pro-Gly-Pro-Pro-Gly (SEQ ID NO: 276),

[0314] Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Lys-Gly-Pro-Pro-Gly (SEQ ID NO: 277),

[0315] Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Lys-Pro-Gly (SEQ ID NO: 278),

[0316] Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Lys-Gly (SEQ ID NO: 279),

[0317] Lys-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly (SEQ ID NO: 280),

[0318] Hyp-Lys-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly (SEQ ID NO: 281),

[0319] Hyp-Pro-Gly-Lys-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly (SEQ ID NO: 282),

[0320] Hyp-Pro-Gly-Hyp-Lys-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly (SEQ ID NO: 283),

[0321] Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Lys-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly (SEQ ID NO: 284),

[0322] Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Lys-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly (SEQ ID NO: 285),

[0323] Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Lys-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly (SEQ ID NO: 286),

[0324] Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Lys-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly (SEQ ID NO: 287),

[0325] Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Lys-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly (SEQ ID NO: 288),

[0326] Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Lys-Pro-Gly-Hyp-Pro-Gly (SEQ ID NO: 289),

[0327] Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Lys-Gly-Hyp-Pro-Gly (SEQ ID NO: 290),

[0328] Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Lys-Pro-Gly (SEQ ID NO: 291),

[0329] Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Lys-Gly (SEQ ID NO: 292),

[0330] Lys-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly (SEQ ID NO: 293),

[0331] Pro-Lys-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly (SEQ ID NO: 294),

[0332] Pro-Hyp-Gly-Lys-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly (SEQ ID NO: 295),

[0333] Pro-Hyp-Gly-Pro-Lys-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly (SEQ ID NO: 296),

[0334] Pro-Hyp-Gly-Pro-Hyp-Gly-Lys-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly (SEQ ID NO: 297),

[0335] Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Lys-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly (SEQ ID NO: 298),

[0336] Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Lys-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly (SEQ ID NO: 299),

[0337] Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Lys-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly (SEQ ID NO: 300),

[0338] Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Lys-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly (SEQ ID NO: 301),

[0339] Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Lys-Hyp-Gly-Pro-Hyp-Gly (SEQ ID NO: 302),

[0340] Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Lys-Gly-Pro-Hyp-Gly (SEQ ID NO: 303),

[0341] Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Lys-Hyp-Gly (SEQ ID NO: 304),

[0342] Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Lys-Gly (SEQ ID NO: 305),

[0343] Lys-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly (SEQ ID NO: 306),

[0344] Pro-Lys-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly (SEQ ID NO: 307),

[0345] Pro-Flp-Gly-Lys-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly (SEQ ID NO: 308),

[0346] Pro-Flp-Gly-Pro-Lys-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly (SEQ ID NO: 309),

[0347] Pro-Flp-Gly-Pro-Flp-Gly-Lys-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly (SEQ ID NO: 310),

[0348] Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Lys-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly (SEQ ID NO: 311),

[0349] Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Lys-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly (SEQ ID NO: 312),

[0350] Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Lys-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly (SEQ ID NO: 313),

[0351] Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Lys-Gly-Pro-Flp-Gly-Pro-Flp-Gly (SEQ ID NO: 314),

[0352] Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Lys-Flp-Gly-Pro-Flp-Gly (SEQ ID NO: 315),

[0353] Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Lys-Gly-Pro-Flp-Gly (SEQ ID NO: 316),

[0354] Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Lys-Flp-Gly (SEQ ID NO: 317),

[0355] Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Lys-Gly (SEQ ID NO: 318),

[0356] Lys-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly (SEQ ID NO: 319),

[0357] Pro-Lys-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly (SEQ ID NO: 320),

[0358] Pro-Flp-Gly-Lys-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly (SEQ ID NO: 321),

[0359] Pro-Flp-Gly-Pro-Lys-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly (SEQ ID NO: 322),

[0360] Pro-Flp-Gly-Pro-Flp-Gly-Lys-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly (SEQ ID NO: 323),

[0361] Pro-Flp-Gly-Pro-Flp-Gly-Pro-Lys-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly (SEQ ID NO: 324),

[0362] Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Lys-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly (SEQ ID NO: 325),

[0363] Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Lys-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly (SEQ ID NO: 326),

[0364] Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Lys-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly (SEQ ID NO: 327),

[0365] Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Lys-Gly-Pro-Flp-Gly-Pro-Flp-Gly (SEQ ID NO: 328),

[0366] Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Lys-Flp-Gly-Pro-Flp-Gly (SEQ ID NO: 329),

[0367] Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Lys-Gly-Pro-Flp-Gly (SEQ ID NO: 330),

[0368] Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Lys-Flp-Gly (SEQ ID NO: 331),

[0369] Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Lys-Gly (SEQ ID NO: 332),

[0370] Lys-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly (SEQ ID NO: 333),

[0371] Flp-Lys-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly (SEQ ID NO: 334),

[0372] Flp-Hyp-Gly-Lys-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly (SEQ ID NO: 335),

[0373] Flp-Hyp-Gly-Flp-Lys-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly (SEQ ID NO: 336),

[0374] Flp-Hyp-Gly-Flp-Hyp-Gly-Lys-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly (SEQ ID NO: 337),

[0375] Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Lys-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly (SEQ ID NO: 338),

[0376] Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Lys-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly (SEQ ID NO: 339),

[0377] Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Lys-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly (SEQ ID NO: 340),

[0378] Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Lys-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly (SEQ ID NO: 341),

[0379] Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Lys-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly (SEQ ID NO: 342),

[0380] Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Lys-Hyp-Gly-Flp-Hyp-Gly (SEQ ID NO: 343),

[0381] Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Lys-Gly-Flp-Hyp-Gly (SEQ ID NO: 344),

[0382] Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Lys-Hyp-Gly (SEQ ID NO: 345),

[0383] Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Lys-Gly (SEQ ID NO: 346),

[0384] Lys-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly (SEQ ID NO: 347),

[0385] Pro-Lys-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly (SEQ ID NO: 348),

[0386] Pro-Clp-Gly-Lys-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly (SEQ ID NO: 349),

[0387] Pro-Clp-Gly-Pro-Lys-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly (SEQ ID NO: 350),

[0388] Pro-Clp-Gly-Pro-Clp-Gly-Lys-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly (SEQ ID NO: 351),

[0389] Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Lys-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly (SEQ ID NO: 352),

[0390] Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Lys-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly (SEQ ID NO: 353),

[0391] Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Lys-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly (SEQ ID NO: 354),

[0392] Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Lys-Gly-Pro-Clp-Gly-Pro-Clp-Gly (SEQ ID NO: 355),

[0393] Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Lys-Clp-Gly-Pro-Clp-Gly (SEQ ID NO: 356),

[0394] Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Lys-Gly-Pro-Clp-Gly (SEQ ID NO: 357),

[0395] Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Lys-Clp-Gly (SEQ ID NO: 358),

[0396] Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Lys-Gly (SEQ ID NO: 359),

[0397] Lys-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly (SEQ ID NO: 360),

[0398] Pro-Lys-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly (SEQ ID NO: 361),

[0399] Pro-Clp-Gly-Lys-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly (SEQ ID NO: 362),

[0400] Pro-Clp-Gly-Pro-Lys-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly (SEQ ID NO: 363),

[0401] Pro-Clp-Gly-Pro-Clp-Gly-Lys-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly (SEQ ID NO: 364),

[0402] Pro-Clp-Gly-Pro-Clp-Gly-Pro-Lys-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly (SEQ ID NO: 365),

[0403] Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Lys-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly (SEQ ID NO: 366),

[0404] Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Lys-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly (SEQ ID NO: 367),

[0405] Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Lys-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly (SEQ ID NO: 368),

[0406] Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Lys-Gly-Pro-Clp-Gly-Pro-Clp-Gly (SEQ ID NO: 369),

[0407] Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Lys-Clp-Gly-Pro-Clp-Gly (SEQ ID NO: 370),

[0408] Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Lys-Gly-Pro-Clp-Gly (SEQ ID NO: 371),

[0409] Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Lys-Clp-Gly (SEQ ID NO: 372),

[0410] Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Lys-Gly (SEQ ID NO: 373),

[0411] Lys-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly (SEQ ID NO: 374),

[0412] Clp-Lys-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly (SEQ ID NO: 375),

[0413] Clp-Hyp-Gly-Lys-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly (SEQ ID NO: 376),

[0414] Clp-Hyp-Gly-Clp-Lys-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly (SEQ ID NO: 377),

[0415] Clp-Hyp-Gly-Clp-Hyp-Gly-Lys-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly (SEQ ID NO: 378),

[0416] Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Lys-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly (SEQ ID NO: 379),

[0417] Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Lys-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly (SEQ ID NO: 380),

[0418] Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Lys-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly (SEQ ID NO: 381),

[0419] Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Lys-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly (SEQ ID NO: 382),

[0420] Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Lys-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly (SEQ ID NO: 383),

[0421] Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Lys-Hyp-Gly-Clp-Hyp-Gly (SEQ ID NO: 384),

[0422] Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Lys-Gly-Clp-Hyp-Gly (SEQ ID NO: 385),

[0423] Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Lys-Hyp-Gly (SEQ ID NO: 386), and

[0424] Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Lys-Gly (SEQ ID NO: 387).

[0425] Another suitable CMP used in accordance with the present invention is a CMP having or comprising the sequence Hyp-Flp-Gly-Hyp-Flp-Gly-Hyp-Flp-Gly-Hyp-Flp-Gly-Hyp-Flp-Gly-Flp-Gly-Hyp-Flp-Gly (SEQ ID NO: 388).

[0426] Other suitable CMPs used in accordance with the present invention include CMPs having or comprising the sequences Gly3-(Pro-Hyp-Gly)6 (SEQ ID NO: 397), Gly3-(Pro-Flp-Gly)6 (SEQ ID NO: 398), Gly3-(Pro-Hyp-Gly)7 (SEQ ID NO: 399), Gly3-(Pro-Flp-Gly)7 (SEQ ID NO: 400), Gly3-(Pro-Hyp-Gly)8 (SEQ ID NO: 401), Gly3-(Pro-Flp-Gly)8 (SEQ ID NO: 402), Gly3-(Pro-Hyp-Gly)9 (SEQ ID NO: 403), Gly3-(Pro-Flp-Gly)9 (SEQ ID NO: 404), (Pro-Hyp-Gly)6-Tyr (SEQ ID NO: 405), (Pro-Flp-Gly)6-Tyr (SEQ ID NO: 406), (Pro-Hyp-Gly)7-Tyr (SEQ ID NO: 407), (Pro-Flp-Gly)7-Tyr (SEQ ID NO: 408), (Pro-Hyp-Gly)8-Tyr (SEQ ID NO: 409), (Pro-Flp-Gly)8-Tyr (SEQ ID NO: 410), Cys-(Pro-Hyp-Gly)3 (SEQ ID NO: 411), Cys-(Pro-Flp-Gly)3 (SEQ ID NO: 412), Cys-(Pro-Hyp-Gly)5 (SEQ ID NO: 413), Cys-(Pro-Flp-Gly)5 (SEQ ID NO: 414), Cys-(Pro-Hyp-Gly)7 (SEQ ID NO: 415), and Cys-(Pro-Flp-Gly)7 (SEQ ID NO: 416), as well as other similar CMPs that may be suitable for use as agents for the modification of collagen in vitro and in vivo in therapeutic and / or diagnostic methods (see, e.g., U.S. Patent Nos. 8,283,414, 8,883,964, 10,632,168, and 11,389,513. The entire disclosures of all of these are hereby incorporated by reference in their entirety).

[0427] In certain other embodiments of the present invention, the collagen mimetic peptide has the amino acid sequence of a 21-mer that contains 7 repeats of a 3-amino acid sequence, i.e., a sequence of Pro-Ala-Gly repeats ((Pro-Ala-Gly)7), namely Pro-Ala-Gly-Pro-Ala-Gly-Pro-Ala-Gly-Pro-Ala-Gly-Pro-Ala-Gly-Pro-Ala-Gly-Pro-Ala-Gly (SEQ ID NO: 418), in which Pro2 of SEQ ID NO: 1 is replaced with Ala, or comprises, consists essentially of, or consists of an amino acid sequence corresponding thereto. In other embodiments, the collagen mimetic peptide has the amino acid sequence of a 21-mer that contains 7 repeats of a 3-amino acid sequence, i.e., a sequence of Pro-Ala-Gly repeats ((Pro-Ala-Gly)7), namely Hyp-Ala-Gly-Hyp-Ala-Gly-Hyp-Ala-Gly-Hyp-Ala-Gly-Hyp-Ala-Gly-Hyp-Ala-Gly-Hyp-Ala-Gly (SEQ ID NO: 419) and Flp-Ala-Gly-Flp-Ala-Gly-Flp-Ala-Gly-Flp-Ala-Gly-Flp-Ala-Gly-Flp-Ala-Gly-Flp-Ala-Gly (SEQ ID NO: 420), in which Pro1 of SEQ ID NO: 418 is replaced with either Hyp or Flp, or comprises, consists essentially of, or consists of an amino acid sequence corresponding thereto.

[0428] Other suitable CMPs used in accordance with the present invention are CMPs having or containing the sequences (Pro-Gly-Glu)7 (SEQ ID NO: 421), (Pro-Gly-Gln)7 (SEQ ID NO: 422), (Pro-Gly-Pro)7 (SEQ ID NO: 423), (Hyp-Gly-Glu)7 (SEQ ID NO: 424), (Hyp-Gly-Gln)7 (SEQ ID NO: 425), (Flp-Gly-Glu)7 (SEQ ID NO: 426), (Flp-Gly-Gln)7 (SEQ ID NO: 427), (Hyp-Gly-Pro)7 (SEQ ID NO: 428), (Hyp-Gly-Gln)7 (SEQ ID NO: 429), (Hyp-Gly-Glu)7 (SEQ ID NO: 430), (Pro-Gly-Asp)7 (SEQ ID NO: 431), (Pro-Gly-Asn)7 (SEQ ID NO: 432), (Lys-Gly-Gln)7 (SEQ ID NO: 433), (Lys-Gly-Glu)7 (SEQ ID NO: 434), (Hyp-Ala-Gly)7 (SEQ ID NO: 435), (Flp-Ala-Gly)7 (SEQ ID NO: 436), (Hyp-Gly-Glu)7 (SEQ ID NO: 437), (Hyp-Gly-Gln)7 (SEQ ID NO: 438), (Flp-Gly-Glu)7 (SEQ ID NO: 439), (Flp-Gly-Gln)7 (SEQ ID NO: 440), (Hyp-Gly-Asp)7 (SEQ ID NO: 441), (Hyp-Gly-Asn)7 (SEQ ID NO: 442), (Flp-Gly-Asp)7 (SEQ ID NO: 443), (Flp-Gly-Asn)7 (SEQ ID NO: 444), (Hyp-Gly-Pro)7 (SEQ ID NO: 445), (Flp-Gly-Pro)7 (SEQ ID NO: 446), (Pro-Gly-Hyp)7 (SEQ ID NO: 447), (Flp-Gly-Hyp)7 (SEQ ID NO: 448), (Hyp-Gly-Hyp)7 (SEQ ID NO: 449), (Hyp-Gly-Flp)7 (SEQ ID NO: 450), (Pro-Gly-Flp)7 (SEQ ID NO: 451), (Flp-Gly-Flp)7 (SEQ ID NO: 452), and other similar CMPs containing one or more additional or substituted amino acids, including one or more cysteine residues, one or more methionine residues, and / or one or more lysine residues inserted or substituted at positions according to the positions defined by SEQ ID NOs: 10 to 135 for cysteine, SEQ ID NOs: 136 to 251 for methionine, and SEQ ID NOs: 262 to 387 for lysine within the aforementioned CMP sequences.

[0429] In certain other embodiments, any of the aforementioned CMPs may optionally have one or more cysteine residues, one or more methionine residues, and / or one or more lysine residues attached to either or both of the N-terminus and C-terminus of the amino acid sequence. Non-limiting examples of such CMPs include the following:

[0430] Those with a cysteine residue attached to the N-terminus of SEQ ID NO: 1, i.e., Cys-((Pro-Pro-Gly)7) (SEQ ID NO: 453), those attached to the C-terminus, i.e., (Pro-Pro-Gly)7-Cys (SEQ ID NO: 454), or those attached to both termini, i.e., Cys-((Pro-Pro-Gly)7)-Cys (SEQ ID NO: 455),

[0431] Those with a cysteine residue attached to the N-terminus of SEQ ID NO: 6, i.e., Cys-((Flp-Hyp-Gly)7) (SEQ ID NO: 456), those attached to the C-terminus, i.e., (Flp-Hyp-Gly)7-Cys (SEQ ID NO: 457), or those attached to both termini, i.e., Cys-((Flp-Hyp-Gly)7)-Cys (SEQ ID NO: 458),

[0432] Those with a methionine residue attached to the N-terminus of SEQ ID NO: 1, i.e., Met-((Pro-Pro-Gly)7) (SEQ ID NO: 459), those attached to the C-terminus, i.e., (Pro-Pro-Gly)7-Met (SEQ ID NO: 460), or those attached to both termini, i.e., Met-((Pro-Pro-Gly)7)-Met (SEQ ID NO: 461),

[0433] Those with a methionine residue attached to the N-terminus of SEQ ID NO: 6, i.e., Met-((Flp-Hyp-Gly)7) (SEQ ID NO: 462), those attached to the C-terminus, i.e., (Flp-Hyp-Gly)7-Met (SEQ ID NO: 463), or those attached to both termini, i.e., Met-((Flp-Hyp-Gly)7)-Met (SEQ ID NO: 464),

[0434] Those in which a lysine residue is bound to SEQ ID NO: 1 at the N-terminus, i.e., Lys-((Pro-Pro-Gly)7) (SEQ ID NO: 465), those bound at the C-terminus, i.e., (Pro-Pro-Gly)7-Lys (SEQ ID NO: 466), or those bound at both termini, i.e., Lys-((Pro-Pro-Gly)7)-Lys (SEQ ID NO: 467),

[0435] Those in which a lysine residue is bound to SEQ ID NO: 6 at the N-terminus, i.e., Lys-((Flp-Hyp-Gly)7) (SEQ ID NO: 468), those bound at the C-terminus, i.e., (Flp-Hyp-Gly)7-Lys (SEQ ID NO: 469), or those bound at both termini, i.e., Lys-((Flp-Hyp-Gly)7)-Lys (SEQ ID NO: 470).

[0436] In other embodiments, the sequences defined by SEQ ID NOs: 453 to 458 may have one or more methionine or lysine residues substituted for one or more of the cysteine residues therein. In other embodiments, the sequences defined by SEQ ID NOs: 459 to 464 may have one or more cysteine or lysine residues substituted for one or more of the methionine residues therein. In other embodiments, the sequences defined by SEQ ID NOs: 465 to 470 may have one or more methionine or cysteine residues substituted for one or more of the lysine residues therein.

[0437] Of course, based on the knowledge in the art and the teachings in this specification, it will be understood by those skilled in the art that such a CMP may contain two or more cysteine, methionine, and / or lysine residues, and in any of the aforementioned CMP sequences containing at least one proline, at least one hydroxyproline, at least one fluoroproline, and / or at least one chloroproline residue, at least one additional cysteine, methionine, and / or lysine residue, or any combination thereof, may replace at least one proline residue, at least one hydroxyproline residue, at least one fluoroproline residue, and / or at least one chloroproline residue. Also, based on the teachings in this specification and information readily available in the art, other combinations of amino acid substitutions are possible and will be understood by those skilled in the art to be within the scope of the present invention.

[0438] The CMP described herein is suitable for various purposes. For example, as described in more detail elsewhere herein, the CMP is directly applied or introduced into the body of a human or veterinary animal, particularly at sites where there is or may be collagen destruction, where the CMP described herein localizes directly to the site of collagen destruction, anneals to the disrupted collagen chains, and stabilizes the collagen structure to resist further destruction, and in some cases, by reforming the native collagen triple helix at the site of collagen destruction, it can be used in various therapeutic or prophylactic applications. Such applications are useful for promoting the repair and strengthening of disrupted collagen in injuries or sites where there is a risk of injury or destruction involving the skin, tendons, ligaments, cartilage, bone, and other collagen-containing structures and organs, such as in wounds, diseases, structural abnormalities or disorders (e.g., scarring, formation of wrinkles, etc.). The CMP described herein is also useful for treating or preventing specific diseases, disorders, and structural abnormalities or injuries in humans and veterinary animals by providing a biocompatible coating to specific medical devices, particularly in the body regions where such devices are used when such diseases, disorders, and structural abnormalities or injuries involve the destruction of collagen and / or collagen-containing structures, to promote the healing of injuries and disorders. The CMP described herein is also particularly useful for providing a unique delivery vehicle suitable for delivering various therapeutic compounds, compositions, and medicaments to sites of diseases, disorders, and structural abnormalities or injuries in humans and veterinary animals for treating, preventing, or ameliorating diseases, disorders, medical conditions, and structural abnormalities or injuries where collagen destruction is the cause of, associated with, or co-localized with the site of the disease, disorder, or injury. In further embodiments, the CMP described herein is useful for providing a diagnostic agent suitable for diagnosing or detecting diseases, disorders, structural abnormalities or injuries in humans and veterinary animals.In certain such embodiments, the CMP may be formulated with one or more suitable diagnostic compounds, agents, labels, etc., or may be conjugated directly or indirectly thereto (see, e.g., U.S. Pat. Nos. 8,283,414, 8,883, 10,632,168, 11,389,513, 11,426,440, and 11,433,112. All of these disclosures are hereby incorporated by reference in their entirety). Other suitable uses of the CMP described herein and used in particular embodiments of the present invention will be readily apparent to those skilled in the art based on the disclosure herein and information readily available in the art.

[0439] In certain embodiments, the CMPs described herein are in a form suitable for introduction or implantation into a human or animal for therapeutic, prophylactic, or diagnostic uses such as the uses described herein and other uses that would be apparent to one of ordinary skill in the relevant art. For example, using methods such as those described in U.S. Patent Nos. 6,197,934, 6,448,378, and 9,289,396 (the entire disclosures of all of which are incorporated herein by reference in their entirety), films, wafers, membranes, spheres, nanoparticles, or gels can be formed from a solution of one or more of the CMPs described herein. Alternatively, the films, wafers, membranes, spheres, nanoparticles, or gels can be formed from other materials such as atelocollagen (see U.S. Patent Nos. 6,197,934, 6,448,378, and 9,289,396), copolymers of poly(lactic acid) and poly(glycolic acid) (PLGA) (see Bala, I., et al., Crit. Rev. Ther. Drug Carrier Syst. 21(5):387-422 (2004)), and other materials known to those of ordinary skill in the art (see, for example, Kumar, V., et al., eds., “Polymer Gels: Perspectives and Applications”, ISBN 978-981-10-6079-3, Singapore: Springer (2018)), and one or more of the CMPs can be suitably incorporated into such films, wafers, membranes, spheres, nanoparticles, gels, etc. during their formation by including the CMPs in the solution at concentrations such as about 1% - 99%, about 2% - 95%, about 3% - 90%, about 4% - 90%, about 5% - 90%, about 10% - 90%, about 15% - 90%, about 20% - 90%, about 25% - 90%, about 25% - 85%, about 25% - 75%, about 25% - 50%, about 35% - 50%, etc. Other suitable amounts or concentrations of the CMPs described herein that can be suitably included in the solution during the formation of films, wafers, membranes, spheres, nanoparticles, gels, etc. will be readily apparent from the teachings herein and information readily available to those of ordinary skill in the art.In certain such embodiments, one or more of the therapeutic compounds described herein, and / or one or more of the CMP-TC conjugates described herein, can be suitably incorporated into a solution that serves as a source for forming films, wafers, membranes, spheres, nanoparticles, gels, and the like. Alternatively, in related aspects, one or more films, wafers, membranes, spheres, nanoparticles, gels, and the like can be formed as described above and then immersed in a solution containing one or more of the CMPs or CMP-TC conjugates described herein in a suitable amount or concentration (e.g., as described herein), particularly a buffered aqueous solution, and then the film, wafer, membrane, etc. can be dried before use in a therapeutic, prophylactic, or diagnostic method as described herein, thereby being treated or coated with one or more of the CMPs and / or CMP-TC conjugates described herein.

[0440] Binding / Conjugation of CMP

[0441] In certain embodiments of the invention, the CMPs described herein are suitably bound or conjugated to one or more therapeutic or diagnostic compounds to produce CMP conjugate compounds. In such embodiments of the invention, the conjugate compounds of CMP-therapeutic compounds or CMP-diagnostic compounds can then be introduced into the body of a human or veterinary animal in a method of treating and / or preventing and / or diagnosing a particular disease, disorder, and structural abnormality in a human or veterinary animal suffering therefrom. Thus, in certain embodiments, the invention also provides for the use of the CMPs described herein that are bound or conjugated to one or more therapeutic compounds to produce conjugate CMPs, compositions comprising such conjugate CMPs (which may optionally contain one or more additional therapeutic or pharmaceutically active ingredients), methods of producing such conjugates, and methods of using such conjugates and compositions in the treatment, prevention, and diagnosis of various diseases, disorders, and medical conditions in humans and veterinary animals.

[0442] According to this aspect of the present invention, a conjugate of a CMP and at least one therapeutic compound (which may be referred to herein as a "CMP-TC conjugate") comprises at least one CMP as described herein bound to at least one therapeutic compound so as to form a CMP-TC conjugate. CMPs preferably used in such an aspect of the present invention include CMPs having an amino acid sequence corresponding to any one of SEQ ID NOs: 1 to 387, specifically, SEQ ID NOs: 1 to 14, 66 to 94, 107 to 135, 136 to 140, 192 to 220, 233 to 261, 260 to 264, 280, 281, 293, 294, 306, 307, 318 to 346, 347, 348, 359 to 388, and 397 to 416, more specifically, CMPs having an amino acid sequence corresponding to any one of SEQ ID NOs: 10 to 27, 81 to 94, 122 to 135, 207 to 220, 248 to 261, 333 to 346, 374 to 388, and 397 to 416, including any of those described herein. Other suitable CMP sequences will be readily apparent to those skilled in the art based on the teachings contained herein. For example, a CMP having at least one, and in some cases more than one, cysteine, methionine or lysine residue substituted for at least one, and in some cases more than one, proline, hydroxyproline, fluoroproline or chloroproline residue in SEQ ID NOs: 1 to 9 is particularly suitable for use in producing the CMP-TC conjugates provided and used by the present invention. Examples of such suitable CMPs include those having an amino acid sequence corresponding to SEQ ID NOs: 10 to 27, 81 to 94, 122 to 135, 207 to 220, 248 to 261, 333 to 346, 374 to 388, 397 to 416, and 453 to 470.

[0443] In other such embodiments, one or more peptide bonds may be used to attach CMP to one or more other peptides or proteins at the C-terminal and / or N-terminal of CMP to produce a CMP-TC conjugate, which is a peptide or protein containing CMP. Any peptide or protein, whether or not the peptide or protein itself is a therapeutic peptide or protein, may be advantageously bound or conjugated to CMP via one or more peptide bonds, resulting in a combination of CMP and the peptide or protein, and a novel compound having biological activity resulting from the combination of the structures and functions of CMP and the conjugated protein or peptide can be obtained. For example, CMP conjugated to the Fc or Fab fraction of an antibody (e.g., a polyclonal or monoclonal antibody) can exhibit the biological activities of both CMP and the antibody fraction, making it a unique compound with multiple functionalities for use in various therapeutic and / or diagnostic methods such as those described elsewhere in this specification. The multiple functionalities can improve the therapeutic and / or diagnostic utility of the compound far beyond that of CMP or the antibody fragment alone, or enable the therapeutic or diagnostic agent to be directly delivered to specific cell, tissue, or organ types when introduced into the body of an animal, particularly a human or veterinary animal. Other peptides or proteins that are therapeutically and / or diagnostically useful alone can also be advantageously bound or conjugated to CMP according to this aspect of the invention. Such peptides or proteins include, but are not limited to, those of specific pharmacological classes including antithrombin, fibrinolytic peptides / proteins, enzymes, anti-neoplastic agents, hormones, fertility agents, immunosuppressive agents (including anti-inflammatory agents), bone-related peptides / proteins, anti-diabetic agents, and antibodies.More specific examples of peptides / proteins included in these classes are those approved by the US Food and Drug Administration as therapeutic agents and / or diagnostic agents, for example, those listed in the Real-Time THPdb database of FDA-approved therapeutic peptides and proteins (available at https: / / webs.iiitd.edu.in / raghava / thpdb / category.php), first published in Usmani, S.S. et al., PLoS ONE 12(7):e0181748 (2017), https: / / doi.org / 10.1371 / journal.pone.0181748, and these databases and published literature are incorporated herein by reference in their entirety. Other suitable peptides and proteins and fragments thereof that can be advantageously conjugated or linked to the CMPs described herein will be apparent to those skilled in the art in view of the teachings herein and information readily available in the relevant art.

[0444] The methods for preparing CMP and CMP-TC described herein and provided and used in the present invention will be apparent to those skilled in the art based on the teachings herein and information readily available in the art. For example, CMP can be synthesized using standard protein / peptide synthesis techniques such as those described in U.S. Patent Nos. 5,973,112, 7,122,521, and 7,858,741, and U.S. Patent Publication No. US2007 / 0275897 A1 (the entire disclosures of all of these are incorporated herein by reference in their entirety). The synthesis of CMP can also be accomplished, for example, by purchasing custom synthesized CMP commercially produced by Bachem (Torrance, CA, USA) and RS Synthesis (Louisville, KY, USA). In other embodiments, the synthesis of CMP can be accomplished using gene engineering of CMP and recombinant expression from prokaryotic or eukaryotic expression systems (see, for example, Buechter, D.D., et al., J. Biol. Chem. 278(1):645-650 (2003)).

[0445] When synthesizing the peptides described herein, in certain embodiments, particularly when hydroxyproline, fluoroproline, or chloroproline is used, a specific stereochemistry is preferably used for the amino acid substitution. That is:

[0446] (1) When hydroxyproline is substituted in place of proline at the Xaa position of the Xaa-Yaa-Gly trimer described above, in certain embodiments, hydroxyproline has (2R,4S) stereochemistry, or cis or trans stereochemistry, preferably cis stereochemistry,

[0447] (2) When hydroxyproline is substituted in place of proline at the Yaa position of the Xaa-Yaa-Gly trimer described above, in certain embodiments, hydroxyproline has (2R,4S) stereochemistry, or cis or trans stereochemistry, preferably cis stereochemistry,

[0448] (3) When fluoroproline is substituted for the proline at the Yaa position of the above Xaa-Yaa-Gly trimer, in certain embodiments, hydroxyproline has (2R,4S) stereochemistry, or cis or trans stereochemistry, preferably cis stereochemistry,

[0449] (4) When chloroproline is substituted for the proline at the Yaa position of the above Xaa-Yaa-Gly trimer, in certain embodiments, hydroxyproline has (2R,4S) stereochemistry, or cis or trans stereochemistry, preferably cis stereochemistry.

[0450] Other suitable stereochemistries can be determined empirically without undue experimentation and will be readily apparent to those skilled in the art. As noted above, certain CMPs provided and used in accordance with the present invention can contain one or more additional substitutions, such as one or more cysteine residues and / or one or more methionine residues, in place of one or more prolines in a given CMP multimer. Such substitutions are preferably accomplished by adding these residues to the growing CMP peptide chain during a synthetic process using standard peptide synthesis methods such as those described elsewhere herein and known in the art.

[0451] Once the CMPs are prepared, they are preferably used in producing the CMP-TCs of the present invention, i.e., the therapeutic or diagnostic compositions of the present invention, by binding one or more therapeutic compounds to the CMPs. In certain embodiments, the CMP-TCs of the present invention are prepared by a method comprising: (a) preparing a collagen mimetic peptide having an amino acid sequence corresponding to any one of SEQ ID NOs: 1-470, specifically a CMP having an amino acid sequence corresponding to any one of SEQ ID NOs: 1-14, 66-94, 107-135, 136-140, 192-220, 233-261, 260-264, 280, 281, 293, 294, 306, 307, 318-346, 347, 348, 359-388, 397-416, and 453-470, more specifically a CMP having an amino acid sequence corresponding to SEQ ID NOs: 10-27, 81-94, 122-135, 207-220, 248-261, 333-346, 374-388, 397-416, and 453-470; (b) preparing at least one therapeutic or diagnostic compound suitable for conjugation to the CMP; and (c) binding the therapeutic or diagnostic compound directly or indirectly to the CMP. In some cases, particularly when the therapeutic compound is a small peptide biological compound, for example, the therapeutic compound can be directly bound to the CMP by peptide bond by simply extending the peptide synthesis beyond the carboxy terminus of the CMP and binding the amino-terminal amino acid of the therapeutic compound to the carboxy-terminal amino acid of the CMP by a peptide bond. An example of such a CMP-TC is a peptide conjugate in which a wound healing peptide known as substance P having the amino acid sequence Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met (SEQ ID NO: 471) is bound to the CMPs described herein. Examples of such conjugates include, for example, the following:

[0452] Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met (SEQ ID NO: 472),

[0453] Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met (SEQ ID NO: 473),

[0454] Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met (SEQ ID NO: 474),

[0455] Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met (SEQ ID NO: 475),

[0456] Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met (SEQ ID NO: 476),

[0457] Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met (SEQ ID NO: 477), and

[0458] Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met (SEQ ID NO: 478).

[0459] In another method of the present invention, one or more therapeutic or diagnostic compounds are suitably conjugated or attached to the CMP by covalent bonds other than peptide bonds (see, for example, U.S. Patent Nos. 3,283,414 and 3,883,964, which are incorporated herein by reference in their entirety). For example, a therapeutic compound can be directly attached to the cysteine or methionine residue of the CMP described herein by covalently bonding the hydroxyl or amino group of an amino acid residue (e.g., a lysine residue) of the therapeutic or diagnostic compound (if it is a biomolecule) to the sulfhydryl group of the cysteine or methionine residue of the CMP. Alternatively, if the CMP does not contain cysteine or methionine residues, one or more therapeutic or diagnostic compounds can be attached or conjugated to the CMP by a reaction between the hydroxyl or amino group of the CMP and the sulfhydryl group of an amino acid residue (e.g., a cysteine or methionine residue) of the therapeutic or diagnostic compound (if it is a biomolecule). In yet another alternative conjugation method, for example, NHS ester conjugation (see, for example, Mattson, G., et al., Molec. Biol. Rep. 17:167-183 (1993), Grabarek, Z. and Gergely, J., Anal. Biochem. 185:131-135 (1990), Staros, J.V. et al., Anal. Biochem. 156:220-2 (1986), Timkovich, R., Anal. Biochem. 79:135-43 (1977)) can be used to covalently attach a therapeutic compound to the amino group of lysine, thereby directly attaching the therapeutic compound to the lysine residue of the CMP described herein. Such direct covalent bonds or conjugations between the CMP and the therapeutic / diagnostic compound can be accomplished using standard reaction techniques known to those of ordinary skill in the field of organic chemistry.

[0460] In other embodiments, particularly where the therapeutic or diagnostic compound is not a biologic such as a low molecular weight organic or inorganic therapeutic or diagnostic compound (and thus does not have a peptide structure or amino acid residues with groups suitable for binding to cysteine, methionine, lysine, or other residues of the CMP), at least one therapeutic or diagnostic compound is indirectly bound to the collagen-mimetic peptide through the use of a binding means. In such embodiments, the binding means has two bindable ends, one of which binds to the sulfhydryl group of a cysteine or methionine residue or the amino group of a lysine residue of the CMP, and the other of which binds to a hydroxyl or amino group of the therapeutic or diagnostic compound. For example, in certain such embodiments, the binding means comprises at least one polymer chain having a first end and a second end, the first end of the polymer chain binding to the sulfhydryl group of a cysteine or methionine residue or the amino group of a lysine residue of the collagen-mimetic peptide, and the opposite or second end of the polymer chain binding to an amino or hydroxyl group of the therapeutic compound. In embodiments where the therapeutic or diagnostic compound is a biologic not suitable for direct binding via peptide synthesis described elsewhere herein, the second end of the binding means can be bound to the amino group of an amino acid residue such as a lysine residue of the biologic therapeutic or diagnostic compound. Such suitable binding means are well known to those of skill in the art. For example, one binding means suitable for use in accordance with this aspect of the invention includes a portion that is a polymer chain having a sulfhydryl-binding group such as maleimide at one end (specifically the CMP-binding end) and an amino-binding group such as N-hydroxysuccinimide at the other end (specifically the end that binds to the therapeutic or diagnostic compound).In certain such embodiments, the polymer chain is a linear polyethylene glycol chain comprising at least 4 ethylene glycol monomers, e.g., 4 to 50 ethylene glycol monomers, 10 to 40 ethylene glycol monomers, 15 to 30 ethylene glycol monomers, 15 to 25 ethylene glycol monomers, 20 to 25 ethylene glycol monomers, particularly 4, 6, 8, 12, 20, 22, 23, 24 or 25 ethylene glycol monomers. Such binding means suitable for attaching one or more therapeutic or diagnostic compounds to the CMP by the methods described herein are commercially available, e.g., from Thermo Fisher Scientific (Waltham, MA) (e.g., SM(PEG)6, SM(PEG)8, SM(PEG)12 and SM(PEG)24). By adjusting the length of the polymer chain, the in vivo bioavailability and persistence of the therapeutic or diagnostic compound can be modulated. The use of longer polymer chains, e.g., polymers containing 24 ethylene glycol monomers, increases the bioavailability rate of the compound when CMP-TC is introduced into the body of a human or veterinary animal, and the use of shorter polymer chains, e.g., polymers containing 6 ethylene glycol monomers, decreases the bioavailability rate of the therapeutic or diagnostic compound and thus increases its persistence (i.e., in other words, results in its delayed or sustained release). Other conjugates using linear or star-shaped PEG moieties that can be suitably prepared using the CMP of the present invention and used in the therapeutic and diagnostic methods of the present invention are disclosed in U.S. Patent Nos. 8,283,414 and 8,883,964, which are hereby incorporated by reference in their entirety. Thus, according to certain such aspects of the present invention, at least one therapeutic compound comprises at least one reactive hydroxyl group that can be crosslinked to a collagen mimetic peptide using a polymer linker.

[0461] Other indirect binding methods for conjugating one or more therapeutic or diagnostic compounds to or onto the CMP are also preferably used in accordance with the present invention. For example, at least one therapeutic or diagnostic compound can be encapsulated in at least one nanoparticle that is bound to a collagen mimetic peptide via a binding means such as those described herein. Alternatively, the collagen mimetic peptide may preferably include at least one biotin moiety, the therapeutic molecule may preferably include at least one avidin or streptavidin moiety, and the biotin moiety of the collagen mimetic peptide binds to the avidin or streptavidin moiety of the therapeutic or diagnostic compound, thereby binding the collagen mimetic peptide to the therapeutic or diagnostic compound. Of course, alternative measures are also suitable for use in which the collagen mimetic peptide may preferably include at least one avidin or streptavidin moiety, the therapeutic or diagnostic compound may preferably include at least one biotin moiety, and the biotin moiety of at least one therapeutic or diagnostic compound binds to the avidin or streptavidin moiety of the collagen mimetic peptide, thereby binding the collagen mimetic peptide to the therapeutic compound.

[0462] Accordingly, according to certain embodiments of the present invention, a therapeutic or diagnostic compound can be preferably directly bound to the CMP described herein. In other embodiments of the present invention, one or more therapeutic or diagnostic compounds can be indirectly bound to the CMP described herein, for example, by use of a spacer, linker, or bridge moiety. It should be understood that whether one or more therapeutic compounds bind directly or indirectly to the CMP, such binding produces a conjugate of the CMP and one or more therapeutic compounds that can be defined herein as a CMP-TC conjugate.

[0463] Suitable therapeutic or diagnostic compounds for conjugating or conjugating to CMP for producing CMP-TC of the present invention include any compounds that have been shown to have specific therapeutic or prophylactic properties against one or more diseases, disorders, physical conditions or diseases when introduced into a human or veterinary animal suffering from or predisposed to such diseases, disorders, physical conditions or diseases. As long as the therapeutic or diagnostic compound can be conjugated or bound to at least one CMP according to the teachings herein, any therapeutic or diagnostic compound may be used in the conjugates, compositions and methods of the present invention. Such suitable therapeutic compounds can be biological or non-biological (e.g., so-called "small molecule") therapeutic compounds. Compounds suitable for use include steroid anti-inflammatory drugs (e.g., prednisolone or a pharmaceutically acceptable salt thereof, such as prednisolone acetate), non-steroidal anti-inflammatory drugs (e.g., acetylsalicylic acid, acetaminophen, ibuprofen, naproxen, nepafenac, bromfenac, diclofenac, flurbiprofen, ketoprofen, ketorolac, and indene derivatives (e.g., indomethacin, sulindac (Clinoril), etc.; for other indene derivatives suitably used as active pharmaceutical ingredients, see, for example, U.S. Patent No. 7,601,874, which is incorporated herein by reference in its entirety), and their pharmaceutically acceptable salts, esters and derivatives), local anesthetics (e.g., tetracaine, lidocaine, oxybuprocaine, propacaine, etc.), vitamins or vitamin derivatives or vitamin precursors (e.g., retinol, tretinoin, retinal, carotenes and other retinoids and retinoid derivatives or precursors; folic acid; α-tocopherol; calciferol; phylloquinone, menadione and other vitamin K forms, precursors or derivatives, ascorbic acid, etc.), therapeutic enzymes or therapeutic fragments thereof (e.g., collagenase and serine proteases, or therapeutically effective fragments thereof), antibiotics (e.g., aminoglycoside antibiotics (e.g., gentamicin, tobramycin, paromomycin, kanamycin, neomycin and amikacin, and their pharmaceutically acceptable salts or esters,For example, tobramycin sulfate), fluoroquinolone antibiotics (e.g., moxifloxacin, gatifloxacin, levofloxacin, gemifloxacin, ciprofloxacin, norfloxacin, and ofloxacin, and their pharmaceutically acceptable salts, esters, or derivatives, e.g., moxifloxacin hydrochloride, ciprofloxacin hydrochloride, and gatifloxacin hydrochloride), sulfonamide antibiotics (e.g., sulfacetamide, sulfadiazine, sulfadimidine, sulfafurazole (sulfisoxazole), sulfisomidine (sulfaisodimidine), sulfadoxine, sulfamethoxazole, sulfamoxole, sulfanitran, sulfadimethoxine, sulfamethoxypyridazine, sulfamethoxydiazine, sulfamethopyrazine, and sulfathiazole, and their pharmaceutically acceptable salts, esters, or derivatives), β-lactam antibiotics (e.g., penicillin or its derivatives (e.g., penicillin G, penicillin V, benzylpenicillin, and phenoxymethylpenicillin), dicloxacillin, flucloxacillin, oxacillin, nafcillin, amoxicillin, ampicillin, ticarcillin, piperacillin, ritipenem, carbapenems (e.g., ertapenem, doripenem, imipenem, and meropenem, and their pharmaceutically acceptable salts, esters, or derivatives), cephems (e.g., cefazolin, cephalexin, cefadroxil, cefapirin, cefaclor, cefotetan, cefoxitin, cefprozil, cefuroxime axetil, ceftriaxone, ceftazidime, cefoperazone, cefdinir, cefcapene, cefdaloxime, ceftizoxime, cefmenoxime, cefotaxime, cefpiramide, cefpodoxime, ceftibuten, cefditoren, cefepime, ceftaroline fosamil, ceftolozane, ceftolozane / tazobactam, ceftiofur, cefquinome, and cefovecin, and their pharmaceutically acceptable salts, esters, or derivatives), monobactams (e.g., aztreonam or its pharmaceutically acceptable salts, esters, or derivatives) and β-lactamase inhibitors (e.g., sulbactam, tazobactam, clavulanic acid, and avibactam, and their pharmaceutically acceptable salts,esters or derivatives)) or cyclic peptide antibiotics (e.g., cyclosporine), therapeutic monoclonal antibodies or their therapeutic fragments (e.g., adalimumab, alizumab, atezolizumab, atorizumab, bevacizumab, canakinumab, catumaxomab, certolizumab, cetuximab, crizanlizumab, edrecolomab, efalizumab, fontolizumab, gilotrif, golimumab, infliximab, labetuzumab, MABp1 (Xilonix™), natalizumab, nimotuzumab, nivolumab, oregovomab, panitumumab, pembrolizumab, pemtumomab, pertuzumab, ramucirumab, ranibizumab, rituximab, rupatadine, tracatuzumab, tocilizumab, trastuzumab, ustekinumab, vedolizumab, visilizumab, bococizumab, zalutumumab and zanilumab, and their active fragments, combinations or conjugates), therapeutic fusion proteins (in certain embodiments, recombinant fusion proteins such as aflibercept (Regeneron), etanercept (Amgen), alefacept (Astellas Pharma), abatacept (Bristol-Myers Squibb), rilonacept (Regeneron), romiplostim (Amgen) and belatacept (Bristol-Myers Squibb)), prostaglandin analogs (e.g., latanoprost, travoprost, tafluprost, unoprostone, netarsudil, latanoprostene bunod, netarsudil and bimatoprost, and their pharmaceutically acceptable salts, esters and derivatives), growth factors (e.g., EGF, PDGF, TGF-β, IGF-1, VEGF, FGF-β, IGF-1) or their therapeutic or growth promoting (particularly skin growth promoting) fragments, neuropeptides (e.g., substance P (SEQ ID NO: 389), α-adrenergic antagonists (e.g., brimonidine, clonidine and apraclonidine, and their pharmaceutically acceptable salts, esters or derivatives), β-adrenergic antagonists (e.g., timolol, propranolol, atenolol, levobunolol, carteolol, betaxolol, and their pharmaceutically acceptable salts, esters and derivatives, e.g.,Timolol maleate), cell surface receptor antagonists (e.g., rifiglutide or etanercept), carbonic anhydrase inhibitors (e.g., dorzolamide, brinzolamide, methazolamide and acetazolamide, and pharmaceutically acceptable salts, esters and derivatives thereof, e.g., dorzolamide hydrochloride), and pharmaceutically acceptable salts, esters and derivatives thereof, including but not limited to. In certain such therapeutic compounds, one or more harmful side effects of the therapeutic compound may be prevented, attenuated, or reduced by administering simultaneously with a CMP described herein, whether as a CMP-TC conjugate or simply by applying one or more CMPs and one or more TCs as a mixture or separately. For example, it is known that the therapeutic administration of certain fluoroquinolone antibiotics can cause damage to collagen and collagen-containing structures (e.g., tendons) in humans or veterinary animals treated with fluoroquinolones (see, e.g., "FDA Drug Safety Communication: FDA updates warnings for oral and injectable fluoroquinolone antibiotics due to disabling side effects", accessed November 6, 2017, https: / / www.fda.gov / Drugs / DrugSafety / ucm511530.htm). As a result, in humans or veterinary animals in need of treatment with fluoroquinolones, by co-administering or administering in combination one or more of the CMPs described herein with one or more fluoroquinolone antibiotics, the patient can receive the therapeutic effect of the fluoroquinolone and it may be possible to reduce, improve, or avoid collagen destruction resulting from such therapy. This is because the CMP can localize to the area of damaged collagen in vivo and repair that area.,

[0464] Other suitable therapeutic compounds for use in the CMP-TC compounds, compositions, and conjugates of the present invention include, but are not limited to, alkylating agents, antitumor antibiotics, antimetabolites, hormonal agents, plant alkaloids, angiogenesis inhibitors, GnRH agonists, tyrosine kinase inhibitors, and other non-biological small molecule therapeutic compounds. Examples of such non-biological small molecule therapeutic compounds that are preferably used in accordance with the present invention include nitrosourea, lenalidomide, imatinib, pemetrexed, bortezomib, abiraterone acetate, everolimus, taxol, docetaxel, paclitaxel, cabazitaxel, mitoxantrone, carboplatin, cisplatin, gemcitabine, doxorubicin, casodex, flutamide, enzalutamide, abiraterone, ciproisomer-T, and ketoconazole, but are not limited thereto. In the formation of the CMP-TC conjugates of the present invention, other suitable non-biological small molecule therapeutic compounds that are advantageously used to produce CMP-TC conjugates particularly useful for the treatment of certain cancers and the prevention of tumor metastasis include inhibitors of lysyl oxidase (LOX), lysyl oxidase-like 1 (LOXL1), and lysyl oxidase-like 2 (LOXL2) enzymes.Such inhibitors have been suggested to have potential therapeutic utility in the treatment and / or prevention of metastases of certain cancers and solid tumors (see, for example, U.S. Pat. Nos. 5,201,456, 5,120,764, 5,252,608, 8,461,303, 8,658,167, 8,680,246, 9,176,139, 9,255,086, and 9,289,447; also see Erler, J.T., et al., Nature 440:1222-1226 (2006), Erler, J.T., et al., Cancer Cell 15(1):35-44 (2009), Bondareva, A., et al., PLoS ONE 4(5):e5620 (2009), Granchi, C., et al., ChemMedChem 4(10):1590-1594 (2009), and Fang, M., et al., Tumor Biol. 35:2871-2882 (2014); the entire disclosures of all of these are hereby incorporated by reference in their entirety). In related aspects of the invention, CMP-TC conjugates comprising one or more inhibitors of LOX or LOX-like enzymes are preferably used in the treatment and / or prevention of certain fibrotic diseases and disorders mediated by oxidoreductase enzymes such as LOX and LOX-like enzymes (e.g., LOXL1 and LOXL2) in humans and veterinary animals. Fibrotic diseases and disorders that are preferably treated and / or prevented according to this aspect of the invention include, but are not limited to, pulmonary fibrosis, cirrhosis, myocardial fibrosis, surgical scarring, systemic sclerosis, scleroderma, keloid formation, proliferative vitreoretinopathy, and other fibrotic diseases and disorders that will be apparent to those of skill in the relevant art.Particularly useful inhibitors of LOX and LOX-like proteins include β-aminopropionitrile and its specific derivatives and prodrugs (see, e.g., U.S. Patent Nos. 5,201,456, 5,120,764, 5,252,608, 8,461,303, 8,680,246, 9,176,139, and 9,255,086; the entire disclosures of all of these are incorporated herein by reference in their entirety), as well as antibodies (which can be polyclonal or preferably monoclonal) and fragments or portions thereof that bind to LOX and LOX-like enzymes to inhibit their activity or function (see, e.g., U.S. Patent No. 8,461,303, the disclosure of which is incorporated herein by reference in its entirety).

[0465] In further embodiments, a compound or composition comprising one or more CMPs and one or more antigens can be prepared as either a mixture or a formulation (optionally containing one or more pharmaceutically suitable carriers or excipients) of one or more CMPs and one or more antigens, or as another compound or composition in which one or more antigens are directly or indirectly linked or conjugated to one or more CMPs. According to certain such embodiments, the antigen can be a complete antigen or an antigenic determinant or fragment thereof (e.g., a hapten) that is capable of inducing an immune response in a human or veterinary animal when provided in a physiological context appropriate for the immune system of the human or veterinary animal, such as in the form of administration of the compound, conjugate, or composition as a vaccine or immunization to the human or veterinary animal. Compounds, conjugates, and compositions useful in such embodiments can be prepared via formulation or direct or indirect conjugation according to methods described elsewhere herein with respect to the formulation and conjugation of therapeutic compounds with or to CMPs. In such compounds, conjugates, and compositions, and thus in their methods of use, suitable antigens or portions thereof include any molecule or particle, or portion thereof, that is capable of inducing an immune response in a human or veterinary animal, and include, but are not limited to, antigens (e.g., proteins, toxins, lipids, and other antigenic moieties, molecules, or complexes) produced or generated from bacteria (wherein the antigen can include the whole bacterium or a portion thereof, such as cell wall or cell membrane components, nuclear components, or toxins produced by the bacterium), viruses (wherein the antigen can include the whole virus particle or a portion thereof, such as coat components (e.g., proteins or lipids or portions thereof), nuclear components, or enzymes that may be encoded by or are part of the virus particle), protists, fungi, plants (which can include plant stimulants or allergens such as pollen particles), animals (wherein the antigen or a portion thereof can be an allogeneic or autoantigen, or a portion thereof), etc. Examples of such antigens or portions thereof will be readily apparent to those of skill in the relevant art.Such compounds, compositions or conjugates are suitably used in methods of treating and / or preventing one or more disorders, diseases and illnesses in humans and veterinary animals, for example by using the compounds, compositions or conjugates to elicit an immune response in an animal or veterinary human. In certain such methods, the disease or disorder is treated and / or prevented in an animal or veterinary animal by administering one or more of the compounds, compositions or conjugates of this aspect of the invention into the human or veterinary animal in the form of a vaccine or immunization, etc. Such vaccines or immunizations are suitably formulated according to methods well known in the relevant art and are administered in any manner that results in the generation of an immune response by a human or veterinary animal against an antigen or a portion thereof, whereby the disease or disorder directly or indirectly caused by the antigen or a portion thereof is treated and / or prevented. Such vaccines or immunizations can be administered to a human or veterinary animal by any suitable route, for example, orally, parenterally (including subcutaneously, intradermally, transdermally, intrathecally, or intravenously), via ocular administration (for example, in the form of drops, gels, wafers, or via injection, as described elsewhere herein for CMP-TC administration to the eye), intranasally, and other routes of administration that will be apparent to those skilled in the art. In such embodiments, the compounds, conjugates or compositions of the invention are suitably administered to a human or veterinary animal until the human or veterinary animal generates an immune response sufficient to treat and / or prevent the target disease or disorder and may be readministered as necessary to enhance the immune response and / or ensure the persistence of immunity against the target antigen or a portion thereof.Diseases and disorders that are preferably treated by the method of the present invention include any disease or disorder involving or resulting from the activity of cells, organs, organ systems, body structures of humans and veterinary animals, or any foreign substance acting on the body, including infectious diseases, cancer, allergies and other immune hypersensitivity reactions (e.g., graft-versus-host disease or host-versus-graft disease), Stevens-Johnson syndrome, mucous membrane pemphigoid, toxic epidermal necrolysis, Behçet's disease uveitis, punctate choroiditis, juvenile idiopathic arthritis (JIA)-associated uveitis, multifocal choroiditis with panuveitis, necrotizing scleritis, serpiginous choroiditis, sympathetic ophthalmia, Vogt-Koyanagi-Harada (VKH) disease, non-infectious panuveitis, etc., but are not limited thereto.

[0466] Diagnostic compounds suitable for binding or conjugating to CMP to produce the conjugates and compositions of the present invention include labeled probes, such as fluorescent dyes (e.g., quantum dots, indocyanine green, fluorescein, rhodamine, merocyanine dyes, near-infrared fluorescent dyes, etc.); radioisotopes, nuclides used in PET, nuclides used in SPECT (in particular, each of the radioisotopes, nuclides used in PET or SPECT is 11 C, 13 N, 15 O, 18 F, 66 Ga, 67 Ga, 68Ga, 60 Cu, 61 Cu, 62 Cu, 67 Cu, 64 Cu, 48 V, Tc-99m, 241 Am, 55 Co, 57 Co, 153 Gd, 111 In, 133 Ba, 82 Rb, 139 Ce, Te-123m, 137 Cs, 86 Y, 90 Y, 185 / 187 Re, 186 / 188 Re, 125(I) selected from the group consisting of those complexes and combinations thereof); and MRI contrast agents, CT contrast agents, and magnetic materials (in particular, each of the MRI contrast agent, CT contrast agent, and magnetic material is selected from the group consisting of gadolinium, Gd-DTPA, Gd-DTPA BMA, Gd-HP-D03A, iodine, iron, iron oxide, chromium, manganese, their complexes or chelate complexes, and combinations thereof), but not limited thereto. According to such an aspect of the present invention, the CMP and the labeling probe are directly bound to each other, for example, by direct conjugation by coordination bond, covalent bond, hydrogen bond, hydrophobic interaction or physical adsorption, or indirectly by using at least one binding means such as those described herein and others known in the art, and are preferably physically or chemically bound. Methods for conjugating or binding diagnostic compounds to proteins such as CMP are known in the art (see, for example, US Patent Application Publication No. US2012 / 0195828 A1, the disclosure of which is incorporated herein by reference in its entirety).

[0467] Use of CMP and CMP-TC conjugates

[0468] Thus, the present invention provides a method for preparing a composition useful in the treatment, prevention, diagnosis, or amelioration of a disease, disorder, or medical condition in a human or veterinary animal. In yet another aspect, the present invention provides a method for treating, preventing, diagnosing, or ameliorating a disease, disorder, or medical or physical condition in a human or veterinary animal using the composition of the present invention.Particularly preferred CMPs for use in such embodiments of the present invention include (Pro-Pro-Gly)7 (SEQ ID NO: 1), (Flp-Pro-Gly)7 (SEQ ID NO: 4), (Pro-Flp-Gly)7 (SEQ ID NO: 5), (Flp-Hyp-Gly)7 (SEQ ID NO: 6), (Clp-Hyp-Gly)7 (SEQ ID NO: 9), (Hyp-Flp-Gly)7 (SEQ ID NO: 388), Gly3-(Pro-Hyp-Gly)6 (SEQ ID NO: 397), Gly3-(Pro-Flp-Gly)6 (SEQ ID NO: 398), Gly3-(Pro-Hyp-Gly)7 (SEQ ID NO: 399), Gly3-(Pro-Flp-Gly)7 (SEQ ID NO: 400), Gly3-(Pro-Hyp-Gly)8 (SEQ ID NO: 401), Gly3-(Pro-Flp-Gly)8 (SEQ ID NO: 402), Gly3-(Pro-Hyp-Gly)9 (SEQ ID NO: 403), Gly3-(Pro-Flp-Gly)9 (SEQ ID NO: 404), (Pro-Hyp-Gly)6-Tyr (SEQ ID NO: 405), (Pro-Flp-Gly)6-Tyr (SEQ ID NO: 406), (Pro-Hyp-Gly)7-Tyr (SEQ ID NO: 407), (Pro-Flp-Gly)7-Tyr (SEQ ID NO: 408), (Pro-Hyp-Gly)8-Tyr (SEQ ID NO: 409), (Pro-Flp-Gly)8-Tyr (SEQ ID NO: 410), Cys-(Pro-Hyp-Gly)3 (SEQ ID NO: 411), Cys-(Pro-Flp-Gly)3 (SEQ ID NO: 412), Cys-(Pro-Hyp-Gly)5 (SEQ ID NO: 413), Cys-(Pro-Flp-Gly)5 (SEQ ID NO: 414), Cys-(Pro-Hyp-Gly)7 (SEQ ID NO: 415), or Cys-(Pro-Flp-Gly)7 (SEQ ID NO: 416), and derivatives thereof containing one or more cysteine, methionine or lysine residues such as those described elsewhere herein, including CMPs that contain, consist essentially of, or consist of such CMPs.

[0469] The CMP and / or CMP-TC conjugate of the present invention is preferably used as, or is included in, a composition for use in a medicament for treating, preventing or ameliorating various diseases or disorders in a human or veterinary animal in need of treatment or prevention, including solutions, gels, films, wafers, membranes, spheres, nanoparticles, and suspensions comprising, consisting essentially of, or consisting of the CMP and / or CMP-TC conjugate of the present invention. Other compositions provided by this aspect of the present invention provide for the use of CMP conjugated to one or more diagnostic compounds or molecules, such as one or more labeled probes, which are then used as diagnostic reagents in various tests and assays, particularly in vivo or in situ, to diagnose diseases, disorders, or physical conditions in human or veterinary animals. Such pharmaceutical or diagnostic compositions may include, in addition to the CMP, CMP-TC conjugate, or CMP conjugated to one or more diagnostic compounds or molecules, one or more additional therapeutic compounds or pharmaceutically active ingredients (e.g., one or more antibiotics, one or more growth factors, autologous platelet-rich growth factor (PRGF), one or more cytokines, one or more antibody fragments thereof, one or more non-biological small molecule therapeutic compounds, and pharmaceutically active salts, esters, and derivatives thereof, etc., including those described herein and others known in the art). The compositions of the present invention may additionally or alternatively include one or more pharmaceutically acceptable carriers or excipients. Pharmaceutically acceptable carriers or excipients suitable for use in the compositions and methods of the present invention include, for example, one or more solvents (which may include water, organic solvents, or inorganic solvents), one or more buffers, one or more polymers, one or more salts, one or more sugars, one or more sugar alcohols, one or more disintegrants, one or more aerosolizing agents or carriers, one or more desiccants, etc. Other pharmaceutically acceptable carriers or excipients suitable for use in the compositions of the present invention will be readily apparent to those of ordinary skill in the relevant art.

[0470] While not wishing to be bound by theory, the CMP provided by and used in the methods of the present invention is believed to be useful, inter alia, in the repair of damaged collagen, specifically damaged helical collagen, resulting from or involved in various diseases, disorders, structural abnormalities, physical and medical conditions in human and veterinary animals. For example, when collagen is structurally damaged, this often results in hydrolysis of at least one of the three helices forming the triple helix collagen, thereby causing disassembly and structural deformation of the triple helix. This destruction and digestion can fragment and break down the collagen into many small pieces that may remain in the extracellular environment or enter the blood or lymphatic circulatory systems. Such fragments may ultimately be phagocytosed or bound by scavenger cells or bind to cell surface receptors on somatic cells in human or veterinary animals. Such receptors (which may include, for example, integrins, discoidin domain receptors, glycoprotein VI and leukocyte-associated immunoglobulin-like receptor 1 (LAIR-1)) regulate cell functions such as growth, differentiation, morphogenesis, tissue repair, adhesion, migration, homeostasis, immune function and wound healing and are often disrupted via binding of such free collagen fragments or their functions or signaling systems are upregulated or downregulated. According to this theory, when CMP contacts damaged collagen or fragments thereof, it dynamically anneals or binds to the disrupted collagen triple helix to repair its structure, resulting in (inter alia) restoration of the cell receptor to appropriate functional and signaling activity levels. Thus, the overall result of applying CMP to a human or veterinary animal having a disease, disorder, structural abnormality or injury involving or resulting from damaged collagen in this way is to cause an accelerated wound healing process (including, in some physiological situations, rapid growth, migration, and adhesion of epithelial, endothelial, or nerve cells in the repaired collagen matrix) and to result in restoration of the normal or near-normal structure and function of such cells, as well as the tissues, organs and organ systems containing such cells.

[0471] Diseases, disorders, physical conditions, and medical conditions that are preferably treated, prevented, ameliorated, or diagnosed using the compositions and methods of the present invention include, but are not limited to, eye diseases or disorders, skin diseases or disorders, cancer, gastrointestinal diseases or disorders, urogenital diseases or disorders, fibrotic diseases or disorders, cardiovascular diseases or disorders, bone diseases or disorders, rheumatic diseases or disorders, and neurological or nervous system diseases or disorders. Suitable dosages of the compositions and conjugates of the present invention for such use are from about 10 ng / ml to about 500 μg / ml, about 15 ng / ml to about 400 μg / ml, about 20 ng / ml to about 300 μg / ml, about 25 ng / ml to about 250 μg / ml, about 30 ng / ml to about 200 μg / ml, about 35 ng / ml to about 200 μg / ml, about 40 ng / ml to about 200 μg / ml, about 50 ng / ml to about 200 μg / ml, about 75 ng / ml to about 200 μg / ml, and about 100 ng / ml to about 200 μg / ml in terms of the concentration of the CMP component in the composition or conjugate. In certain such embodiments, the conjugate or composition is preferably applied to the tissue, organ, or organ system being treated at a dosage corresponding to a CMP concentration of about 25 μg / ml to about 500 μg / ml, for example, about 25 μg / ml, about 30 μg / ml, about 35 μg / ml, about 40 μg / ml, about 45 μg / ml, about 50 μg / ml, about 75 μg / ml, about 100 μg / ml, about 125 μg / ml, about 150 μg / ml, about 175 μg / ml, about 200 μg / ml, about 225 μg / ml, about 250 μg / ml, about 300 μg / ml, about 350 μg / ml, about 400 μg / ml, about 450 μg / ml, or about 500 μg / ml. In certain such embodiments, a concentration corresponding to a CMP concentration between about 25 μg / ml, 50 μg / ml, 75 μg / ml, or 100 μg / ml is used. Further concentrations and amounts of the conjugates or compositions of the present invention preferably used in such methods can be readily determined by one of ordinary skill in the art based on the information contained herein and available in the art, without relying on undue experimentation.

[0472] Eye diseases or disorders that can be treated, prevented, improved, or diagnosed using the compositions and methods of the present invention include, but are not limited to, those involving the cornea and / or sclera of the eye, i.e., diseases, disorders, and conditions of the corneosclera. Without wishing to be bound by theory, it is believed that the compositions of the present invention, particularly one or more CMPs contained in such compositions, repair the collagen matrix / substantia of the cornea and / or sclera and restore the homeostatic structure and function (including hardening or strengthening) by repairing the disordered, disrupted, or digested collagen found in the extracellular matrix and / or substantia of the cornea and sclera, thereby treating or improving such diseases and disorders and their signs / symptoms. In other aspects, the compositions of the present invention, particularly one or more CMPs contained in such compositions, preserve the collagen matrix / substantia of the cornea and / or sclera and thus the homeostatic structure and function by preventing the breakdown and digestion of collagen in the extracellular matrix and / or substantia of the cornea and sclera in response to injury or trauma, thereby preventing such diseases and disorders and their signs / symptoms. Examples of corneoscleral diseases, disorders, or conditions that are preferably treated, prevented, improved, or diagnosed using the compositions and methods of the present invention include myopia, presbyopia, hyperopia, keratitis, episcleritis, scleritis, corneal ulceration, sequelae of corneal ulceration, corneal ectasia, acquired corneal shape abnormalities, keratoconus, corneal astigmatism, globus corneae, posterior corneal staphyloma, corneal ectasia, corneal tumor, desmoid tumor, marginal degeneration of the cornea, Terrien marginal dystrophy, Mooren ulcer, central corneal ulcer, marginal corneal ulcer, staphylococcal marginal ulceration, Salzmann nodular dystrophy, age-related peripheral atrophy of the cornea, geographic ulceration, disciform keratitis, metaherpetic ulceration, keratomalacia, after penetrating keratoplasty, incisional wounds, anterior membrane dystrophy, stromal dystrophy, ocular mucous membrane pemphigoid, necrotizing scleritis, scleromalacia, coloboma, scleral buckle-induced scleromalacia, congenital hereditary stromal dystrophy, congenital anterior staphyloma, corneal sclerosis, traumatic rupture of Descemet's membrane, corneal keloid, scleral ectasia, scleral staphyloma, deep scleritis, necrotizing scleritis, perforating scleromalacia, hyaline degeneration of the sclera, scleromalacia perforans marginalis, graft-versus-host disease of the eye, and chorioretinalemia, but are not limited thereto.In particular, the compositions and methods of the present invention are suitable for treating, ameliorating, preventing and / or diagnosing myopia, presbyopia, and keratoconus. Other corneal and scleral diseases, disorders, and conditions that can be suitably prevented, treated, ameliorated or diagnosed using the compositions and methods of the present invention will be apparent to those skilled in the art based on information readily available in the literature.

[0473] Other eye diseases or disorders that can be treated, prevented, improved, or diagnosed using the compositions and methods of the present invention include anterior segment diseases and disorders, including glaucoma, cataracts, vitreous adhesions or floaters, macular degeneration, dry eye syndrome (also known as dry eye disease), keratitis, non-infectious corneal ulceration, non-infectious corneal melting, infectious corneal ulceration, infectious corneal melting, conjunctivitis, Stevens-Johnson syndrome, iritis, uveitis, vitritis, Behçet's disease uveitis, punctate choroidopathy, juvenile idiopathic arthritis (JIA)-associated uveitis, multifocal choroiditis with panuveitis, necrotizing scleritis, serpiginous choroidopathy, sympathetic ophthalmia, Vogt-Koyanagi-Harada (VKH) disease, non-infectious panuveitis, ectasia, corneal lacerations, corneal erosions, corneal abrasions, acute or chronic corneal pain (particularly those resulting from damage or injury to or denervation of the corneal nerves; see, for example, Rosenthal, P. and Borsook, D., Br J Ophthalmol. 2016;100(1):128-134, Theophanous, C., et al., Optom. Vis. Sci. 2015;92(9):e233-240, Belmonte, C., et al., Ocul. Surf. 2004;2(4):248-253, Belmonte, C., et al., Exp. Eye Res. 2004;78(3):513-525, Belmonte, C., et al., Curr. Ophthalmol Rep. 2015;3(2):111-121) (including, but not limited to, periorbital pain, extraocular pain, and postherpetic neuralgia, as well as postoperative eye diseases resulting from ophthalmic surgery). Such postoperative eye diseases resulting from ophthalmic surgery can be, for example, diseases that occur postoperatively from cataract surgery or glaucoma surgery, particularly those that result in or are such postoperative eye conditions that require medication.

[0474] Additional eye diseases or disorders that can be treated, prevented, ameliorated or diagnosed using the compositions and methods of the present invention include, but are not limited to, posterior diseases and disorders, particularly those involving the retina, such as age-related macular degeneration (wet, dry, and age-related), retinitis pigmentosa, retinal holes or detachments, retinopathies (e.g., diabetic retinopathy), arterial or venous occlusions (e.g., branch retinal artery occlusion (BRAO), central retinal artery occlusion (CRAO), branch retinal vein occlusion (BRVO), and central retinal vein occlusion (CRVO)), optic neuritis, optic neuropathies (e.g., including anterior ischemic optic neuropathy (AION), and traumatic optic neuropathy), optic atrophy (e.g., glaucomatous optic atrophy), third cranial nerve palsy, fourth cranial nerve palsy, fifth cranial nerve palsy (e.g., trigeminal neuralgia and postherpetic neuralgia), sixth cranial nerve palsy, and seventh cranial nerve palsy (e.g., Bell's palsy), among others, as well as periorbital diseases, disorders or conditions, and extraocular diseases, disorders or conditions, including one or more neuropathies affecting the eye or periorbital region, such as those involving the retinal epithelium, particularly the retinal pigment epithelium, retinal blood vessels, and / or retinal nerves, cranial nerves, or optic nerves, and other retinal and posterior-related disorders and diseases, including, but not limited to, those involving the retinal epithelium, particularly the retinal pigment epithelium, retinal blood vessels, and / or retinal nerves, cranial nerves, or optic nerves. Further eye disorders that are advantageously treated, ameliorated and / or prevented using the compositions and methods of the present invention include, but are not limited to, refractive eye disorders, including myopia, presbyopia, and amblyopia. For example, myopia is known to be associated with axial eye elongation, which may be accompanied to some extent by destruction of collagen in the sclera of the eye (see, e.g., Guo, P. et al., Trans. Vis. Sci. Tech. 9(9):45 (2020); Zhao, F. et al., Am. J. Pathol. 188:1754 - 1767 (2018)), and may be improved by crosslinking of the scleral connective tissue or other manipulation to strengthen the sclera (see, e.g., Backhouse, S. et al., Ann. Eye Sci. 3:5 (2018); Grytz, R. et al., Curr. Opin. Biomed. Eng. 15:40 - 50 (2020); Garcia, M. B. et al., Invest. Ophthalmol. Vis. Sci. 58:1875 - 1886 (2017)).

[0475] According to this aspect of the present invention, a method for treating or preventing an eye disease, disorder or wound in a human or veterinary animal suffering from or having a predisposition to an eye disease, disorder or wound comprises administering to the eye of the human or veterinary animal a composition described herein, in particular a CMP or CMP-TC conjugate and / or a composition comprising such a conjugate. Without wishing to be bound by theory, in areas with an eye disease or disorder, type I collagen is sufficiently disrupted, so that CMP specifically targets the site of the eye disease or disorder and inserts into the collagen structure, for example by inserting into one or more damaged helices in helical collagen, whereby a functional collagen helix or matrix is directly reformed, or, if the CMP is conjugated to a therapeutic compound, the therapeutic compound is delivered to the site where it needs to act to treat, prevent or improve the eye disease or disorder. The inventors speculate. In certain such anterior eye diseases or disorders, such as acute or chronic corneal pain (including but not limited to periorbital pain, extraocular pain, and post-herpetic neuralgia), the denervated cornea has a low healing capacity, and thus local therapies that can affect nerve regeneration would be a desirable therapy in this area. Pain is mediated by damaged corneal nerves in both acute and chronic cases (see, for example, Rosenthal, P. and Borsook, D., Br J Ophthalmol. 2016;100(1):128-134, Theophanous, C., et al., Optom. Vis. Sci. 2015;92(9):e233-240, Belmonte, C., et al., Ocul. Surf. 2004;2(4):248-253, Belmonte, C., et al., Exp. Eye Res. 2004;78(3):513-525, Belmonte, C., et al., Curr.Ophthalmol Rep. 2015;3(2):111-121). Therefore, therapeutic agents that may be beneficial to nerve health would be clinically useful for such patients.Based on the findings described herein regarding the behavior of dorsal root ganglion cells when exposed to the CMP of the present invention (SEQ ID NO: 1) after damage to the collagen support layer (see Example 4 below), it can be predicted that any cranial nerve will behave similarly. Thus, for the corneal nerves, which are branches of the trigeminal nerve, a therapy comprising locally administering to the cornea one or more of the CMPs or CMP-TC conjugates described herein would be effective. When the nerve is repaired and regenerated, subsequent corneal recovery and pain relief will occur, and acute or chronic corneal pain will be improved.

[0476] The conjugate or composition is suitably applied to the eye in a dosage sufficient to treat or prevent an eye disease, disorder or wound, and then the eye condition of the human or veterinary animal is monitored over time for improvement in the pathological or physical condition. If necessary, the conjugate or composition of the present invention is then re-administered to the eye periodically according to the dosing and treatment schedules and protocols described herein and others that will be apparent to those skilled in the art until the eye disease, disorder or wound is cured, prevented or improved. In such embodiments, the conjugate or composition of the present invention for treating anterior diseases and disorders can be suitably administered to the eye by instilling the conjugate or composition onto the surface of the eye, into the conjunctiva, or subconjunctivally, particularly onto the surface of the eye or within a subconjunctival dome. In other embodiments, the conjugate or composition of the present invention for treating anterior diseases and disorders can be suitably administered to the anterior aspect of the eye, including the sclera and vitreous, by instillation (depending on the ability of the CMP-containing formulation to migrate across the entire surface epithelium) or by injection, such as intravitreal injection, according to methods well known to those skilled in the medical and pharmaceutical arts. In other embodiments related to the treatment, prevention, cure or diagnosis of posterior diseases and disorders, the conjugates and compositions of the present invention can be administered to the posterior portion, e.g., the retina or in the vicinity thereof, by mechanical introduction, such as by injection using a needle or other suitable device, or by administering the conjugate or composition (or a component thereof, e.g., CMP or CMP-TC conjugate) to the surface of the eye in the form of droplets that transport or transfer the conjugate or composition (or a component thereof) to the posterior portion of the eye (e.g., the retina or in the vicinity thereof).Administration of the conjugate or composition to the eye may be accomplished by any well-known means, including in the form of one or more droplets or aliquots of a solution, gel, or suspension containing the composition or conjugate; by injection; in the form of a solid material such as a wafer or film (e.g., as described herein) implanted into the eye structure; in the form of a mesh or patch; or by binding or encapsulating the conjugate or composition in one or more gels, spheres or nanoparticles and then delivering it to the eye structure. Other suitable methods of applying the conjugate or composition to the eye to effect the therapeutic and diagnostic methods of the present invention will be readily apparent to those skilled in the art.

[0477] Skin diseases or disorders that can be treated, prevented, ameliorated or diagnosed using the compositions and methods of the present invention include, but are not limited to, skin wounds, scarring, wrinkles, "crepey skin", skin cancer (e.g., melanoma, cutaneous carcinoma, cutaneous sarcoma, histiocytoma), and skin burns including sunburn. Other skin diseases or disorders that are preferably treated, prevented, ameliorated, or diagnosed in accordance with the present invention include psoriasis and eczema, herpes zoster, irritant contact dermatitis as well as allergic contact dermatitis (e.g., poison ivy, poison oak or poison sumac).

[0478] According to this aspect of the present invention, a method for treating or preventing a skin disease, disorder or wound in a human or veterinary animal suffering from or predisposed to a skin disease, disorder or wound comprises administering a composition described herein, particularly a CMP and a CMP-TC conjugate and a composition containing such CMP and CMP-TC conjugate, to the skin of a human or veterinary animal at a site close to the location of a lesion associated with or causing the skin disease, wound or disorder. Without wishing to be bound by theory, in an area with a skin disease or disorder, type I collagen is sufficiently destroyed, so that CMP specifically targets the site of the skin disease or disorder, inserts into the collagen structure, whereby a functional collagen matrix is directly reformed, or when CMP is conjugated to a therapeutic compound, whereby CMP and / or the therapeutic compound is delivered to the site where it is necessary to act to treat, prevent or improve the skin disease or disorder. Alternatively, a disease or disorder affecting the skin may be excised or removed from the skin (e.g., by surgical removal of skin cancer, etc.), and a skin wound resulting from such excision or removal may be treated with one or more compositions of the present invention according to the methods described herein. In certain embodiments, one or more CMPs themselves, or one or more CMP-TC conjugates, or any combination thereof, can be introduced into the skin, particularly into the epidermis, dermis or subcutaneous tissue, in the form of so-called "cosmeceuticals" (see, e.g., Epstein, H., Clin. Dermatol. 27(5):453-460(2009)). Particularly preferred CMP-TC conjugates or compositions used in such aspects of the present invention include those in which the therapeutic compound is substance P (SEQ ID NO: 389), particularly those in which the CMP-TC conjugate has an amino acid sequence corresponding to any one of SEQ ID NOs: 390 to 396. Additional particularly preferred CMP-TC conjugates or compositions used in such aspects of the present invention include those in which the therapeutic compound is retinol or a derivative or precursor thereof.Additional preferred compositions include compositions that contain or further contain at least one growth factor, at least one antibiotic, at least one antifungal compound, or at least one antiviral compound. Suitable growth factors, antibiotics, antifungal compounds, and antiviral compounds include those described herein as well as those well known in dermatology and other related technical fields. According to this aspect of the invention, the conjugate or composition is suitably applied to or within the skin in a dosage sufficient to treat or prevent a skin disease, disorder, or wound, and then the skin condition of the human or veterinary animal is monitored over time for improvement in the medical condition or physical state. If necessary, the conjugate or composition of the invention is then re-administered periodically to or within the skin according to the dosing and treatment schedules and protocols described herein as well as others that will be apparent to those skilled in the art until the skin disease, disorder, or wound is cured, prevented, or improved. In such embodiments, the conjugate or composition of the invention is suitably administered topically, intradermally, intracutaneously, or subcutaneously to or within the skin. Administration of the conjugate or composition to or within the skin may be accomplished by any well-known means, including in the form of a solution, ointment, plaster, patch, cream, topical solution, and drug-eluting wafer. For example, the conjugate or composition may be in the form of one or more droplets of a solution or suspension containing the composition or conjugate; by injection; in the form of a coating on a solid material implanted in the skin; in the form of a mesh or patch; or the conjugate or composition may be applied or introduced to or within the skin by binding or encapsulating the conjugate or composition in one or more nanoparticles and then delivering them into the skin. Other suitable methods for applying the conjugate or composition to or within the skin to carry out the therapeutic and diagnostic methods of the invention will be readily apparent to those skilled in the art.

[0479] The cancers that can be treated, prevented, ameliorated or diagnosed using the compositions and methods of the present invention include, but are not limited to, skin cancer (e.g., as described elsewhere herein), luminal cancer, and brain cancer. The luminal cancers that are preferably treated, prevented, diagnosed or ameliorated using the conjugates, compositions and methods of the present invention include, but are not limited to, colorectal cancer, bowel cancer, duodenal cancer, gastric cancer, pancreatic cancer, esophageal cancer, bladder cancer (e.g., muscle-invasive bladder cancer or bladder intraepithelial neoplasia), cancers of the upper urinary tract (also known as the renal pelvis and known to those skilled in the art) (e.g., upper urothelial carcinoma, Wilms tumor, and renal carcinoma), vaginal cancer, cervical cancer, uterine cancer, ovarian cancer, luminal breast cancer, and lung cancer. The brain cancers that are preferably treated, prevented, diagnosed or ameliorated using the conjugates, compositions and methods of the present invention include, but are not limited to, glioma, glioblastoma, meningioma, pituitary tumor, craniopharyngioma, and hemangioblastoma. Other non-luminal cancers, including, but not limited to, prostate cancer, testicular cancer, non-luminal breast cancer, bone cancer, head and neck cancer, thyroid cancer, liver cancer, sarcoma (e.g., Kaposi sarcoma, Ewing sarcoma, osteosarcoma, soft tissue sarcoma, and rhabdomyosarcoma), etc. can also be preferably treated, prevented, diagnosed or ameliorated using the conjugates, compositions and methods of the present invention.

[0480] According to this aspect of the present invention, a method for treating or preventing cancer in a human or veterinary animal suffering from cancer or having a predisposition thereto comprises administering the compositions described herein, particularly CMP and CMP and / or conjugates, at a site close to the location of the cancer or tumor, into the lumen of an organ of the human or veterinary animal, or into the skull, or into or onto the brain. Without wishing to be bound by theory, in the region where there is cancer, type I collagen is sufficiently destroyed, or in the case of brain cancer, type I collagen is upregulated, so that CMP specifically targets the site of the cancer, inserts into the collagen structure, whereby a functional collagen matrix is directly reformed, or if CMP is conjugated to a therapeutic compound, whereby the CMP and / or the therapeutic compound are delivered to the site where they need to act to treat, prevent or ameliorate the cancer. Particularly preferred conjugates or compositions for use in this aspect of the present invention are those in which the therapeutic compound is a biological therapeutic compound, particularly one or more monoclonal antibodies or fragments thereof, or one or more therapeutic fusion proteins, particularly recombinant fusion proteins as described herein. Additional preferred compositions include those further comprising at least one growth factor, at least one antibiotic, at least one antifungal compound, or at least one antiviral compound. Suitable growth factors, antibiotics, antifungal compounds, and antiviral compounds include those described herein, as well as those well known in dermatology and other related technical fields. According to this aspect of the present invention, the conjugate or composition is suitably applied in an amount sufficient to treat, prevent or ameliorate the cancer, into the lumen of an organ, or into the skull, or into the brain, or onto it, and then the progression, remission or arrest of cancer in the human or veterinary animal is monitored over time for improvement of the cancer condition (e.g., shrinkage of the tumor, or at least non-progression or remission of the cancer).If necessary, the conjugate or composition of the present invention is then redosed periodically into an organ lumen, or into the skull, or into or onto the brain, according to the dosing and treatment schedules and protocols described herein and others that will be apparent to those of skill in the art, until the cancer is cured, prevented or improved, or in permanent remission. In such embodiments, the conjugate or composition of the present invention is preferably administered into an organ lumen or the brain or into or onto the brain parenterally, or via direct application to the tumor site, or, in the case of resection or excision of the tumor, via direct application to the tumor bed or the wound remaining after resection or excision of the tumor. Parenteral administration of the conjugate or composition of the present invention can be accomplished via a route selected from the group consisting of subcutaneous injection, intravenous infusion, intraarterial infusion, transdermal diffusion, implantation of a drug eluting wafer or film, sublingual, oral, aerosol inhalation, vaginal, rectal, or intracranial. In certain such embodiments, the conjugate or composition can be administered parenterally to a human or veterinary animal in the form of a mesh, film, wafer, sphere, nanoparticle, gel or patch that is implanted at or near the site of the cancer. In other such embodiments, particularly where the cancer is a luminal cancer, the conjugate or composition of the present invention is administered into the lumen of a cancerous organ of a human or veterinary animal using a medical instrument suitable for such purpose, such as an endoscope, bronchoscope (e.g., via bronchial lavage for treating, preventing or diagnosing lung duct cancers such as bronchial or lung cancer), proctoscope, colonoscope, cystoscope (e.g., into the bladder or upper urinary tract via cystoscopic lavage), gastroscope and laparoscope, or other suitable surgical / medical instrument capable of delivering a pharmaceutical dose such as the conjugate and composition of the present invention to the site of the cancer in a human or veterinary animal. In certain such embodiments, the conjugate or composition can be administered after surgical resection or excision of a solid tumor, or after removal or aspiration of tumor ascites, for example, using a trocar introduced into the abdomen for removal of ascites.In such embodiments, the conjugate or composition of the invention may be introduced directly into the surgical resection site or ascites, for example, via any of the above-described instruments or devices (optionally, together with one or more additional therapeutic agents).

[0481] In other embodiments, administration of the conjugate or composition into an organ lumen or the brain or into the brain may be accomplished by any well-known means, including in the form of a solution, ointment, plaster, patch, cream, topical solution, and drug-eluting wafer. For example, the conjugate or composition may be in the form of one or more droplets of a solution or suspension containing the composition or conjugate; by injection; in the form of a coating on a solid material implanted into an organ lumen or the brain; in the form of a mesh or patch; or the conjugate or composition may be bound to or encapsulated within one or more nanoparticles and then delivered into the organ lumen or the brain, whereby it may be applied or introduced into or onto the organ lumen or the brain or into the brain. Other suitable methods for applying the conjugate or composition into an organ lumen or the brain or into the brain to carry out the treatment and diagnostic methods of the invention will be readily apparent to those skilled in the art.

[0482] Gastrointestinal diseases or disorders that can be treated, prevented, ameliorated, or diagnosed using the compositions and methods of the invention include, but are not limited to, irritable bowel syndrome, Crohn's disease, ulcers, ulcerative colitis, esophagitis, Barrett's esophagitis, gastritis, and proctitis.

[0483] According to this aspect of the present invention, a method for treating or preventing a gastrointestinal disease or disorder in a human or veterinary animal suffering from or having a predisposition to a gastrointestinal disease or disorder comprises administering a composition described herein, particularly CMP and CMP-TC conjugate and a composition containing such CMP and / or conjugate, to the gastrointestinal tract of the human or veterinary animal at a site close to the location of the lesion associated with or causing the gastrointestinal disease or disorder. Without wishing to be bound by theory, in areas where certain gastrointestinal diseases and disorders are present, type I collagen is sufficiently disrupted, so that CMP specifically targets the site of the gastrointestinal disease or disorder, inserts into the collagen structure, thereby directly reforming a functional collagen matrix, or, if CMP is conjugated to a therapeutic compound, thereby delivering the CMP and / or therapeutic compound to the site where it is necessary to act to treat, prevent or ameliorate the gastrointestinal disease or disorder. Particularly preferred conjugates or compositions for use in this aspect of the present invention are those in which the therapeutic compound is a biological therapeutic compound, particularly one or more monoclonal antibodies or fragments thereof, or one or more therapeutic fusion proteins, particularly recombinant fusion proteins including those described herein. According to this aspect of the present invention, the conjugate or composition is suitably applied to the gastrointestinal tract or therein in a dosage sufficient to treat, prevent or ameliorate the gastrointestinal disease or disorder, and then the progression, remission or arrest of the gastrointestinal disease or disorder in the human or veterinary animal is monitored over time with respect to improvement in the condition of the disease or disorder. If necessary, the conjugate or composition of the present invention is then re-administered regularly into the gastrointestinal tract according to the dosing and treatment schedules and protocols described herein and others that will be apparent to those skilled in the art until the gastrointestinal disease or disorder is cured, prevented or ameliorated. In such embodiments, the conjugate or composition of the present invention is suitably administered parenterally or topically to the gastrointestinal tract or therein.Parenteral administration is carried out via any of the routes known in the art for administering a therapeutic agent to the gastrointestinal tract, for example, via a route selected from the group consisting of subcutaneous injection, intravenous infusion, intra-arterial infusion, transdermal diffusion, implantation of a drug eluting wafer, sublingual, oral, or rectal. In such methods, the composition is in the form of a pill, capsule, solution, suspension, or powder to be ingested by a human or veterinary animal, or in the form of a mesh or patch to be implanted into the gastrointestinal tract at or near the site of the disease or disorder, and is preferably administered parenterally to a human or veterinary animal. In other such embodiments, particularly where the disease or disorder is within the lumen of the gastrointestinal tract, the conjugate or composition of the present invention is administered into the lumen of the gastrointestinal organs of a human or veterinary animal using a suitable medical instrument such as a rectoscope, colonoscope, cystoscope (e.g., into the bladder or upper urinary tract by cystoscope), gastroscope and laparoscope, or other suitable surgical / medical instrument capable of delivering a dosage of a medicament such as the conjugate and composition of the present invention to the site of a gastrointestinal disease or disorder in a human or veterinary animal.

[0484] In other embodiments, administration of the conjugate or composition to or into the gastrointestinal tract may be accomplished by any well-known means, including in the form of a solution, ointment, plaster, patch, cream, topical solution, and drug eluting wafer. For example, the conjugate or composition may be in the form of one or more droplets of a solution or suspension containing the composition or conjugate; by injection; in the form of a coating on a solid material implanted into the gastrointestinal tract; in the form of a mesh or patch; or the conjugate or composition may be bound to or encapsulated within one or more nanoparticles and then delivered into the gastrointestinal tract, and thus may be applied or introduced to or into the gastrointestinal tract. Other suitable methods for applying the conjugate or composition to or into the gastrointestinal tract to carry out the therapeutic and diagnostic methods of the present invention will be readily apparent to those skilled in the art.

[0485] Genitourinary diseases or disorders that can be treated, prevented, improved or diagnosed using the compositions and methods of the present invention include, but are not limited to, female urinary incontinence, cystitis, interstitial cystitis, overactive bladder syndrome, urethritis and vaginitis.

[0486] According to this aspect of the present invention, a method for treating or preventing a urogenital disease or disorder in a human or veterinary animal suffering from or having a predisposition to a urogenital disease or disorder comprises administering a composition described herein, particularly a CMP and a CMP-TC conjugate and a composition comprising such CMP and / or conjugate, to the urogenital tract of the human or veterinary animal at a site close to the location of a lesion associated with or causing the urogenital disease or disorder. Without wishing to be bound by theory, in areas where certain urogenital diseases and disorders are present, type I collagen is sufficiently disrupted, so that CMP specifically targets the site of the urogenital disease or disorder, inserts into the collagen structure, whereby a functional collagen matrix is directly reformed, or, if the CMP is conjugated to a therapeutic compound, whereby the CMP and / or the therapeutic compound is delivered to the site where it is necessary to act to treat, prevent or ameliorate the urogenital disease or disorder. According to this aspect of the present invention, the conjugate or composition is suitably applied to or into the urogenital tract in a dosage sufficient to treat, prevent or ameliorate the urogenital disease or disorder, and then the progression, remission or arrest of the urogenital disease or disorder in the human or veterinary animal is monitored over time for improvement in the condition of the disease or disorder. If necessary, the conjugate or composition of the present invention is then readministered periodically into the urogenital tract according to the dosing and treatment schedules and protocols described herein and others that will be apparent to those skilled in the art until the urogenital disease or disorder is cured, prevented or ameliorated. In such embodiments, the conjugate or composition of the present invention is suitably administered parenterally or topically to or into the urogenital tract. Parenteral administration is effected via any of the routes known in the art for administering a therapeutic agent to the gastrointestinal tract, for example, via a route selected from the group consisting of subcutaneous injection, intravenous infusion, intraarterial infusion, transdermal diffusion, implantation of a drug-eluting wafer, sublingual, oral, vaginal, or rectal.In such a method, the composition is preferably parenterally administered to a human or veterinary animal in the form of a pill, capsule, solution, suspension, or powder for ingestion by the human or veterinary animal, or in the form of a mesh or patch implanted into the urogenital tract at or near the site of the disease or disorder. In other such embodiments, particularly where the disease or disorder is within the lumen of the gastrointestinal tract, the conjugate or composition of the present invention can be administered into the lumen of the urogenital organs of a human or veterinary animal using a medical instrument suitable for such purposes, such as an endoscope, vaginoscope, and laparoscope, or other suitable surgical / medical instruments capable of delivering a dosage of a medicament such as the conjugate and composition of the present invention to the site of a urogenital disease or disorder in a human or veterinary animal.

[0487] In other embodiments, administration of the conjugate or composition to or into the urogenital tract can be accomplished by any well-known means, including in the form of a solution, ointment, plaster, patch, wafer, film, gel, sphere, nanoparticle, cream, topical solution, and drug-eluting wafer. For example, the conjugate or composition can be in the form of one or more droplets of a solution or suspension containing the composition or conjugate; by injection; in the form of a coating on a solid material implanted into the urogenital tract; in the form of a mesh or patch; or the conjugate or composition can be bound to or encapsulated within one or more nanoparticles and then delivered into the urogenital tract, whereby it can be applied or introduced to or into the urogenital tract. Other suitable methods for applying the conjugate or composition to or into the urogenital tract to carry out the treatment and diagnostic methods of the present invention will be readily apparent to those skilled in the art.

[0488] Fibrotic diseases or disorders that can be treated, prevented, ameliorated, or diagnosed using the compositions and methods of the present invention include, but are not limited to, pulmonary fibrosis, cirrhosis, myocardial fibrosis, surgical scarring, systemic sclerosis, scleroderma, keloid formation, proliferative vitreoretinopathy, and the like.

[0489] According to this aspect of the invention, a method for treating or preventing a fibrotic disease or disorder in a human or veterinary animal suffering from or predisposed to a fibrotic disease or disorder comprises administering a composition described herein, particularly a CMP and a CMP-TC conjugate and a composition comprising such CMP and / or conjugate, to one or more tissues, organs, or organ systems of a human or veterinary animal at or near the location of a fibrotic lesion associated with or causing the fibrotic disease or disorder. Without wishing to be bound by theory, in areas where certain fibrotic diseases and disorders are present, type I collagen is sufficiently disrupted so that CMP specifically targets the site of the fibrotic disease or disorder, inserts into the collagen structure, whereby a functional collagen matrix is directly reformed, or, if the CMP is conjugated to a therapeutic compound, whereby the therapeutic compound is delivered to the site where it is necessary to act to treat, prevent or ameliorate the fibrotic disease or disorder. According to this aspect of the invention, the conjugate or composition is suitably applied at, near or within a tissue, organ, or organ system in a dosage sufficient to treat, prevent or ameliorate the fibrotic disease or disorder, and then the progression, remission or arrest of the fibrotic disease or disorder in the human or veterinary animal is monitored over time for improvement in the condition of the disease or disorder. If necessary, the conjugate or composition of the invention is then re-administered periodically into, near, on or within one or more tissues, organs, or organ systems according to a dosing and treatment schedule and protocol described herein and known to those skilled in the art until the fibrotic disease or disorder is cured, prevented or ameliorated. In such embodiments, the conjugate or composition of the invention is suitably administered parenterally or topically to, near, on or within a tissue, organ, or organ system.Parenteral administration is effected via any of the routes known in the art for administering a therapeutic agent to a tissue, organ, or organ system, for example, by subcutaneous injection, intravenous infusion, intra-arterial infusion, endoscopic application, transdermal diffusion, implantation of a drug-eluting wafer, film, gel, or paste, via a route selected from the group consisting of sublingual, oral, or rectal. In such methods, the composition is in the form of a pill, capsule, solution, suspension, or powder ingested by a human or veterinary animal, or in the form of a mesh, film, wafer, gel, sphere, nanoparticle, paste, or patch implanted near, on, or within a fibrous tissue, organ, or organ system at or near the site of a disease or disorder, and is preferably administered parenterally to a human or veterinary animal.

[0490] In other embodiments, administration of the conjugate or composition into or near a tissue, organ, or organ system may be effected by any well-known means, including in the form of a solution, ointment, plaster, patch, film, gel, sphere, nanoparticle, paste, cream, topical solution, and drug-eluting wafer. For example, the conjugate or composition may be in the form of one or more droplets of a solution or suspension containing the composition or conjugate; by injection; in the form of a coating on a solid material implanted into, near, or on a tissue, organ, or organ system; in the form of a mesh or patch; by binding or encapsulating the conjugate or composition into one or more nanoparticles and then delivering them into, near, or on a tissue, organ, or organ system, and may be applied or introduced into a tissue, organ, or organ system or near or within it. Other suitable methods for applying the conjugate or composition into or near a tissue, organ, or organ system or on it to carry out the therapeutic and diagnostic methods of the present invention will be readily apparent to those skilled in the art.

[0491] Cardiovascular diseases or disorders that can be treated, prevented, ameliorated or diagnosed using the compositions and methods of the present invention include, but are not limited to, myocardial infarction, heart failure, heart valve disorders, atherosclerosis, cardiomyopathy, arrhythmia, congenital heart disease, coronary artery disease, pericardial disease, vascular occlusive diseases (e.g., those affecting the carotid artery, aorta, renal artery, femoral artery, pulmonary artery, as well as other large and small blood vessels that can be arteries, arterioles, veins, venules, etc.), Marfan syndrome, and the like.

[0492] According to this aspect of the present invention, a method for treating or preventing a cardiovascular disease or disorder in a human or veterinary animal suffering from or having a predisposition to a cardiovascular disease or disorder comprises administering a composition described herein, particularly a CMP and / or a CMP-TC conjugate and a composition comprising such a CMP and / or conjugate, into the vasculature of a human or veterinary animal suffering from or having a predisposition to such a disease or disorder. Without wishing to be bound by theory, in areas where certain cardiovascular diseases and disorders are present, type I collagen is sufficiently disrupted, so that CMP introduced into the vasculature of a subject specifically targets the site of the cardiovascular disease or disorder, inserts into the collagen structure, whereby a functional collagen matrix is directly reformed, or if the CMP is conjugated to a therapeutic compound, whereby the CMP and / or the therapeutic compound are delivered to the site where they need to act to treat, prevent or ameliorate the cardiovascular disease or disorder. According to this aspect of the present invention, the conjugate or composition is suitably applied to or into the vasculature in a dosage sufficient to treat, prevent or ameliorate the cardiovascular disease or disorder, and then the progression, remission or arrest of the cardiovascular disease or disorder in the human or veterinary animal is monitored over time for improvement in the condition of the disease or disorder. If necessary, the conjugate or composition of the present invention is then readministered periodically into the vasculature according to the dosing and treatment schedules and protocols described herein and others that will be apparent to those skilled in the art until the cardiovascular disease or disorder is cured, prevented or ameliorated. In such embodiments, the conjugate or composition of the present invention is suitably administered parenterally or topically to or into the heart, pericardium, blood vessels, or other relevant components of the vasculature. Parenteral administration is accomplished via any of the routes known in the art for administering therapeutic agents to the vasculature, for example, subcutaneous injection, intravenous infusion, intra-arterial infusion, transdermal diffusion, catheterization, embolization, implantation of a drug-eluting wafer or film, sublingual, oral, rectal.In such a method, the composition is preferably parenterally administered to a human or veterinary animal in the form of a pill, capsule, solution, suspension, or powder, or in the form of a mesh, wafer, film, gel, paste, sphere, nanoparticle, or patch that is implanted into or near a site involved in a cardiovascular disease or disorder within the heart, pericardium, vasculature, or other related components of the vasculature.

[0493] In other embodiments, administration of the conjugate or composition to or into the vasculature may be accomplished by any well-known means, including in the form of a solution, ointment, plaster, patch, film, gel, sphere, nanoparticle, cream, topical solution, and drug-eluting wafer. For example, the conjugate or composition may be in the form of one or more droplets of a solution or suspension containing the composition or conjugate; by injection; in the form of a coating on a solid material implanted into the heart, pericardium, vasculature, or other related components of the vasculature; in the form of a mesh or patch; by binding or encapsulating the conjugate or composition in one or more nanoparticles and then delivering it into the heart, pericardium, vasculature, or other related components of the vasculature, whereby it can be applied or introduced into or within the heart, pericardium, vasculature, or other related components of the vasculature. Other suitable methods for applying the conjugate or composition to or into the vasculature to practice the therapeutic and diagnostic methods of the present invention will be readily apparent to those skilled in the art.

[0494] Bone diseases or disorders that can be treated, prevented, ameliorated, or diagnosed using the compositions and methods of the present invention include, but are not limited to, osteoporosis, fractures, osteomyelitis, osteogenesis imperfecta, Paget's disease of bone, osteonecrosis, kuru, osteomalacia, acromegaly, and the like.

[0495] According to this aspect of the invention, a method for treating or preventing a bone disease or disorder in a human or veterinary animal suffering from or predisposed to a bone disease or disorder comprises administering a composition described herein, particularly a CMP and a CMP-TC conjugate and a composition containing such CMP and / or conjugate, into or near one or more bones of a human or veterinary animal at a site close to the location of a lesion associated with or causing the bone disease or disorder. Without wishing to be bound by theory, in areas where certain bone diseases and disorders are present, type I collagen is sufficiently disrupted, so that CMP specifically targets the site of the bone disease or disorder, inserts into the collagen structure, whereby a functional collagen matrix is directly reformed, or, if the CMP is conjugated to a therapeutic compound, whereby the therapeutic compound is delivered to the site where it needs to act to treat, prevent or ameliorate the bone disease or disorder. According to this aspect of the invention, the conjugate or composition is suitably applied into, near or in the bone in a dosage sufficient to treat, prevent or ameliorate the bone disease or disorder, and then the progression, remission or arrest of the bone disease or disorder in the human or veterinary animal is monitored over time for improvement in the condition of the disease or disorder. If necessary, the conjugate or composition of the invention is then re-administered periodically into, near or on one or more bones according to the dosing and treatment schedules and protocols described herein and others known to those skilled in the art until the bone disease or disorder is cured, prevented or ameliorated. In such embodiments, the conjugate or composition of the invention is suitably administered parenterally or topically into, near, on or in the bone. Parenteral administration is effected via any of the routes known in the art for administering therapeutic agents to bone, for example, subcutaneous injection, intravenous infusion, intra-arterial infusion, endoscopic application, transdermal diffusion, implantation of a drug eluting wafer, film, gel, or pate, sublingual, oral, or rectal routes selected from the group consisting of.In such a method, the composition is preferably parenterally administered to a human or veterinary animal in the form of a pill, capsule, solution, suspension, or powder for ingestion by the human or veterinary animal, or in the form of a mesh, film, wafer, gel, sphere, nanoparticle, paste, or patch to be implanted near, on, or in bone at or near the site of a disease or disorder.

[0496] In other embodiments, administration of the conjugate or composition into, near, or in bone may be accomplished by any well-known means, including in the form of a solution, ointment, plaster, patch, film, gel, sphere, nanoparticle, paste, cream, topical solution, and drug-eluting wafer. For example, the conjugate or composition may be in the form of one or more droplets of a solution or suspension containing the composition or conjugate; by injection; in the form of a coating on a solid material implanted into, near, or on bone; in the form of a mesh or patch; or the conjugate or composition may be bound to or encapsulated within one or more nanoparticles and then delivered into, near, or on bone, whereby the conjugate or composition may be applied or introduced into bone or near or in it. Other suitable methods for applying the conjugate or composition to, on, near, or in bone to carry out the therapeutic and diagnostic methods of the present invention will be readily apparent to those skilled in the art.

[0497] Rheumatic diseases or disorders that can be treated, prevented, ameliorated, or diagnosed using the compositions and methods of the present invention include, but are not limited to, arthritis (particularly rheumatoid arthritis, osteoarthritis, and psoriatic arthritis), synovitis, crepitus, spondylosis, scleroderma, polymyalgia rheumatica, and arthritic syndromes.

[0498] According to this aspect of the invention, a method of treating or preventing a rheumatic disease or disorder in a human or veterinary animal suffering from or predisposed to a rheumatic disease or disorder comprises administering to the human or veterinary animal, at a site close to the location of a lesion associated with or causing the rheumatic disease or disorder, a composition described herein, particularly a CMP or CMP-TC conjugate and a composition comprising such CMP and / or conjugate. Without wishing to be bound by theory, in areas where certain rheumatic diseases and disorders are present, type I collagen is sufficiently disrupted such that CMP specifically targets the site of the rheumatic disease or disorder, inserts into the collagen structure, thereby directly reforming a functional collagen matrix, or, when CMP is conjugated to a therapeutic compound, thereby delivering the therapeutic compound to the site where it needs to act to treat, prevent or ameliorate the rheumatic disease or disorder. According to this aspect of the invention, the conjugate or composition is suitably applied to a human or veterinary animal or in a human or veterinary animal in a dosage sufficient to treat, prevent or ameliorate the rheumatic disease or disorder, and then the progression, remission or arrest of the rheumatic disease or disorder in the human or veterinary animal is monitored over time for improvement in the state of the disease or disorder. If necessary, the conjugate or composition of the invention is then readministered periodically to the human or veterinary animal according to the dosing and treatment schedules and protocols described herein and others known to those of skill in the art until the rheumatic disease or disorder is cured, prevented or ameliorated. In such embodiments, the conjugate or composition of the invention is suitably administered parenterally or topically to a human or veterinary animal or in a human or veterinary animal. Parenteral administration is effected via any of the routes known in the art for administering therapeutic agents designed to treat, prevent or ameliorate a rheumatic disease or disorder, for example, via a route selected from the group consisting of subcutaneous injection, intravenous infusion, intraarterial infusion, transdermal diffusion, implantation of a drug-eluting wafer, sublingual, oral, vaginal, or rectal.In such a method, the composition is preferably parenterally administered to a human or veterinary animal in the form of a pill, capsule, solution, suspension, or powder that is ingested by the human or veterinary animal, or in the form of a mesh or patch that is implanted into the human or veterinary animal at or near the site of the disease or disorder. In other such embodiments, particularly where a rheumatic disease or disorder is located in or near bone, tendon, cartilage, ligament, bursa, joint, or related structures, the composition or conjugate of the present invention is administered to a human or veterinary animal using a suitable medical instrument, such as a laparoscope, or other suitable surgical / medical instrument capable of delivering a dose of a medicament, such as the conjugate and composition of the present invention, to the site of a urogenital disease or disorder in the human or veterinary animal, for such purposes.

[0499] In other embodiments, administration of the conjugate or composition to a human or veterinary animal or into the human or veterinary animal may be accomplished by any well-known means, including in the form of a solution, ointment, plaster, patch, cream, topical solution, and drug-eluting wafer. For example, the conjugate or composition may be in the form of one or more droplets of a solution or suspension containing the composition or conjugate; by injection; in the form of a coating on a solid material implanted into the human or veterinary animal; in the form of a mesh or patch; by binding the conjugate or composition to, or encapsulating it within, one or more nanoparticles and then delivering it into the human or veterinary animal, such that the conjugate or composition may be applied or introduced to the human or veterinary animal or into the human or veterinary animal. Other suitable methods for applying the conjugate or composition to a human or veterinary animal or into the human or veterinary animal to effect the treatment and diagnostic methods of the present invention will be readily apparent to those of ordinary skill in the art.

[0500] Diseases or disorders of the nerves or nervous system (including the central nervous system ("CNS") and the peripheral nervous system ("PNS")) that can be treated, prevented, ameliorated or diagnosed using the compositions and methods of the present invention include injury to one or more nerves or neurites (including axons, dendrites and nerve cells or cell bodies, ganglia, nerve tracts, etc.), neurodegeneration (in many different physiological or disease settings, such as multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, traumatic brain injury, non-Alzheimer's type dementia, encephalitis, meningitis, etc.), disorders involving the peripheral nerves (such as diabetic peripheral neuropathy, nutritional neuropathy, and alcoholic neuropathy, etc.), or specific neuroocular diseases and disorders including those involving or affecting the corneal nerves, retinal nerves and optic nerves, including but not limited to glaucoma, macular degeneration (wet and / or dry, age-related or not), neurotrophic keratitis, retinopathy (including diabetic retinopathy, ischemic retinopathy, proliferative retinopathy, geographic atrophy, and other gene-based retinopathies and hereditary retinal diseases or disorders known in the art), injury or inflammation of one or more corneal nerves (which may result from external diseases or eye injury or inflammation via trauma / wound including nerve or neurite transection or crush or torsion injury), corneal pain (which can be acute or chronic and may result from injury or damage to or corneal denervation of the corneal nerves, e.g., periorbital pain, extraocular pain, and post-herpetic neuralgia), encephalopathy (such as traumatic encephalopathy like concussion, encephalitis, meningitis), etc., but not limited to these. In certain such embodiments, the compositions and methods of the present invention can be used to induce nerve repair or regrowth (e.g., via nerve regeneration) in cranial nerves including but not limited to the optic nerve, retinal nerve, auditory nerve or spinal nerve.In other such embodiments, the compositions and methods of the invention can be used to protect a particular nerve from degeneration or the progression or persistence of degeneration (i.e., provide a neuroprotective function), which can, for example, prevent, reduce, or slow the progression of nerve degeneration for the prevention and / or treatment of, e.g., diabetic neuropathy, nutritional neuropathy, and alcoholic neuropathy, and prevent, reduce, or slow the progression of corneal nerve, optic nerve, and / or retinal nerve degeneration for the prevention and / or treatment of corneal pain (e.g., acute or chronic corneal pain including, but not limited to, periorbital pain, extraocular pain, and postherpetic neuralgia), glaucoma, hereditary retinal diseases or disorders, and gene-based retinopathies (e.g., diabetic retinopathy). Other beneficial uses of the compositions and methods of the invention in the treatment, prevention, amelioration, or diagnosis of diseases or disorders of the nerves and nervous system will be apparent to those skilled in the art based on the guidance provided herein and considering information readily available in the relevant art.

[0501] According to this aspect of the present invention, a method for treating or preventing a disease or disorder of the nerve or nervous system in a human or veterinary animal suffering from or having a predisposition to a disease or disorder of the nerve or nervous system comprises administering a composition described herein, particularly a CMP and a CMP-TC conjugate, and a composition comprising such CMP and / or conjugate, to one or more tissues, organs, or organ systems of the human or veterinary animal at a site near the location of a nerve or nervous system lesion associated with or causing the disease or disorder of the nerve or nervous system, within or near the same. Without wishing to be bound by theory, in regions where certain nerve or nervous system diseases and disorders are present, type I collagen is sufficiently (perhaps particularly among the components of the local extracellular matrix) disrupted, so that CMP specifically targets the site of the nerve or nervous system disease or disorder, inserts into the collagen structure, thereby directly inducing nerve regeneration and / or nerve protection through the reformation of a functional collagen matrix, or, when the CMP carries a therapeutic compound, the therapeutic compound is delivered to the site where it needs to act to treat, prevent or ameliorate the nerve or nervous system disease or disorder. According to this aspect of the present invention, the conjugate or composition is preferably applied at a dosage sufficient to treat, prevent or ameliorate the disease or disorder of the nerve or nervous system, to a tissue, organ, or organ system, near or within the same, and then the progression, remission or arrest of the disease or disorder of the nerve or nervous system in the human or veterinary animal is monitored over time for improvement in the condition of the disease or disorder. Further concentrations and amounts of the conjugate or composition of the present invention preferably used in such methods can be readily determined by one of ordinary skill in the art based on information included herein and available in the art, without relying on undue experimentation. If necessary, the conjugate or composition of the present invention is then periodically re-administered into, near or onto one or more tissues, organs, or organ systems according to a dosing and treatment schedule and protocol described herein and known to one of ordinary skill in the art until the disease or disorder of the nerve or nervous system is cured, prevented or ameliorated.In such embodiments, the conjugate or composition of the present invention is preferably administered parenterally or topically to, in the vicinity of, on, or within a tissue, organ, or organ system. Parenteral administration is by any of the routes known in the art for administering a therapeutic agent to a tissue, organ, or organ system, for example, subcutaneous injection, intradermal injection, intramuscular injection, intracranial injection, intraspinal injection, or injection into any tissue, organ, or organ system in which a disease or disorder of the nerve or nervous system is manifest, intravenous infusion, intra-arterial infusion, endoscopic application, transdermal diffusion, implantation of a drug-eluting wafer, film, gel, or paste, sublingual, oral, or rectal routes selected from the group consisting of. In certain such methods, the composition is in the form of an injection solution or paste, a pill, capsule, solution, suspension, or powder inhaled or ingested by a human or veterinary animal, or a mesh, film, wafer, gel, sphere, nanoparticle, paste, pate, or patch implanted in the vicinity of, on, or within a tissue, organ, or organ system near or at the site of a disease or disorder of the nerve or nervous system, and is preferably administered parenterally to a human or veterinary animal. In certain such embodiments, one or more of the compounds, compositions, or conjugates of the present invention may be coated on or in a mesh or "sleeve" material to permeate the mesh or sleeve material with one or more of the compounds, compositions, or conjugates of the present invention, and then the mesh or sleeve may be applied to a damaged (e.g., transected) or injured nerve, neurite, or nerve bundle.

[0502] In other embodiments, administration of the conjugate or composition into or near or within a tissue, organ, or organ system may be accomplished by any well-known means, including in the form of a solution, ointment, plaster, patch, film, gel, paste, sphere, nanoparticle, pate, cream, topical solution, and drug eluting wafer. For example, the conjugate or composition may be in the form of one or more droplets of a solution or suspension containing the composition or conjugate (e.g., in the form of a topical ophthalmic eye drop when used in the eye fundus); by injection; in the form of a coating on a solid material implanted into, near, or on a tissue, organ, or organ system; in the form of a mesh or patch; by binding the conjugate or composition to or encapsulating it within one or more nanoparticles and then delivering it into, near, or on a tissue, organ, or organ system, the conjugate or composition may be applied or introduced into or near or within a tissue, organ, or organ system. Other suitable methods for applying the conjugate or composition into or on or near a tissue, organ, or organ system or within it to carry out the therapeutic and diagnostic methods of the present invention will be readily apparent to those skilled in the art.

[0503] In related embodiments, the present invention provides a device, particularly a medical device, suitable for treating or preventing a disease, disorder or medical condition in a human or veterinary animal suffering from or predisposed to the disease, disorder or medical condition. Such a device preferably comprises at least one of the compositions of the present invention in the form of a coating on the device or a composition encapsulated within the device so as to be released or eluted from the device when implanted into the body of a human or veterinary animal. Suitable such devices include, but are not limited to, artificial joints, stents, catheters, sutures, bone screws, bone plates, prostheses (e.g., artificial limbs, body structures, organs, etc.), absorbent or non-absorbent meshes, absorbent or non-absorbent patches, drug-eluting wafers, cranial nerve stimulation devices (e.g., deep brain stimulation devices), gastric stimulation devices, cochlear implants, cardioverter defibrillators, cardiac pacemakers, insulin pumps, internal infusion pumps, and the like. Other suitable devices useful in accordance with this aspect of the present invention will be readily apparent to those skilled in the art.

[0504] The devices provided by this aspect of the invention are useful for treating, preventing, ameliorating, or diagnosing such diseases, disorders, and medical conditions in humans or veterinary animals suffering from or predisposed to such diseases, disorders, and medical conditions. In a method according to this aspect, one or more medical devices of the invention are implanted in a human or veterinary animal, and the medical condition of the human or veterinary animal is monitored until the disease, disorder, or medical condition in the human or veterinary animal is cured, ameliorated, or prevented. Suitable diseases, disorders, and medical conditions that can be treated, ameliorated, or prevented using the devices and methods of the invention include cancer (such as those described elsewhere herein), as well as the integumentary system (particularly skin diseases or disorders, such as those detailed herein), the muscular system, the skeletal system (particularly diseases or disorders of bone, joints, cartilage, tendons, or ligaments, such as those detailed herein), the nervous system (particularly those of the brain or eyes (e.g., those involving corneal nerves (e.g., those resulting from damage or disorder or denervation of corneal nerves, e.g., corneal pain (which can be acute or chronic) including periorbital pain, extraocular pain, and post-herpetic neuralgia), glaucoma, cataract, vitreous adhesion or floaters, macular degeneration, dry eye syndrome, keratitis, non-infectious corneal ulceration, non-infectious corneal melting, infectious corneal ulceration, infectious corneal melting, conjunctivitis, Stevens-Johnson syndrome, scleritis, episcleritis, iritis, uveitis, vitritis, Behçet's disease uveitis, punctate choroidopathy, juvenile idiopathic arthritis (JIA)-associated uveitis, multifocal choroiditis with panuveitis, necrotizing scleritis, serpiginous choroidopathy, sympathetic ophthalmia, Vogt-Koyanagi-Harada (VKH) disease, non-infectious panuveitis, ectasia, keratoconus, corneal laceration, corneal erosion, corneal abrasion, and postoperative diseases of the eye resulting from ophthalmic surgery, e.g., postoperative conditions of cataract surgery requiring medication or postoperative conditions of glaucoma surgery requiring medication, including but not limited to anterior segment diseases and disorders, or macular degeneration (wet, dry, and age-related), retinitis pigmentosa, retinal holes and detachments, retinopathies (e.g., diabetic retinopathy), occlusion of retinal arteries or veins (e.g., branch retinal artery occlusion (BRAO), central retinal artery occlusion (CRAO),Posterior segment disorders of the eye, such as BRVO (branch retinal vein occlusion) and CRVO (central retinal vein occlusion), optic neuritis, optic nerve disorders (including, for example, AION (anterior ischemic optic neuropathy), traumatic optic neuropathy, and optic nerve atrophy (such as glaucomatous optic atrophy)), and disorders involving the retina, retinal epithelium (particularly retinal pigment epithelium), retinal blood vessels, retinal nerves, or optic nerve, as well as cranial nerve palsies, including but not limited to third cranial nerve palsy, fourth cranial nerve palsy, fifth cranial nerve palsy (such as trigeminal neuralgia and postherpetic neuralgia), sixth cranial nerve palsy, and seventh cranial nerve palsy (such as Bell's palsy), and other neurological disorders, circulatory system, lymphatic system, respiratory system (diseases or disorders affecting the larynx, trachea, bronchi, bronchioles, or lungs of humans or veterinary animals, particularly including the diseases and disorders detailed herein), endocrine system, urogenital / excretory system (diseases or disorders affecting the kidneys, ureters, bladder, upper urinary tract (i.e., renal pelvis), ureters, or urethra of humans or veterinary animals, particularly including the diseases and disorders detailed herein), genital system (diseases and disorders affecting the testes, prostate, penis, vagina, cervix, uterus, fallopian tubes, or ovaries of the human or veterinary animal, particularly including the diseases and disorders detailed herein), digestive system (diseases or disorders affecting the esophagus, stomach, small intestine, colon, or rectum of the human or veterinary animal, particularly including the diseases and disorders detailed herein), and nerves or nervous system (including the peripheral and central nervous systems, particularly including injuries, diseases, and disorders of the nerves or nervous system detailed herein) that affect the eye or the periorbital region. Suitable methods for implanting one or more of the devices provided by this aspect of the invention into a human or veterinary animal to perform treatment, prevention, improvement, or diagnosis of a disease, disorder, or medical or physical condition in a human or veterinary animal will be apparent to those of ordinary skill in the relevant medical and surgical arts.

[0505] The concentration of CMP or CMP-TC conjugate useful in treating, preventing, ameliorating or diagnosing one or more diseases or disorders according to the method of the present invention will be readily apparent to those skilled in the art of pharmacy and medicine. In the case of unconjugated CMP, suitable amounts or concentrations of CMP administered to a subject, particularly a human or veterinary animal, and suitable amounts or concentrations of CMP used include those described above herein. Those skilled in the art of medicine, pharmacy and / or pharmacology can, based on the guidance provided herein, determine the appropriate amounts of the conjugates and compositions of the present invention to be used per kilogram (kg) of body weight of a human or veterinary animal. In the case of conjugated CMP-TC, the CMP described herein is preferably administered to the subject in the same amount or concentration, whether in terms of concentration (e.g., ng / ml or μg / ml) or amount (e.g., mg / kg body weight), and the amount of the pharmaceutical active ingredient or biologic is calculated during the conjugation process to deliver the desired pharmaceutical active ingredient or biologic in a therapeutically effective amount depending on the disease or disorder to be treated, prevented, ameliorated or diagnosed in a human or veterinary animal. Suitable amounts or concentrations of the pharmaceutical active ingredient or biologic used according to this aspect of the present invention will be known to those skilled in the art and can be readily determined from the information contained herein and other information available in the relevant art.

[0506] It will be readily apparent to those skilled in the relevant art that other suitable modifications and applications to the methods and applications described herein can be made without departing from the scope of the present invention or its embodiments. Although the present invention has been described in detail up to this point, the present invention will be more clearly understood by reference to the following examples. The examples are included herein for illustrative purposes only and are not intended to limit the present invention.

Examples

[0507] Example 1: Effects of CMP and CMP-TC Conjugates in the Treatment of Myopia

[0508] To investigate the potential therapeutic effects of the CMPs of the present invention in the treatment of myopia, studies were designed to test specific CMP conjugates in an in vivo setting (the potential for the treatment and recovery of myopia in experimental animals such as mice and rats). In such studies, the animals were anesthetized and their eyes were treated by instillation of 1 - 3 days of 60 nM human matrix metalloproteinase 1 (MMP - 1; Biolegend, San Diego, CA) pre - activated with 2 mM 4 - aminophenylmercury acetate (APMA, Sigma, St. Louis, MO) as previously reported (Ribeiro, M. et al., Int. J. Mol. Sci. 23:7004 (2022)). Negative control animals were treated with vehicle only (PBS). After MMP treatment, the animals were treated by daily instillation of 25 μg / ml or 50 μg / ml of CMP (especially SEQ ID NO: 1 or SEQ ID NO: 6) or vehicle (PBS) for negative control animals for up to 3 weeks. After these treatments, the axial length of the eye was measured using standard ophthalmic techniques, and the structure of the scleral collagen matrix was determined using various microscopy techniques including confocal microscopy, second harmonic generation microscopy (Guo, P. et al., Trans. Sci. Tech. 9(9):45 (2020)). The results of these studies correlate an increase in collagen de - aggregation and disassembly with an increase in axial length, indicating that the collagen matrix within the sclera is involved in maintaining the optimal eye structure and shape, and that disruption of the collagen matrix is associated with decreased vision and the onset of myopia. Furthermore, as indicated by the results of these studies, animals treated with the CMP - containing compositions of the present invention showed an increase in the level of collagen organization and a recovery of the underlying collagen matrix structure of the sclera, resulting in a decrease in axial length that can be used to indicate treatment of myopia symptoms and / or signs. Therefore, the CMPs and CMP - TC conjugates of the present invention, as well as compositions containing them, are useful for promoting the reduction of axial length in in vivo animal eyes as models of various human and veterinary ophthalmic pathologies including myopia and presbyopia.

[0509] Example 2: Activity of CMP in the recovery of the collagen matrix structure and function in the sclera around the papilla of the mouse eye

[0510] The sclera of the mammalian eye is rich in collagen, which together with elastin constitutes most of the sclera (Guo, P. et al., Trans. Vis. Sci. Tech. 9:45 (2020)). The collagen of the sclera is thought to be related to the rigidity of the sclera in humans and veterinary animals, and thus to the shape of the eye (Schultz, D. S. et al., Invest. Ophthalmol. Vis. Sci. 49:4232 - 4236 (2008)). Numerous studies have shown that changes in the collagen structure, including narrowing of collagen bundles and reduction in the size of individual collagen bundles in the corneosclera, can lead to a reduction in scleral rigidity. Such a reduction in scleral rigidity results in an increase in the permeability of the corneosclera and affects the shape of the eye, leading to axial elongation of the eyeball and the onset of myopia (Jonas, J. B. and Xu, I., Eye 28:113 - 117 (2014), Guo, P. et al., Trans. Vis. Sci. Tech. 9:45 (2020), Hou, W. et al., Eye Contact Lens 44:248 - 259 (2018), Xue, C. C., et al., Br. J. Ophthalmol., doi:10.1136 / bjophthalmol - 2022 - 321868 (2022), Pugazhendhi, S., et al., Clin. Ophthalmol. 14:853 - 873 (2020), Metlapally, R. and Wildsoet, C. F., Prog. Mol. Biol. Transl. Sci 134:241 - 248 (2015)). In some studies, it has been found that an increase in the expression of matrix metalloproteinase (MMP) in the scleral matrix, which can occur from hereditary, environmental, or inflammatory etiologies, and the accompanying destruction of the scleral collagen matrix can lead to the onset of myopia in mice (Zhao, F. et al., Am. J. Pathol. 188:1754 - 1767 (2018), Guo, P. et al., Trans. Vis. Sci. Tech. 9:45 (2020)).Such effects on the corneal-scleral matrix can similarly result in other eye diseases and disorders, such as glaucoma, cataracts, grape tumors, and retinal complications (Wang, B., et al., PLoS ONE 12:e0175913, https: / / doi.org / 10.1371 / journal.pone.0175913 (2017)).

[0511] Efforts to treat or prevent myopia by strengthening the sclera have met with varying degrees of success. For example, treating myopic eyes with atropine may slow the progression of myopia (Upadhyay, A. and Beuerman, R. W., Eye & Contact Lens 46:129 - 135 (2020), Pugazhendhi, S., et al., Clin. Ophthalmol. 14:853 - 873 (2020), Gwiazda, J., Optom. Vis. Sci. 86:624 - 628 (2009)). This is probably due to inducing the production of type I collagen in scleral fibroblasts (Cristaldi, M. et al., Biomedicines 8:78 (2020)). In other studies, collagen fibrils in the corneoscleral matrix are hardened by chemical cross - linking or photo - induced cross - linking (Guo, P. et al., Trans. Vis. Sci. Tech. 9:45 (2020), Backhouse, S. and Gentle, A., Ann. Eye Sci. 3:5 (2018), Garcia, M. B. et al., Invest. Ophthalmol. Vis. Sci. 58:1875 - 1886 (2017), Elsheikh, A., and Phillipa, J. R., Ophthalmic Physiol. Opt. 33:385 - 389 (2013), Wang, W.-Y. et al., Biomed. Pharmacother. 133:111092 (2021)). However, one of the drawbacks of such approaches to treat or prevent myopia is that artificial connective tissue remodeling, as described in the literature cited above, can increase the risk of glaucoma in patients undergoing such treatments (Grytz, R., et al., Curr. Opin. Biomed. Eng. 15:40 - 50 (2020)).

[0512] Accordingly, the inventors have inferred that a method of hardening the corneoscleral matrix that is more closely similar to natural collagen repair as occurs during the treatment of the mammalian eye with a formulation comprising one or more collagen mimetic peptides (CMPs) including those of the present invention may be useful in treating myopia and preventing its progression by restoring the structure and function of the corneoscleral collagen matrix. Accordingly, such an approach may be useful in treating or preventing various corneoscleral diseases and disorders including, inter alia, myopia, presbyopia, scleritis, episcleritis, and keratoconus.

[0513] Accordingly, to investigate the potential therapeutic effect of the CMPs of the present invention in the treatment of myopia, studies were designed to test the effect of specific CMP conjugates in an in vivo - setting model and ex vivo studies of the collagen matrix in the peripapillary sclera of the mouse eye. To conduct these studies, mouse eyes were explanted, sectioned, and sections of the peripapillary sclera (the scleral region adjacent to the optic nerve head) were examined by atomic force microscopy (AFM). FIG. 1 shows the morphology of the peripapillary sclera in a representative sample of such a section, and the arrows in FIGS. 1A (low - magnification image) and 1B (high - magnification image of the same section) indicate the regions targeted by the AFM probe that can measure the Young's modulus of the corresponding tissue area as a determinant of the stiffness or elasticity of the structure at the measurement points (see, for example, Girard, M.J. et al., J. Biomech. Eng. 131:051012, doi:10.1115 / 1.3113683 (2009)). Specifically, a higher measured value of the Young's modulus at a given point by AFM indicates that the sclera has lower elasticity, i.e., higher stiffness and higher resistance to deformation, than the region where a lower Young's modulus was measured.

[0514] To investigate the effect on the stiffness of mouse peripapillary scleral explants by treatment with matrix metalloproteinase (MMP) with or without subsequent CMP treatment, samples were treated with MMP (50 μg / ml for 30 minutes), and then either PBS washout or treatment with the CMP-containing formulation of the present invention was performed for 60 minutes. Next, the Young's modulus was measured at several different positions using AFM. The results are shown in Figure 2. As expected from the fact that the stiffness of the sclera varies point by point between normal eyes and myopic eyes (Grytz, R., et al., Curr. Opin. Biomed. Eng. 15:40-50 (2020), Jonas, J.B. and Xu, I., Eye 28:113-117 (2014)), the baseline (i.e., untreated) explant samples showed various stiffness coefficients across the surface of the sclera. Treatment of the scleral explants with MMP significantly reduced the scleral stiffness to be nearly uniform and well below the baseline (represented by the decrease in Young's modulus). This result is consistent with what is seen in high myopia in humans and other animals. In contrast, 60 minutes of treatment with the CMP3 (SEQ ID NO: 1)-containing formulation of the present invention enhanced scleral hardening significantly above what was seen in the MMP-treated samples, indicating that the destruction of the scleral matrix caused by MMP could be at least partially reversed by CMP treatment. Similar results were observed when MMP-treated samples were treated with the CMP3-containing formulation for 30 minutes (Figures 3A-3B, 4A-4B, 5A-5B, 6A-6B), but in some samples, 60 minutes of treatment with CMP (Figures 3B-3C, 5B-5C) further improved the recovery of scleral stiffness. When these results were plotted in a scatter diagram (Figure 7), it was clear that treatment of MMP-treated scleral explants with the CMP-containing formulation for only 30 minutes induced significant hardening of the scleral matrix, but extending the treatment with CMP to 60 minutes appeared to improve the response to some extent beyond that seen with the 30-minute treatment.

[0515] To enhance the statistical significance of these studies, AFM was used to measure the Young's modulus at multiple points in multiple individual sites in a given peripapillary scleral sample. As above, the samples were either left untreated (baseline) or treated with 50 μg / ml of MMP1 for 30 minutes followed by treatment with the CMP-containing formulation of the present invention (either CMP3, i.e., SEQ ID NO: 1, or CMP13, i.e., SEQ ID NO: 6) for 60 minutes, and then the Young's modulus was measured by AFM at multiple points in multiple sites. The results are shown in FIGS. 8 and 9.

[0516] As seen in FIG. 8 and as seen in the preceding figures, treatment of scleral explants with MMP1 significantly decreased the Young's modulus of the samples compared to untreated (baseline) samples. However, treatment with the CMP3-containing formulation rapidly increased the rigidity of the sclera (FIG. 8A), and the statistical significance between groups was very tight (ANOVA p < 0.001) (FIG. 8B). Similar results were observed for the treatment of peripapillary scleral samples with the CMP13-containing formulation of the present invention (FIGS. 9A, 9B). Indeed, treatment with CMP13 (SEQ ID NO: 6) appeared to improve the rigidity of the peripapillary sclera beyond that observed in untreated baseline samples.

[0517] In summary, these results indicate that the CMP-containing formulations of the present invention can reverse collagen matrix destruction and thereby restore (or at least partially restore) the strength and rigidity of the peripapillary sclera in mouse eye explants. Since CMPs are, of course, mimics of naturally occurring collagen chains, these results suggest that the CMP-containing formulations of the present invention, and methods of using such formulations, may have fewer side effects than conventional treatments such as atropine or collagen crosslinking and may be useful in treating eye diseases and disorders characterized by disruption of the scleral structure and rigidity.

[0518] Example 3: Activity of CMP in restoring collagen matrix structure and function in the glial lamina of the mouse eye

[0519] Based on the research detailed in Example 2 of this specification, the inventors considered that CMP is useful for the reformation of the collagen fibril bundle structure within the sclera around the mouse papilla, and thus can strengthen the scleral matrix. Therefore, it was inferred that such CMP-containing formulations may also be useful in strengthening the collagen structure of the glial lamina in the region adjacent to the sclera around the papilla, particularly at the optic nerve head. To conduct these studies, mouse eyes were explanted, sectioned, and sections of the glial lamina and sclera around the papilla were examined by atomic force microscopy (AFM) as described in Example 2 above. Figure 10 shows the morphology of the sclera around the papilla and the glial lamina in three representative samples of such sections, and the arrows indicate the regions targeted by the AFM probe for measuring the Young's modulus of the corresponding tissue areas. Figure 10A is an untreated sample, Figure 10B is a sample treated with 5 μg / ml of MMP1 for 30 minutes, and Figure 10C is a sample treated with the CMP formulation of the present invention (containing SEQ ID NO: 6, i.e., "CMP13") for 30 minutes after treatment with 5 μg / ml of MMP1 for 30 minutes. As can be easily observed from these micrographs, no observable differences in the microscopic morphology among these samples were found. However, as shown in Figure 11, the measured values of the Young's modulus in the glial lamina among these three samples showed significant differences in tissue stiffness, and MMP adversely affected the stiffness of the glial lamina, reminiscent of what was seen in the sclera around the papilla samples (Figures 11A - 11C). In contrast, the recovery of tissue stiffness by the CMP-containing formulation of the present invention was close to that observed for the baseline untreated sample (Figure 11A), and in some cases even exceeded it (Figure 11B). To ensure that this effect was not simply due to the washout of MMP in response to treatment with the CMP-containing formulation, the MMP-treated samples were treated with a medium (PBS). Such treatment did not restore the stiffness of the glial lamina, which was approximated to what was seen in the MMP-treated samples (Figure 11C).

[0520] To enhance the statistical significance of these studies, as performed in Example 2 for the peripapillary sclera, AFM was used to measure the Young's modulus at multiple points at a number of individual sites in a given glial lamina sample. The samples were left untreated (baseline), or treated with 5 μg / ml of MMP1 for 30 minutes and then with the CMP-containing formulation of the present invention (CMP3, i.e., SEQ ID NO: 1) for 60 minutes, and then the Young's modulus was measured by AFM at multiple points at a number of sites. The results are shown in Figure 12. As observed for the peripapillary sclera and as seen in the fewer glial lamina samples in Figure 11, treatment of the glial lamina with MMP1 significantly decreased the Young's modulus of the samples compared to the untreated (baseline) samples. However, treatment with the CMP3-containing formulation rapidly increased the stiffness of the glial lamina (Figure 12A), and the statistical significance between groups was very tight (ANOVA p < 0.001) (Figure 12B).

[0521] To examine the distribution of disrupted and intact collagen in such explants, the samples prepared as above were treated with DAPI (to identify the location of cell nuclei), a fluorescently labeled antibody against type I collagen ("Col1"), and a Cy3-labeled collagen hybridization peptide ("RCHP") that binds only to regions where collagen has been disrupted. The results are shown in FIG. 13. AFM examination of the morphology of these samples was reminiscent of what was seen above and in Example 2 (FIG. 13a), enabling the identification of the glial lamina ("A") and the peripapillary sclera ("B") in such samples. Fluorescence microscopy of the various labels showed that in the MMP-treated samples, a large amount of disrupted collagen was present in both the glial lamina (FIG. 13b) and the peripapillary sclera (FIG. 13d), and that there was virtually no intact collagen in the glial lamina sections (FIG. 13b). In contrast, the samples treated with CMP3 (i.e., SEQ ID NO: 1) showed that there was virtually no disrupted collagen in either the glial lamina (FIG. 13c) or the peripapillary sclera (FIG. 13e), and in fact, the glial lamina showed a recovery of a more robust, intact collagen network with rapidity within 60 minutes (FIG. 13c). These results indicate that when the CMP-containing formulation of the present invention is used by the method of the present invention, the collagen network rapidly recovers in mouse eye explants, particularly in the sclera and the glial lamina, and thus the degradation of the collagen matrix by matrix metalloproteinases can be reversed.

[0522] When combined with the results of Example 2, these results indicate that the CMP-containing formulations of the present invention can reverse collagen matrix destruction and thus restore (or at least partially restore) the strength and rigidity of the peripapillary sclera and the lamina cribrosa in mouse eye explants in which the structure and function of the collagen matrix have failed. Since such breakdown of the collagen matrix is characteristic of certain corneal scleral diseases and disorders such as myopia, presbyopia, keratoconus, etc., these formulations and methods of the present invention have fewer side effects than conventional treatments such as atropine or collagen crosslinking, and are proven to be useful in treating eye diseases and disorders characterized by breakdown of the structure and function of the corneal sclera and optic nerve.

[0523] Example 4: Activity of CMP in the Restoration of Collagen Structure: Molecular Analysis

[0524] To further examine the effect of the CMP-containing formulation on the structure and function of collagen at the molecular level, samples of type I collagen plated on a substrate were examined microscopically to examine fiber / fibril formation and the presence or absence of a fibril network. Human type I collagen was plated on the substrate at a concentration of 10 μg / ml in PBS, air-dried, and then left untreated or treated with MMP1 (60 ng / ml) for 30 minutes. The samples were then examined by scanning electron microscopy (SEM). The results are shown in Figure 14. The untreated collagen samples showed extensive fiber and fibril formation (Figures 14A, 14C), and significant amounts of network formation were observed in the low magnification image (Figure 14A) and high magnification image (Figure 14C). In contrast, MMP treatment of the substrate resulted in easily observable amounts of collagen fiber, fibril, and network disruption (Figure 14B), and at higher magnifications (Figure 14D), it was also observed to contain large amounts of collagen fragments and in some cases single-stranded collagen. Thus, MMP treatment of the collagen substrate resulted in rapid disassembly and extensive destruction of the collagen structure, which is reminiscent of prior studies by the present inventors (see, for example, U.S. Patent No. 11,389,513, the disclosure of which is incorporated herein by reference).

[0525] Samples treated simultaneously for 30 minutes with 100 ng / ml of MMP1 and 1 μg / ml of the CMP13 (SEQ ID NO: 6)-containing formulation of the present invention were also examined by AFM for these same substrates, and the effect of the CMP-containing formulation of the present invention that prevents the destruction of the collagen structure seen on the substrate was shown. The results of these studies are shown in FIG. 15. In untreated (baseline) samples, a broad and multi-layered network of collagen fibers, fibrils, and bundles could be easily observed (FIGS. 15A, 15B). However, in the MMP-treated samples, a significant amount of disassembled collagen was shown, and little of the fiber / fibril structure remained (FIGS. 15C, 15D). However, when CMP was included simultaneously with MMP, in such samples, extensive collagen fiber / fibril formation (FIG. 15E) could be observed, along with long fiber bundles and a network across the substrate surface (FIG. 15F), from which it is seen that the effect of MMP on the collagen network on the substrate was prevented. In summary, these studies indicate that the CMP-containing formulation of the present invention may not only be useful for treating and reversing the collagen-destructive action of MMPs that result in corneal-scleral abnormalities in certain eye diseases and disorders, but may also be useful in preventing such action. Therefore, the CMP-containing formulation provided by the present invention and methods of using such a formulation should be proven useful in both the treatment and prevention of certain eye diseases and disorders characterized by loss of corneal-scleral rigidity and strength, including but not limited to myopia, presbyopia, and keratoconus.

[0526] The present invention has been described above by using functional components to exemplify the realization of its specific functions and relationships. The boundaries of these functional components are defined at the discretion for the convenience of explanation in this specification. Alternative boundaries can be defined as long as their specific functions and relationships are properly fulfilled. For example, the description of a range of values (e.g., a range of dosages or dosing concentrations) is to be understood as including the starting and ending values of the range, as well as all values between those starting and ending values. To illustrate this concept, the range of "about 25 ng / ml to about 250 ng / ml" is to be interpreted as including "about 25 ng / ml", "about 250 ng / ml", and all individual concentration values between those two values. The term "about" used in conjunction with a numerical value typically means the actual value described plus or minus 10% of that value.

[0527] The foregoing description of specific embodiments is to fully clarify the general nature of the present invention so that others, by applying knowledge within the skills of those skilled in the art, can easily modify and / or apply such specific embodiments for various uses without undue experimentation and without departing from the general concept of the present invention. Accordingly, in addition to the embodiments specifically described herein, other suitable embodiments of the present invention will be readily apparent to those skilled in the art based on the foregoing description and examples, as well as knowledge generally available in the relevant technical fields. Such applications and modifications are therefore intended to be within the meaning and scope of the equivalents of the disclosed embodiments based on the teachings and guidance presented herein. The expressions or terms in this specification are for the purpose of explanation rather than limitation, and thus it should be understood that those skilled in the art should interpret the terms or expressions in this specification in light of the teachings and guidance.

[0528] The breadth and scope of the present invention should not be limited by any of the above exemplary embodiments, but should be defined only in accordance with the following claims and their equivalents.

[0529] All references cited herein, including U.S. patents and published patent applications, international patents and patent applications, and references in academic journals or other published documents, are hereby incorporated by reference in their entirety to the same extent as if each such reference were specifically cited as part of the portion(s) of this application to which it is relevant.

Claims

1. A pharmaceutical composition for treating a disease, disorder, or pathological condition of the cornea and sclera in a human or veterinary animal requiring treatment, comprising (a) at least one collagen-mimicking peptide (CMP), and (b) one or more pharmaceutically suitable carriers.

2. The aforementioned diseases, disorders, or conditions of the cornea and sclera include keratitis, episcleritis, scleritis, corneal ulcer formation, sequelae of corneal ulcer formation, corneal dilation, acquired corneal morphological abnormalities, keratoconus, corneal astigmatism, keratoglobus, posterior corneal cupping, corneal ectasia, keratocele, Descemet's membrane aneurysm, marginal degeneration of keratocarcinoma, Tellien's marginal dystrophy, Mohlen's ulcer, central corneal ulcer, corneal marginal ulcer, staphylococcal marginal ulcer formation, Saltzman nodular dystrophy, age-related peripheral corneal atrophy, geographic ulcer formation, discoid keratostromitis, metaherpetic ulcer formation, keratomalacia, and full-thickness corneal transplantation. The pharmaceutical composition according to claim 1, selected from the group consisting of postoperative incision, anterior membrane dystrophy, stromal dystrophy, mucosal pemphigoid, necrotizing scleritis, scleromalacia, coloboma, myopia, presbyopia, hyperopia, scleral buckle-induced scleromalacia, congenital hereditary stromal dystrophy, congenital anterior staphyloma, corneal sclerosis, traumatic destruction of Descemet's membrane, corneal keloid, scleral dilation, scleral staphyloma, deep scleritis, necrotizing scleritis, perforating scleromalacia, hyaline degeneration of the sclera, perilimbal scleromalacia, ocular graft-versus-host disease, and colloideremia.

3. The pharmaceutical composition according to claim 1, wherein the disease, disorder, or pathological condition of the cornea and sclera is myopia, presbyopia, or keratoconus.

4. The pharmaceutical composition according to claim 1, wherein at least one CMP is bound to at least one therapeutic compound (TC) to form a CMP-TC conjugate.

5. The pharmaceutical composition according to claim 1, wherein the at least one collagen-mimicking peptide has an amino acid sequence corresponding to any one of SEQ ID NOs: 1-388, 397-416, and 418-470.

6. The pharmaceutical composition according to claim 1, wherein the at least one collagen-mimicking peptide has an amino acid sequence corresponding to any one of SEQ ID NOs: 1-14, 66-94, 107-135, 136-140, 192-220, 233-261, 260-264, 280, 281, 293, 294, 306, 307, 318-346, 347, 348, 359-388, 397-416, and 418-452.

7. The pharmaceutical composition according to claim 1, wherein the at least one collagen-mimicking peptide has an amino acid sequence corresponding to SEQ ID NO:

12.

8. The pharmaceutical composition according to claim 1, wherein the at least one collagen-mimicking peptide has an amino acid sequence corresponding to SEQ ID NO:

6.

9. The pharmaceutical composition according to claim 1, wherein the at least one collagen-mimicking peptide has an amino acid sequence corresponding to SEQ ID NO:

3.

10. The pharmaceutical composition according to claim 1, wherein the at least one collagen-mimicking peptide has an amino acid sequence corresponding to SEQ ID NO:

1.

11. The pharmaceutical composition according to claim 1, wherein the at least one collagen-mimicking peptide has an amino acid sequence corresponding to any one of SEQ ID NOs: 4, 5, and 9.

12. The pharmaceutical composition according to claim 1, wherein the at least one collagen-mimicking peptide has an amino acid sequence corresponding to any one of SEQ ID NOs: 388, 397-416, and 418-470.

13. The pharmaceutical composition according to claim 1, wherein the at least one collagen-mimicking peptide has an amino acid sequence corresponding to any one of SEQ ID NOs: 10-27, 81-94, 122-135, 207-220, 248-261, 333-346, and 374-387.

14. The pharmaceutical composition according to claim 1, wherein the disease, disorder, or pathological condition of the cornea and sclera is myopia.

15. The pharmaceutical composition according to claim 1, wherein the disease, disorder, or pathological condition of the cornea and sclera is presbyopia.

16. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is configured to be administered to the conjunctiva or subconjunctiva of the eye.

17. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is configured to be administered to the eye in the form of one or more droplets of a solution or suspension containing the pharmaceutical composition.

18. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is configured to be administered to the eye by injection.

19. The pharmaceutical composition according to claim 18, wherein the injection is an intravitreous injection.

20. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is configured to be administered to the eye in the form of a coating on a solid material that is implanted within the structure of the eye.

21. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is configured to be administered to the eye in the form of a wafer, film, gel, mesh, or patch.

22. The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is bound to one or more spheres or nanoparticles that are delivered to or into the structure of the eye.

23. A medical device for treating a disease, disorder, or condition of the cornea or sclera in a human or veterinary animal requiring treatment or prevention, wherein the device comprises the pharmaceutical composition described in claim 5.

24. The medical device according to claim 23, wherein the device is selected from the group consisting of a stent, a shunt, sutures, absorbable mesh, absorbable patch, drug release wafer, film, and internal injection pump.

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