Collagen peptide-based pharmaceutical composition and application thereof

Abstract

The invention belongs to the fields of medicinal chemistry, biotechnology and pharmacy. The present invention provides compositions comprising one or more collagen mimetic peptides, optionally linked to one or more therapeutic compounds or one or more imaging compounds, and methods of using such compositions to treat, prevent, ameliorate, cure and / or diagnose certain diseases and physical conditions in humans and veterinary animals, including anterior ocular diseases and physical conditions, including keratoscleral diseases, conditions or conditions, such as myopia, presbyopia, keratoconus, and the like, as well as methods of treating, preventing, ameliorating, curing and / or diagnosing certain diseases and physical conditions in humans and veterinary animals, including anterior ocular diseases and physical conditions, including keratoscleral diseases, conditions or conditions. The invention also provides the use of such compositions in the treatment, prevention, amelioration, cure and / or diagnosis of diseases, disorders and conditions in a variety of other tissues, organs and organ systems. The invention also provides methods of making such collagen mimetic peptides and compositions. The invention also provides medical devices comprising one or more such compositions of the invention.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS AND INCORPORATION BY REFERENCE

[0002] 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, the entire contents of which are incorporated herein by reference.

[0003] STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH AND DEVELOPMENT

[0004] not applicable.

[0005] Names of Parties to the Joint Research Agreement

[0006] not applicable.

[0007] Reference to electronically submitted sequence listings

[0008] not applicable. Background of the Invention Field of the Invention

[0010] The present invention relates to the fields of medicinal chemistry, biotechnology, pharmaceuticals and medical devices, and the use of pharmaceutical compounds and medical devices to treat, prevent and ameliorate diseases, disorders and physical ailments of humans and veterinary animals, particularly certain ocular diseases and disorders, including corneal diseases and disorders, such as myopia, keratoconus, scleritis, episcleritis and presbyopia. Background Art

[0011] Collagen is the most abundant protein in vertebrates and is the basic structural protein of vertebrate tissues. It is present in almost all tissues including skin and other epithelial tissues (including the inner wall of most luminal organs such as the gastrointestinal tract), tendons, bones, blood vessels, cartilage, ligaments and teeth. In humans, collagen accounts for about one-third of the total protein and about three-quarters of the dry weight of the skin (see Shoulders, MD and Raines, RT, Ann. Rev. Biochem. 78: 929-958 (2009); Gelse, K., et al., Adv. Drug Deliv. Rev. 55: 1531-1546 (2003)).

[0012] Collagen is a fibrous protein composed of a triple helix, usually consisting of two identical chains and a third chain of 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 described. Collagen types are generally grouped according to their structural form: fibrillar (types I, II, III, V, and XI) accounting for about 90% of all collagen found in mammals; non-fibrillar (basement membrane or type IV, and other non-fibrillar collagen types with interrupted helical structures, see above). The five most common collagen types and their tissue distribution are as follows:

[0013] Type I: skin, tendons, organs, bones, vascular connective tissue;

[0014] Type II: cartilage;

[0015] Type III: reticular connective tissue, often associated with type I collagen;

[0016] Type IV: basement membranes of epithelial tissues and some solid tumors; and

[0017] Type V: hair, placenta, outer cell membrane.

[0018] In each of these variants, the polypeptide chain of collagen consists of approximately 300 repeats of the amino acids proline (Pro), 4 (R) -hydroxyproline (Hyp) and glycine (Gly), typically in the sequence XY-Gly, where X is typically a Pro residue and Y is typically a (Hyp) residue; in vertebrates, the typical repeating motif in collagen is ProProGly (see Hulmes, DJS, "Collagen Diversity, Synthesis and Assembly," In: Collagen: Structure and Mechanics, P. Fratzl, ed., New York: Springer, pp. 15-47 (2008)). Subsequently, in vivo, hydroxylation of the Pro residue is enzymatically performed after collagen biosynthesis but before the chain begins to form a triple helix. Thus, hydroxylation of at least one Pro residue in the ProProGly motif (usually to form ProHypGly) appears to be important for the correct 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, MD and Raines, RT, Ann. Rev. Biochem. 78:929-958 (2009)). For example, (ProHypGly) 10The melting temperature of the triple helix of (SEQ ID NO: 396) is 58°C, while (ProProGly) 10 The melting temperature of the triple helix of (SEQ ID NO: 397) chain is only 24°C (Sakakibara et al., Biochim. Biophys. Acta, 303: 198-202 (1973)), and (ProHypGly) 10 The rate at which the (SEQ ID NO:396) chain folds into a triple helix is ​​significantly higher than that of (ProProGly) 10 SEQ ID NO: 397) chain (Chopra and Ananthanarayanan, Proc. Natl. Acad. Sci. USA, 79: 7180-7184 (1982)).

[0019] Type I collagen is the most abundant and most studied collagen. In humans and most other animals, it constitutes more than 90% of the organic mass of bones and is the main collagen of tendons, skin, ligaments, corneas and many interstitial connective tissues (except for very few tissues such as hyaline cartilage, brain and vitreous). Type I collagen triple helices are usually formed into heterotrimers by two identical α1 chains and one α2 chain. The triple helical fibers are mainly incorporated into complex fibrils containing other types of collagen in the body, which, as mentioned above, vary according to tissue type and location (Fleischmajer, ED et al., J. Struct. Biol. 105: 162–169 (1990); Niyibizi, C. and Eyre, DR, Connect. Tissue Res. 20: 247–250 (1989)). In most organs, especially in tendons and fascia, type I collagen provides tensile stiffness, whereas in bones it determines biomechanical properties related to load bearing, tensile strength, and torsional stiffness.

[0020] In connective tissue (such as bone, tendon, cartilage, ligament, skin, blood vessel and tooth), single collagen molecule is wound together with tight triple helix. These helices are cross-linked (Lodish, H. et al., "Collagen:The Fibrous Proteins of the Matrix", in: Molecular Cell Biology, 4th edition, Section 22.3, New York: WH Freeman (2000)) by single triple helical fiber and are organized into fibrils with high tensile strength (Jones & Miller, J.Mol.Biol., 218:209-219 (1991)). Changing the arrangement and cross-linking of collagen fibrils enables vertebrates to withstand one-dimensional (tendon), two-dimensional (skin) or three-dimensional (cartilage) pressure.

[0021] Collagen plays a role in maintaining the structural integrity of tissues and organs to a great extent in vivo. In all parenchymal organs, collagen is the main component of interstitial matrix and basement membrane, and in all connective tissues, particularly bone and cartilage, collagen is the main functional skeleton of structure. However, in addition to biomechanical aspects, collagen also participates in a variety of other functions. For example, specific cell surface and intracellular receptors interact with collagen, and the signal transduction of these receptors participates in cell adhesion, differentiation, growth and other cell activities, as well as the survival of cells in vivo and in vitro (Vogel, WF, Eur. J. Dermatol. 11: 506-514 (2001); Gelse, K., et al., Adv. Drug Deliv. Rev. 55: 1531-1546 (2003)). Collagen also participates in capturing, local storage and delivery of growth factors and cytokines in various tissues where collagen is present. Through these receptor interactions as well as storage and delivery functions, collagen plays a key 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, ED, J. Cell Biol. 91:205s-223s (1981); Bautista, CM et al., Metabolism 39:96-100 (1990); Zhu, Y. et al., J. Cell Biol. 144:1069-1080 (1998); Schlegel, K. A. Chattopadhyay, S. et al., J. Tissue Eng. Regen., Biomaterials 25:5387-5393 (2004); Kumar, VA, et al., Biomacromol. 15:1484-1490 (2014)).These functions also qualify collagen as a candidate transport vehicle for delivering therapeutic compounds (see, e.g., Chattopadhyay, S. et al., J. Tissue Eng. Regen. Med. 10:1012-1020 (2012); Schuppan, D. et al., Gastroenterol. 114:139-152 (1998); Frenkel, SR et al., J. Bone Jt. Surg. 79-B:831-836 (1997); Albu, MG 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, available at: https: / / www.intechopen.com / books / biomaterials-applications-for-nanomedicine / collagen-based-drug-delivery-systems-for-tissue-engineering (2011)), and for wound healing by directly promoting tissue repair or regeneration (Wakitani, S. et al., J. Bone Jt. Surg. 71-B: 74–80 (1989); Kumar, VA, et al., Biomacromol. 15: 1484-1490 (2014)). Collagen, and more specifically disrupted collagen, has also been implicated in tumor progression and metastasis in humans and other vertebrates (for a review of this issue, see Fang, M., et al., Tumor Biol. 35:2871-2882 (2014)).

[0022] However, in addition to intact collagen molecules, collagen fragments may also have potential therapeutic uses and may actually work in a better way than native collagen. For example, it has been shown that non-collagen fragments of types IV, XV, and XVIII collagen promote the growth of blood vessels and tumor cells and affect a variety of other cell activities (Ortega, N. and Werb, Z., J. Cell Sci. 115: 4201-4214 (2002); Davis, GE et al., Am. J. Pathol. 156: 1489-1498 (2000); O'Reilly, MS et al., Cell 88: 277-285 (1997)). Similarly, as described in more detail below, fragments of type I collagen or synthetic collagen mimetic peptides (CMPs) have recently been investigated for their utility in treating diseases and medical conditions, both as active pharmaceutical ingredients (APIs) themselves and for the delivery of skin wound healing agents (see U.S. Pat. Nos. 5,973,112, 7,122,521, 7,858,741, and U.S. Patent Publication No. US2007 / 0275897 A1, the entire disclosures of which are incorporated herein by reference in their entireties; see also, e.g., Chattopadhyay, S. et al., J. Tissue Eng. Regen. Med. 10:1012-1020 (2012); Kumar, VA et al., Biomacromolecules 15:1484-1490 (2014)).

[0023] Abnormal collagen is associated with a 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, HS, et al., Br. J. Ophthalmol. 98:691–697 (2014)), arthritis, rheumatism, osteoporosis, atherosclerosis, and cirrhosis. Destruction of collagen is also associated with certain human and veterinary diseases, such as certain cancers (particularly luminal organ cancers and certain sarcomas); see, for example, Lauer, JL, and Fields, GB, “Collagen in Cancer”, in The Tumor Microenvironment, New York: Springer, pp. 477-507 (2010). Collagen is also critical in wound healing, and is known to be upregulated in areas of healing epithelial wounds (see, e.g., U.S. Pat. Nos. 5,973,112 and 7,122,521, which are incorporated herein by reference in their entirety; see also 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, VA, et al., Biomacromol. 15: 1484-1490 (2014)), including in the skin and cornea. In fact, it has been reported that collagen, collagen fragments or certain mimetic peptides of natural collagen show good prospects in treating certain wounds and diseases in humans and animals, especially skin wounds (see, for example, U.S. Pat. Nos. 5,973,112, 7,122,521, 7,858,741 and U.S. Patent Publication No. US 2007 / 0275897A1, the entire contents of which are incorporated herein by reference; see also Kumar, VA et al., Biomacromolecules 15: 1484-1490 (2014)). It is believed that these collagen fragments or collagen mimetic peptides can specifically target collagen damage areas associated with skin wounds by inserting into the damaged collagen and reforming the native collagen I triple helix (see, e.g., Chattopadhyay, S., et al., J. Tissue Eng. Regen. Med. 10: 1012-1020 (2012); Chattopadhyay, S., et al., Org. Biomol. Chem. 10: 5892-5897 (2012)). Therefore, attempts have been made to use collagen as a vehicle for delivering certain drugs with varying degrees of success (see, e.g., 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 bound therapeutic compound (a neuropeptide called substance P) to areas of skin wounds; this CMP-substance P conjugate has 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, including collagen, are also involved in maintaining the normal structure and function of the nervous system, particularly the peripheral nervous system, and the destruction or damage of these ECM components often leads to nerve cell disorder and / or death (see, e.g., Koopmans G, Hasse B, Sinis N. The role of collagen in peripheral nerve repair (Chapter 19). International Review of Neurobiology. Vol. 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, JCF, "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., IntechOpen, ISBN 978-953-51-2416-0 (2016), accessed on November 8, 2019, at http: / / dx.doi.org / 10.5772 / 62527).

[0024] Treatments for diseases / disorders are expensive, difficult to deliver specifically, and may have deleterious effects at sites far from the intended site of action. For example, many pharmaceutical compositions, including antibiotics, small molecule therapeutics (e.g., anticancer compounds), and biologics (e.g., monoclonal antibody therapeutics), are administered parenterally in a non-targeted manner, and must diffuse or otherwise find their way to the site of affliction before providing a therapeutic benefit. This "shotgun" approach to treatment necessarily requires higher doses, and may result in longer treatment times and reduced patient compliance, compared to treatments that deliver therapeutic compounds and compositions in a more targeted manner (allowing controlled or programmable release at or near the site of disease in humans or veterinary animals). In particular, ocular diseases, disorders, and medical conditions, particularly those involving the cornea and / or sclera (referred to herein as "corneosclera"), have generally proven difficult to treat and / or remedy. For example, presbyopia is an eye condition often associated with aging (Lafosse, E. et al., Cont. Lens Ant. Eye 43(2):103-114 (2020); Balgos, MJTD et al., Taiwan J. Ophthalmol 8:121-140 (2018); Katz, JA et al., Clin. Ophthalmol. 15:2167-2178 (2021)) and is typically treated by mechanical optical correction (e.g., by glasses or contact lenses) or by refractive surgery (e.g., conductive keratoplasty, LASIK / LASEK surgery, photorefractive keratectomy, or by lens implantation).Myopia is an eye disorder that affects 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)), which is treated with corrective lenses and / or medications such as atropine or pirenzepine (Gwiazda, J., Optom. Vis. Sci. 86(6):624-628(2009)) and other drug treatments (Wang, W.-Y. et al., Biomed. Pharmacother. 133:111092(2021)). Especially for children and the elderly, due to inconvenience, discomfort, etc., patients are usually unable to fully comply with these corrective measures, resulting in continued loss of vision, and in some cases even worsening.

[0025] Previous work by some of the present inventors has demonstrated and / or suggested that certain CMP-containing formulations may be used to treat certain anterior ocular diseases, such as dry eye and other corneal diseases, disorders and injuries (see, e.g., U.S. Pat. No. 10,632,168; Baratta, RO et al., Baratta et al., Front. Pharmacol. 12:705623 (2021); Baratta, RO et al., Surv. Ophthalmol. 67:60-67 (2022)), as well as certain posterior ocular diseases and disorders, such as glaucoma, macular degeneration, optic neuropathy, etc. (see, e.g., U.S. Pat. No. 11,389,513; McGrady, NR 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 disclosures of each of these references are incorporated herein by reference in their entirety. However, previous work has been largely silent on the potential impact of CMP-containing formulations in the treatment and / or prevention of other ocular afflictions (such as corneoscleral disorders, diseases and conditions, including but not limited to myopia, presbyopia and keratoconus), most of which require mechanical and / or surgical interventions that are often incomplete, uncomfortable or inconvenient for the patient and often require adjustment and / or re-intervention as the patient ages.

[0026] Therefore, there is a need in the art for a formulation and method of use that overcomes many of the shortcomings of conventional treatments for certain ocular diseases and conditions, particularly corneoscleral diseases, conditions and disorders in humans and veterinary animals. Such formulations and methods of use would allow for the use of lower doses of the drug and more targeted delivery of the drug to the intended site of action, as well as reducing treatment problems or delays due to patient noncompliance. Finally, there is a need in the art for methods of producing such compositions that would meet the needs of the medical and patient populations to maximize treatment effectiveness while reducing costs. Summary of the invention

[0027] The inventors have inferred that since collagen destruction is associated with a variety of diseases and conditions in humans and other animals, conjugating a variety of therapeutic and / or diagnostic compounds to collagen or collagen mimetic peptides would provide an elegant, rapid, and repeatable method to overcome many of the above-mentioned limitations in the treatment and diagnosis of certain physical diseases and conditions, as well as drug delivery. Therefore, the present invention provides compositions suitable for methods of treating and diagnosing physical conditions and diseases, particularly corneoscleral diseases, conditions, and disorders, and provides drug delivery systems, medical devices, and methods for making the same. Therefore, the present invention meets the needs of the art as described above.

[0028] In one aspect, the present invention provides compositions comprising one or more collagen mimetic peptides (CMPs), which in certain embodiments have been conjugated to one or more therapeutic compounds and / or one or more diagnostic compounds to form CMP conjugates and compositions. Such CMPs and CMP conjugates and compositions comprising such CMPs and / or CMP conjugates can be used to treat, prevent, improve and diagnose various diseases, disorders and physical conditions of humans and veterinary animals. In certain embodiments of this aspect, the present invention provides compositions comprising such CMPs and / or CMP conjugates and one or more pharmaceutically acceptable carriers, excipients or compounding agents and optionally one or more additional therapeutic or diagnostic agents to provide therapeutic and diagnostic compositions that can be used to treat, prevent, improve or diagnose certain diseases and disorders of humans and veterinary animals.

[0029] In another aspect, the invention provides methods for treating, preventing, ameliorating or diagnosing certain diseases and conditions in humans and veterinary animals by administering the conjugates and / or compositions of the invention to humans or veterinary animals suffering from or susceptible to such diseases or conditions. Diseases and conditions that are suitably treated, prevented, cured, ameliorated or diagnosed according to this aspect of the invention include ocular diseases or conditions, particularly corneoscleral diseases, conditions and disorders, including but not limited to keratoconus, myopia and presbyopia; skin diseases or conditions; cancer; gastrointestinal diseases or conditions; urogenital diseases or conditions; fibrotic diseases or conditions; cardiovascular diseases or conditions; bone diseases or conditions; and rheumatic diseases or conditions.

[0030] In another aspect, the invention provides a medical device coated with or comprising one or more conjugates or compositions of the invention. In a related aspect, the invention provides a method for treating, curing, preventing or ameliorating a disease or condition in a human or veterinary animal, comprising implanting one or more medical devices of this aspect of the invention into a human or veterinary animal under conditions of treating, curing, preventing or ameliorating the disease or condition.

[0031] In other aspects, the invention provides methods of making the compositions, conjugates and medical devices of the invention.

[0032] Other objects, advantages and features of the present invention will become apparent to one of ordinary skill in the art after reading the description, drawings, examples and claims given herein. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 is a pair of micrographs depicting atomic force microscopy ("AFM") images of sections of the mouse eye sclera in a region near the optic nerve head (peripapillary sclera). The white arrows depict the points where Young's modulus was measured, as shown in subsequent figures. Figure 1 A: low-power view; Figure 1 B: High-power view. The white bar in each micrograph represents 100 μm.

[0034] Figure 2 It is shown that after 30 minutes of treatment with 50 μg / ml MMP1, and then no subsequent treatment or after 60 minutes of treatment with the CMP formulation of the present invention (comprising SEQ ID NO: 1), Figure 1 Shown is a bar graph of Young's modulus measurements (in kilopascals (KPa)) at representative peripapillary sclera locations measured by AFM. Each individual point represents one Young's modulus measurement at a single location. Baseline: No MMP or CMP treatment. Bar height represents the mean of all measurements in that group (ANOVA p<0.0001).

[0035] Figure 3 is shown in the case of treatment with 50 μg / ml MMP1 for 30 minutes ( Figure 3 A) before and after treatment with the CMP formulation of the present invention (comprising SEQ ID NO: 1) for 30 minutes ( Figure 3 B) or 60 minutes ( Figure 3 C), A series of bar graphs of Young's modulus measurements at representative peripapillary sclera locations measured by AFM. Each individual dot represents one Young's modulus measurement at a single location. Baseline: No MMP or CMP treatment. Bar height represents the mean of all measurements in that group, with p values ​​(ANOVA) shown between groups in a given pair.

[0036] Figure 4 is shown in the case of treatment with 50 μg / ml MMP1 for 30 minutes ( Figure 4 A) before and after treatment with the CMP formulation of the present invention (comprising SEQ ID NO: 1) for 30 minutes ( Figure 4B), A series of bar graphs of Young's modulus measurements at representative peripapillary sclera locations measured by AFM. Each individual dot represents one Young's modulus measurement at a single location. Baseline: No MMP or CMP treatment. Column height represents the mean of all measurements in that group, with p values ​​(ANOVA) shown between groups in a given pair.

[0037] Figure 5 is shown in the case of treatment with 50 μg / ml MMP1 for 30 minutes ( Figure 5 A) before and after treatment with the CMP formulation of the present invention (comprising SEQ ID NO: 1) for 30 minutes ( Figure 5 B) or 60 minutes ( Figure 5 C), A series of bar graphs of Young's modulus measurements at representative peripapillary sclera locations measured by AFM. Each individual dot represents one Young's modulus measurement at a single location. Baseline: No MMP or CMP treatment. Bar height represents the mean of all measurements in that group, with p values ​​(ANOVA) shown between groups in a given pair.

[0038] Figure 6 is shown in the case of treatment with 50 μg / ml MMP1 for 30 minutes ( Figure 6 A) before and after treatment with the CMP formulation of the present invention (comprising SEQ ID NO: 1) for 30 minutes ( Figure 6 B), A series of bar graphs of Young's modulus measurements at representative peripapillary sclera locations measured by AFM. Each individual dot represents one Young's modulus measurement at a single location. Baseline: No MMP or CMP treatment. Column height represents the mean of all measurements in that group, with p values ​​(ANOVA) shown between groups in a given pair.

[0039] Figure 7 is a scatter plot showing the average Young's modulus measurements of representative scleral locations measured by AFM before and after treatment with 50 μg / ml MMP1 for 30 minutes or 45 minutes, and samples treated with MMP for 45 minutes and then treated with a CMP formulation of the invention (comprising SEQ ID NO: 1) for 30 minutes or 60 minutes. Each point represents the average of hundreds of measurements at a specific peripapillary scleral location, all normalized to their own baseline value (so that the baseline average is 1). Baseline: No MMP or CMP treatment. Error bars show the standard error of the measurements.

[0040] Figure 8is a series of bar graphs showing Young's modulus measurements of representative peripapillary sclera locations measured by AFM before and after treatment with 50 μg / ml MMP1 for 30 minutes, followed by treatment with a CMP formulation of the invention (comprising SEQ ID NO: 1, or "CMP3") for 60 minutes. Baseline: no MMP or CMP treatment; 26 locations, 6656 independent measurements. MMP1: treatment with MMP1 for 30 minutes; 20 locations, 5120 independent measurements. CMP3: treatment with MMP1 for 30 minutes, followed by treatment with a formulation containing CMP3 for 60 minutes; 12 locations, 2938 independent measurements. The height of the bar represents the average of all measurements in that group. Figure 8 A: The average measurement for each location is shown; each individual point represents the average of multiple individual measurements of Young's modulus at a single location. Figure 8 B: Figure 8 Mean measurements shown in A, with the mean of individual locations removed and rescaled to show differences in Young's modulus measurements between treatment groups. Error bars represent the standard deviation of all measurements in that group (between group ANOVA p<0.001).

[0041] Fig. 9 is a series of bar graphs showing Young's modulus measurements of representative peripapillary sclera locations measured by AFM before and after treatment with 50 μg / ml MMP1 for 45 minutes, followed by treatment with a CMP formulation of the invention (comprising SEQ ID NO:6, or "CMP13") for 60 minutes. Baseline: no MMP or CMP treatment; 3 locations, 768 independent measurements. MMP1: treatment with MMP1 for 45 minutes; 3 locations, 768 independent measurements. CMP13: treatment with MMP1 for 45 minutes, followed by treatment with a formulation containing CMP13 for 60 minutes; 3 locations, 768 independent measurements. The height of the bar represents the average of all measurements in that group. Fig. 9 A: The average measurement for each location is shown; each individual point represents the average of multiple individual measurements of Young's modulus at a single location. Fig. 9 B: Fig. 9 Mean measurements shown in A, with individual site means removed and rescaled to show differences in Young's modulus measurements between treatment groups. Error bars represent standard deviation of all measurements in that group (between group ANOVA p<0.001).

[0042] Fig.10 is a series of photomicrographs depicting atomic force microscopy images of a portion of the glial layer near the peripapillary sclera of a mouse eye. White arrows depict the measurement points of Young's modulus as shown in subsequent figures. Fig.10A: Baseline, no MMP or CMP treatment. Fig.10 B: After treatment with 5 μg / ml MMP1 for 30 minutes. Fig.10 C: After treatment with 5 μg / ml MMP1 for 30 minutes, treatment with the CMP formulation of the present invention (comprising SEQ ID NO: 6 or "CMP13") was performed for another 30 minutes. Fig.10 The white bar in A represents 100 μm (same scale for each micrograph).

[0043] Fig.11 A series of bar graphs showing Young's modulus measurements of representative glial layer locations measured by AFM before and after treatment with 5 μg / ml MMP1 for 30 minutes, followed by treatment with a CMP formulation of the invention (comprising SEQ ID NO: 1) or vehicle (PBS) for 30 minutes. Two locations were sampled, and 256 independent measurements were made for each treatment condition. Each individual point represents one Young's modulus measurement at a single location. Baseline: no MMP or CMP treatment. Column height represents the mean of all measurements in that group, with p values ​​(ANOVA) shown between groups in a given pair. Fig.11 A: Sample 1, baseline vs. MMP treatment vs. MMP+CMP treatment. Fig.11 B: Sample 2, baseline vs. MMP treatment vs. MMP+CMP treatment. Fig.11 C: Sample 2, baseline vs. MMP treatment vs. MMP+PBS treatment.

[0044] Fig.12 is a series of bar graphs showing Young's modulus measurements of representative glial locations measured by AFM before and after treatment with 5 μg / ml MMP1 for 30 minutes, followed by treatment with a CMP formulation of the invention (comprising SEQ ID NO: 1, or "CMP3") for 60 minutes. Baseline: no MMP or CMP treatment; 43 locations, 13,996 independent measurements. MMP1: treatment with MMP1 for 30 minutes; 9 locations, 2304 independent measurements. CMP3: treatment with MMP1 for 30 minutes, followed by treatment with a formulation containing CMP3 for 60 minutes; 9 locations, 2229 independent measurements. PBS: treatment with MMP1 for 30 minutes, followed by treatment with PBS for 60 minutes; 4 locations, 1024 independent measurements. The height of the bar represents the average of all measurements in that group. Fig.12 A: The average measurement for each location is shown; each individual point represents the average of multiple individual measurements of Young's modulus at a single glial layer location. Fig.12 B: Fig.12Mean measurements shown in A, with individual site means removed and rescaled to show differences in Young's modulus measurements between treatment groups. Error bars represent standard deviation of all measurements in that group (between group ANOVA p<0.001).

[0045] Fig.13 is a series of photomicrographs showing the microscopic morphology of the glial layer and peripapillary sclera after treatment with MMP1 with or without subsequent treatment with a CMP formulation of the invention (comprising SEQ ID NO: 1). Fig.13 a: Representative AFM microscopic views; “A” locates the glial layer and “B” locates the peripapillary sclera. Fig.13 b-13e: Treatment with MMP1 only for 30 minutes ( Fig.13 b, 13d) or treated with MMP1 for 30 minutes followed by CMP preparation for 30 minutes ( Fig.13 c, 13e) of the glial layer ( Fig.13 b and 13c) and peripapillary sclera ( Fig.13 d and 13e). The fluorescent colors represent the different components of these areas of the glial layer and sclera: blue indicates nuclei (DAPI staining); green indicates type I collagen (stained with anti-type I collagen antibody ("Col1")); and red indicates areas of disrupted or digested collagen (stained with Cy3-labeled collagen hybrid peptide ("RCHP")).

[0046] Fig.14 Before treatment with 60ng / ml MMP1 for 30 minutes ( Fig.14 A, 14C) and later ( Fig.14 B, 14D), a series of scanning electron micrographs of human type I collagen samples deposited on a matrix at 10 g / ml. Magnification: Fig.14 A = 10Kx; Fig.14 B = 8.2Kx; Fig.14 C = 31Kx; Fig.14 D=16Kx.

[0047] Fig.15 Before treatment with 60ng / ml MMP1 for 30 minutes ( Fig.15 A, 15B) and after ( Fig.15 C, 15D), or treated with 100 ng / ml MMP1 and 1 μg / ml of the preparation of the present invention containing CMP13 (SEQ ID NO: 6) for 30 minutes ( Fig.15E, 15F), a series of AFM micrographs of 10 μg / ml human type I collagen samples deposited on a matrix. Depicted is the height of collagen deposited by the sample under each treatment condition by examining the focal point ( Fig.15 A, 15C, 15E), or the three-dimensional fibrous structure of collagen on the matrix ( Fig.15 B, 15D, 15F). Scale bars are indicated below each micrograph. DETAILED DESCRIPTION

[0048] 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 the invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, preferred methods and materials are described below.

[0049] According to a first aspect, the present invention provides a composition suitable for use in a medicament, the medicament being suitable for treating or preventing a disease, disorder, structural abnormality or injury in a human or animal that needs treatment or prevention, such as a disease, disorder, structural abnormality or injury. In certain embodiments, the composition provided by the present invention comprises (a) at least one collagen mimetic peptide (CMP), which is connected to at least one additional therapeutic compound (TC) to form a CMP-TC conjugate, 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, which is suitable for diagnosing or detecting a disease, disorder, structural abnormality or injury in a human or animal that needs it. In certain embodiments, the composition provided by the present invention comprises (a) at least one collagen mimetic peptide (CMP), which is connected to at least one diagnostic compound or agent (DC) to form a CMP-DC conjugate, and (b) one or more pharmaceutically suitable carriers. In other related embodiments, the compositions provided herein comprise (a) at least one collagen mimetic peptide (CMP) and (b) at least one additional therapeutic compound, wherein the CMP and at least one additional therapeutic compound are mixed in a formulation, or "co-formulated", optionally with one or more pharmaceutically suitable carriers. In similar embodiments, the compositions provided herein comprise (a) at least one collagen mimetic peptide (CMP) and (b) at least one diagnostic compound or agent, such as a labeling compound or agent, wherein the CMP and at least one diagnostic compound or agent are mixed in a formulation, or "co-formulated", optionally with one or more pharmaceutically suitable carriers, for use in one or more diagnostic methods of the present invention.

[0050] In certain embodiments of the present invention, the collagen mimetic peptide comprises, consists essentially of, or consists of a multimeric repeating amino acid sequence of a specific tripeptide having the sequence (Xaa-Yaa-Gly): n (SEQ ID NO:417), wherein Xaa is independently selected from the group consisting of proline, 4S-hydroxyproline, fluoroproline, chloroproline, lysine, cysteine ​​and methionine; wherein Yaa is independently selected from the group consisting of proline, 4R-hydroxyproline, fluoroproline, chloroproline, lysine, cysteine ​​and methionine; wherein Gly is a glycine residue; and wherein n is an integer ranging from 1 to 20, such as 3 to 15, 5 to 15 or 5 to 10, and is preferably 5, 6, 7, 8, 9 or 10.

[0051] In other embodiments, the present invention provides collagen mimetic peptides comprising one or more alternative amino acids replacing at least one amino acid listed in the tripeptide shown in SEQ ID NO:417, including but not limited to alanine (Ala), glutamine (Gln), glutamic acid (Glu), asparagine (Asn) and aspartic acid (Asp).

[0052] In certain embodiments of the invention, the collagen mimetic peptide comprises, consists essentially of, or consists of an amino acid sequence that is or corresponds to a 21-mer comprising seven repeats of a three amino acid sequence of proline-proline-glycine ((Pro-Pro-Gly)7), i.e., the amino acid sequence: Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Gly-Pro-Gly (SEQ ID NO:1).

[0053] In certain other embodiments of the invention, the collagen mimetic peptide comprises, is essentially composed of, or consists of an amino acid sequence that is or corresponds to a 21-mer comprising seven repeats of three amino acid sequences, in which a hydroxyproline (Hyp), preferably a 4S-hydroxyproline residue, has substituted Proline 1 in SEQ ID NO:1, resulting in a sequence of seven repeats of 4S-hydroxyproline-proline-glycine ((Hyp-Pro-Gly)7), i.e., the amino acid sequence: Hyp-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:2).

[0054] In certain other embodiments of the invention, the collagen mimetic peptide comprises, is essentially composed of, or consists of an amino acid sequence that is or corresponds to a 21-mer comprising seven repeats of three amino acid sequences, wherein Hyp, preferably a 4S-hydroxyproline residue, has replaced Proline 2 in SEQ ID NO:1, resulting in a sequence of seven repeats of 4S-hydroxyproline-proline-glycine ((Pro-Hyp-Gly)7), i.e., the amino acid sequence: 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).

[0055] In certain other embodiments of the invention, the collagen mimetic peptide comprises, is essentially composed of, or consists of an amino acid sequence that is or corresponds to a 21-mer comprising seven repeats of three amino acid sequences, in which fluoroproline (Flp) has substituted Proline 1 in SEQ ID NO:1, resulting in a sequence of seven repeats of fluoroproline-proline-glycine ((Flp-Pro-Gly)7), i.e., the amino acid sequence: 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).

[0056] In certain other embodiments of the invention, the collagen mimetic peptide comprises, is essentially composed of, or consists of an amino acid sequence that is or corresponds to a 21-mer comprising seven repeats of three amino acid sequences, wherein Flp has replaced Proline 2 in SEQ ID NO:1, resulting in a sequence of seven repeats of Proline-Fluoroproline-Glycine ((Pro-Flp-Gly)7), i.e., the amino acid sequence: 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).

[0057] In certain other embodiments of the invention, the collagen mimetic peptide comprises, is essentially composed of, or consists of an amino acid sequence that is or corresponds to a 21-mer comprising seven repeats of three amino acid sequences, wherein fluoroproline (Flp) has substituted proline 1 in SEQ ID NO:1 and Hyp has substituted proline 2 in SEQ ID NO:1, resulting in a sequence of seven repeats of fluoroproline-hydroxyproline-glycine ((Flp-Hyp-Gly)7), i.e., the amino acid sequence: 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).

[0058] In the Flp-containing CMP, the Flp moiety may be in the 4-cis or 4-trans configuration, and is preferably in the 4-cis configuration.

[0059] In certain other embodiments of the present invention, the collagen mimetic peptide comprises, consists of or has an amino acid sequence that is or corresponds to a 21-mer comprising seven repeats of three amino acid sequences, wherein chloroproline (Clp) has replaced Proline 1 in SEQ ID NO:1, resulting in a sequence of seven repeats of chloroproline-proline-glycine ((Clp-Pro-Gly)7), i.e., the amino acid sequence: 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).

[0060] In certain other embodiments of the present invention, the collagen mimetic peptide comprises, consists of or has an amino acid sequence that is or corresponds to a 21-mer comprising seven repeats of three amino acid sequences, wherein chloroproline (Clp) has replaced Proline 2 in SEQ ID NO:1, resulting in a sequence of seven repeats of Proline-Chloroproline-Glycine ((Pro-Clp-Gly)7), i.e., the amino acid sequence: 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).

[0061] In certain other embodiments of the invention, the collagen mimetic peptide comprises, is essentially composed of, or consists of an amino acid sequence that is or corresponds to a 21-mer comprising seven repeats of three amino acid sequences, wherein Clp has substituted proline 1 in SEQ ID NO:1 and Hyp has substituted proline 2 in SEQ ID NO:1, resulting in a sequence of seven repeats of chloroproline-hydroxyproline-glycine ((Clp-Hyp-Gly)7), i.e., the amino acid sequence: Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly (SEQ ID NO:9).

[0062] In the CMP containing Clp, the Clp moiety may be in the 4-cis or 4-trans configuration, and is preferably in the 4-cis configuration.

[0063] In certain other embodiments of the present invention, the collagen mimetic peptide may comprise, consist of, or have a 21-mer amino acid sequence that is or corresponds to any one of SEQ ID NOs: 1-9, wherein at least one cysteine ​​(Cys) residue has substituted at least one proline residue in SEQ ID NO: 1, at least one hydroxyproline residue in SEQ ID NOs: 2-3 and 6, at least one fluoroproline residue in SEQ ID NOs: 4-6, or at least one chloroproline residue in SEQ ID NOs: 7-9, thereby producing, for example, the following sequence:

[0064] 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);

[0065] 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);

[0066] 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);

[0067] 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);

[0068] Pro-Clp-Gly-Pro-Clp-Gly-Pro-Cys-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly(SEQ ID NO:14);

[0069] 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);

[0070] 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);

[0071] 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);

[0072] 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);

[0073] 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);

[0074] 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);

[0075] 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);

[0076] 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);

[0077] 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);

[0078] 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);

[0079] 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);

[0080] 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);

[0081] 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);

[0082] Cys-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly(SEQ ID NO:28);

[0083] Hyp-Cys-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly(SEQ ID NO:29);

[0084] Hyp-Pro-Gly-Cys-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly(SEQ ID NO:30);

[0085] Hyp-Pro-Gly-Hyp-Cys-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly(SEQ ID NO:31);

[0086] Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Cys-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly(SEQ ID NO:32);

[0087] 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);

[0088] 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);

[0089] 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);

[0090] 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);

[0091] 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);

[0092] 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);

[0093] 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);

[0094] 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);

[0095] 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);

[0096] Pro-Cys-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly(SEQ ID NO:42);

[0097] Pro-Hyp-Gly-Cys-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly(SEQ ID NO:43);

[0098] Pro-Hyp-Gly-Pro-Cys-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly(SEQ ID NO:44);

[0099] Pro-Hyp-Gly-Pro-Hyp-Gly-Cys-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly(SEQ ID NO:45);

[0100] 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);

[0101] 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);

[0102] 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);

[0103] 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);

[0104] 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);

[0105] 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);

[0106] 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);

[0107] 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);

[0108] 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);

[0109] 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);

[0110] 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);

[0111] 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);

[0112] 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);

[0113] 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);

[0114] 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);

[0115] 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);

[0116] 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);

[0117] 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);

[0118] 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);

[0119] 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);

[0120] 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);

[0121] 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);

[0122] 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);

[0123] 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);

[0124] 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);

[0125] 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);

[0126] 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);

[0127] 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);

[0128] 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);

[0129] 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);

[0130] 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);

[0131] 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);

[0132] 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);

[0133] 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);

[0134] 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);

[0135] 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);

[0136] 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);

[0137] 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);

[0138] Flp-Hyp-Gly-Flp-Cys-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly(SEQ ID NO:84);

[0139] Flp-Hyp-Gly-Flp-Hyp-Gly-Cys-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly(SEQ ID NO:85);

[0140] Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Cys-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly(SEQ ID NO:86);

[0141] Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Cys-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly(SEQ ID NO:87);

[0142] Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Cys-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly(SEQ ID NO:88);

[0143] Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Cys-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly(SEQ ID NO:89);

[0144] Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Cys-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly(SEQ ID NO:90);

[0145] 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);

[0146] 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);

[0147] 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);

[0148] 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);

[0149] 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);

[0150] 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);

[0151] 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);

[0152] Pro-Clp-Gly-Pro-Cys-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly(SEQ ID NO:98);

[0153] Pro-Clp-Gly-Pro-Clp-Gly-Cys-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly(SEQ ID NO:99);

[0154] 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);

[0155] 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);

[0156] 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);

[0157] 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);

[0158] 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);

[0159] 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);

[0160] 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);

[0161] 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);

[0162] 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);

[0163] 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);

[0164] 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);

[0165] 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);

[0166] Pro-Clp-Gly-Pro-Clp-Gly-Cys-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly(SEQ ID NO:112);

[0167] 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);

[0168] 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);

[0169] 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);

[0170] 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);

[0171] 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);

[0172] 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);

[0173] 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);

[0174] 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);

[0175] 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);

[0176] 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);

[0177] 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);

[0178] 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);

[0179] 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);

[0180] 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);

[0181] 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);

[0182] 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);

[0183] 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);

[0184] 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);

[0185] 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);

[0186] 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);

[0187] 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);

[0188] and

[0189] 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).

[0190] In certain other embodiments of the invention, the collagen mimetic peptide may comprise, consist of, or have a 21-mer amino acid sequence that is or corresponds to any one of SEQ ID NOs: 1-9, wherein at least one methionine (Met) residue has substituted at least one proline residue in SEQ ID NO: 1, at least one hydroxyproline residue in SEQ ID NOs: 2-3 and 6, at least one fluoroproline residue in SEQ ID NOs: 4-6, or at least one chloroproline residue in SEQ ID NOs: 7-9, thereby producing, for example, the following sequence:

[0191] 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);

[0192] 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);

[0193] Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Met-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly (SEQ ID NO: 138);

[0194] Pro-Flp-Gly-Pro-Flp-Gly-Pro-Met-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly(SEQ ID NO:139);

[0195] 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);

[0196] 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);

[0197] 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);

[0198] 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);

[0199] 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);

[0200] Pro-Pro-Gly-Pro-Pro-Gly-Pro-Met-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly(SEQ ID NO:145);

[0201] Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Met-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly(SEQ ID NO:146);

[0202] 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);

[0203] 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);

[0204] 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);

[0205] 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);

[0206] 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);

[0207] 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);

[0208] 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);

[0209] Met-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly(SEQ ID NO:154);

[0210] Hyp-Met-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly(SEQ ID NO:155);

[0211] Hyp-Pro-Gly-Met-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly(SEQ ID NO:156);

[0212] Hyp-Pro-Gly-Hyp-Met-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly(SEQ ID NO:157);

[0213] Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Met-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly(SEQ ID NO:158);

[0214] Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Met-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly(SEQ ID NO:159);

[0215] 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);

[0216] 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);

[0217] 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);

[0218] 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);

[0219] 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);

[0220] 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);

[0221] 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);

[0222] 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);

[0223] 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);

[0224] 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);

[0225] 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);

[0226] 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);

[0227] 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);

[0228] 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);

[0229] 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);

[0230] 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);

[0231] 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);

[0232] 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);

[0233] 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);

[0234] 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);

[0235] 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);

[0236] 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);

[0237] 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);

[0238] 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);

[0239] 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);

[0240] 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);

[0241] 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);

[0242] 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);

[0243] 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);

[0244] 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);

[0245] 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);

[0246] 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);

[0247] 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);

[0248] 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);

[0249] Pro-Met-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly(SEQ ID NO:194);

[0250] Pro-Flp-Gly-Met-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly(SEQ ID NO:195);

[0251] Pro-Flp-Gly-Pro-Met-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly(SEQ ID NO:196);

[0252] Pro-Flp-Gly-Pro-Flp-Gly-Met-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly(SEQ ID NO:197);

[0253] Pro-Flp-Gly-Pro-Flp-Gly-Pro-Met-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly(SEQ ID NO:198);

[0254] Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Met-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly(SEQ ID NO:199);

[0255] Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Met-Gly-Pro-Flp-Gly-Pro-Flp-Gly-Pro-Flp-Gly(SEQ ID NO:200);

[0256] 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);

[0257] 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);

[0258] 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);

[0259] 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);

[0260] 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);

[0261] 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);

[0262] 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);

[0263] Flp-Met-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly-Flp-Hyp-Gly(SEQ ID NO:208);

[0264] 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);

[0265] 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);

[0266] 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);

[0267] 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);

[0268] 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);

[0269] 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);

[0270] 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);

[0271] 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);

[0272] 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);

[0273] 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);

[0274] 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);

[0275] 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);

[0276] 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);

[0277] Pro-Met-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly(SEQ ID NO:222);

[0278] Pro-Clp-Gly-Met-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly(SEQ ID NO:223);

[0279] Pro-Clp-Gly-Pro-Met-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly(SEQ ID NO:224);

[0280] Pro-Clp-Gly-Pro-Clp-Gly-Met-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly(SEQ ID NO:225);

[0281] Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Met-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly(SEQ ID NO:226);

[0282] Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Met-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly(SEQ ID NO:227);

[0283] Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Met-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly(SEQ ID NO:228);

[0284] 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);

[0285] 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);

[0286] 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);

[0287] 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);

[0288] 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);

[0289] 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);

[0290] 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);

[0291] Pro-Clp-Gly-Met-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly(SEQ ID NO:236);

[0292] Pro-Clp-Gly-Pro-Met-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly(SEQ ID NO:237);

[0293] Pro-Clp-Gly-Pro-Clp-Gly-Met-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly(SEQ ID NO:238);

[0294] Pro-Clp-Gly-Pro-Clp-Gly-Pro-Met-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly(SEQ ID NO:239);

[0295] Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Met-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly(SEQ ID NO:240);

[0296] Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Met-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly(SEQ ID NO:241);

[0297] Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Met-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly(SEQ ID NO:242);

[0298] 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);

[0299] 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);

[0300] 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);

[0301] 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);

[0302] 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);

[0303] 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);

[0304] 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);

[0305] 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);

[0306] 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);

[0307] 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);

[0308] 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);

[0309] 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);

[0310] 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);

[0311] 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);

[0312] 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);

[0313] 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);

[0314] 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);

[0315] and

[0316] 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).

[0317] In certain other embodiments of the present invention, the collagen mimetic peptide may comprise, consist of or have a 21-mer amino acid sequence that is or corresponds to any one of SEQ ID NOs: 1-9, wherein at least one lysine (Lys) residue has substituted at least one proline residue in SEQ ID NO: 1, at least one hydroxyproline residue in SEQ ID NOs: 2-3 and 6, at least one fluoroproline residue in SEQ ID NOs: 4-6, or at least one chloroproline residue in SEQ ID NOs: 7-9, thereby producing, for example, the following sequence:

[0318] Pro-Pro-Gly-Pro-Pro-Gly-Lys-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly (SEQ ID NO: 262);

[0319] Hyp-Pro-Gly-Hyp-Pro-Gly-Lys-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly (SEQ ID NO: 263);

[0320] 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);

[0321] 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);

[0322] 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);

[0323] 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);

[0324] 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);

[0325] Pro-Pro-Gly-Lys-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly-Pro-Pro-Gly(SEQ ID NO:269);

[0326] 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);

[0327] 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);

[0328] 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);

[0329] 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);

[0330] 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);

[0331] 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);

[0332] 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);

[0333] 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);

[0334] 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);

[0335] 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);

[0336] 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);

[0337] 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);

[0338] 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);

[0339] Hyp-Pro-Gly-Hyp-Lys-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly(SEQ ID NO:283);

[0340] Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Lys-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly(SEQ ID NO:284);

[0341] Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Lys-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly-Hyp-Pro-Gly(SEQ ID NO:285);

[0342] 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);

[0343] 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);

[0344] 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);

[0345] 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);

[0346] 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);

[0347] 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);

[0348] 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);

[0349] 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);

[0350] 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);

[0351] 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);

[0352] 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);

[0353] Pro-Hyp-Gly-Pro-Hyp-Gly-Lys-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly(SEQ ID NO:297);

[0354] Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Lys-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly-Pro-Hyp-Gly(SEQ ID NO:298);

[0355] 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);

[0356] 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);

[0357] 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);

[0358] 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);

[0359] 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);

[0360] 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);

[0361] 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);

[0362] 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);

[0363] 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);

[0364] 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);

[0365] 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);

[0366] 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);

[0367] 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);

[0368] 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);

[0369] 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);

[0370] 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);

[0371] 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);

[0372] 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);

[0373] 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);

[0374] 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);

[0375] 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);

[0376] 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);

[0377] 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);

[0378] 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);

[0379] 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);

[0380] 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);

[0381] 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);

[0382] 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);

[0383] 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);

[0384] 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);

[0385] 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);

[0386] 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);

[0387] 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);

[0388] 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);

[0389] 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);

[0390] 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);

[0391] 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);

[0392] 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);

[0393] 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);

[0394] 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);

[0395] 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);

[0396] 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);

[0397] 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);

[0398] 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);

[0399] 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);

[0400] 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);

[0401] 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);

[0402] 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);

[0403] 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);

[0404] 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);

[0405] 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);

[0406] 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);

[0407] 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);

[0408] 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);

[0409] 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);

[0410] 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);

[0411] 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);

[0412] 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);

[0413] 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);

[0414] 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);

[0415] 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);

[0416] Lys-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly-Pro-Clp-Gly(SEQ ID NO:360);

[0417] 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);

[0418] 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);

[0419] 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);

[0420] 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);

[0421] 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);

[0422] 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);

[0423] 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);

[0424] 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);

[0425] 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);

[0426] 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);

[0427] 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);

[0428] 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);

[0429] 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);

[0430] 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);

[0431] 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);

[0432] 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);

[0433] 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);

[0434] 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);

[0435] 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);

[0436] 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);

[0437] Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Lys-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly-Clp-Hyp-Gly(SEQ ID NO:381);

[0438] 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);

[0439] 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);

[0440] 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);

[0441] 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);

[0442] and

[0443] 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).

[0444] Another suitable CMP for use according to 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-Hyp-Flp-Gly-Hyp-Flp-Gly-Flp-Gly-Hyp-Flp-Gly (SEQ ID NO: 388).

[0445] Other suitable CMPs for use according to the present invention are CMPs having or comprising the following 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), ID: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 modifying collagen in vitro and in vivo for therapeutic and / or diagnostic methods (see, e.g., U.S. Pat. Nos. 8,283,414, 8,883,964, 10,632,168, and 11,389,513, the disclosures of all of which are incorporated herein by reference in their entireties).

[0446] In certain other embodiments of the invention, the collagen mimetic peptide comprises, consists essentially of, or consists of an amino acid sequence that is or corresponds to a 21-mer comprising seven repeats of a three amino acid sequence, wherein Ala has substituted Proline 2 in SEQ ID NO:1 to produce a sequence of seven repeats of Proline-Alanine-Glycine ((Pro-Ala-Gly)7), i.e., the amino acid sequence: Pro-Ala-Gly-Pro-Ala-Gly-Pro-Ala-Gly-Pro-Ala-Gly-Pro-Ala-Gly-Pro-Ala-Gly (SEQ ID NO:418). In other embodiments, the collagen mimetic peptide comprises, consists essentially of, or consists of an amino acid sequence that is or corresponds to a 21-mer comprising seven repeats of a three amino acid sequence, wherein Hyp or Flp has substituted Proline 1 in SEQ ID NO:418 to produce a sequence of seven repeats of Proline-Alanine-Glycine ((Pro-Ala-Gly)7), i.e., the amino acid sequence: Hyp-Ala-Gly-Hyp-Ala-Gly-Hyp-Ala-Gly-Hyp-Ala-Gly-Hyp-Ala-Gly-Hyp-Ala-Gly-Hyp-Ala-Gly (SEQ ID NO:418). 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).

[0447] Other suitable CMPs for use according to the present invention are CMPs having or comprising the following 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), (Hyp-Gly-Glu)7 (SEQ ID NO:432), (Hyp-Gly-Asp)7 (SEQ ID NO:433), (Hyp-Gly-Glu)7 (SEQ ID NO:434), (Hyp-Gly-Gln)7 (SEQ ID NO:435), (Hyp-Gly-Glu)7 (SEQ ID NO:436), (Hyp-Gly-Gln)7 (SEQ ID NO:437), (Hyp-Gly-Pro)7 (SEQ ID NO:438), (Hyp-Gly-Gln)7 (SEQ ID NO:439), (Hyp-Gly-Glu)7 (SEQ ID NO:440), (Pro-Gly-Asp)7 (SEQ ID NO:441), (Hyp- 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,Said other similar CMPs contain 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 into the positions of the aforementioned CMP sequences, according to the positions indicated by the cysteine ​​in SEQ ID Nos: 10-135, the methionine in SEQ ID Nos: 136-251 and the lysine in SEQ ID Nos: 262-387. ,

[0448] 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 the N-terminus or C-terminus or to both ends of the amino acid sequence. Non-limiting examples of such CMPs include:

[0449] SEQ ID NO: 1, wherein the cysteine ​​residue is linked to the N-terminus, i.e., Cys-((Pro-Pro-Gly)7) (SEQ ID NO: 453), to the C-terminus, i.e., (Pro-Pro-Gly)7-Cys (SEQ ID NO: 454), or to both ends, i.e., Cys-((Pro-Pro-Gly)7)-Cys (SEQ ID NO: 455);

[0450] SEQ ID NO:6, wherein the cysteine ​​residue is linked to the N-terminus, i.e., Cys-((Flp-Hyp-Gly)7)(SEQ ID NO:456), to the C-terminus, i.e., (Flp-Hyp-Gly)7-Cys (SEQ ID NO:457), or to both ends, i.e., Cys-((Flp-Hyp-Gly)7)-Cys (SEQ ID NO:458);

[0451] SEQ ID NO: 1, wherein the methionine residue is linked to the N-terminus, i.e., Met-((Pro-Pro-Gly)7) (SEQ ID NO: 459), or to the C-terminus, i.e., (Pro-Pro-Gly)7-Met (SEQ ID NO: 460), or to both ends, i.e., Met-((Pro-Pro-Gly)7)-Met (SEQ ID NO: 461);

[0452] SEQ ID NO:6, wherein the methionine residue is linked to the N-terminus, i.e., Met-((Flp-Hyp-Gly)7) (SEQ ID NO:462), to the C-terminus, i.e., (Flp-Hyp-Gly)7-Met (SEQ ID NO:463), or to both ends, i.e., Met-((Flp-Hyp-Gly)7)-Met (SEQ ID NO:464);

[0453] SEQ ID NO: 1, wherein the lysine residue is linked to the N-terminus, i.e., Lys-((Pro-Pro-Gly)7)(SEQ ID NO: 465), or to the C-terminus, i.e., (Pro-Pro-Gly)7-Lys (SEQ ID NO: 466), or to both ends, i.e., Lys-((Pro-Pro-Gly)7)-Lys (SEQ ID NO: 467);

[0454] SEQ ID NO:6, wherein the lysine residue is linked to the N-terminus, i.e., Lys-((Flp-Hyp-Gly)7)(SEQ ID NO:468), to the C-terminus, i.e., (Flp-Hyp-Gly)7-Lys (SEQ ID NO:469), or to both ends, i.e., Lys-((Flp-Hyp-Gly)7)-Lys (SEQ ID NO:470).

[0455] In other embodiments, the sequences listed in SEQ ID No: 453-458 may have one or more methionine or lysine residues substituted for one or more cysteine ​​residues. In other embodiments, the sequences listed in SEQ ID No: 459-464 may have one or more cysteine ​​or lysine residues substituted for one or more methionine residues. In other embodiments, the sequences listed in SEQ ID No: 465-470 may have one or more methionine or cysteine ​​residues substituted for one or more lysine residues.

[0456] Of course, based on the knowledge in the art and the teachings herein, one of ordinary skill in the art will understand that such CMPs may comprise two or more cysteine, methionine and / or lysine residues, wherein 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 in any of the aforementioned CMP sequences comprising at least one proline, at least one hydroxyproline, at least one fluoroproline residue and / or at least one chloroproline residue. One of ordinary skill in the art will also understand based on the teachings herein and information readily available in the art that other combinations of amino acid substitutions are possible and fall within the scope of the present invention.

[0457] The CMP described herein is suitable for a variety of purposes. For example, as described in further detail elsewhere herein, CMP can be used for a variety of therapeutic applications or preventive applications by being directly applied to or introduced into a human or animal body, particularly at a site where collagen is destroyed or potential collagen is destroyed, wherein the CMP described herein will be directly positioned at the site where collagen is destroyed, annealing with the destroyed collagen chains and stabilizing the collagen structure to resist further destruction, and in some cases re-forming the native collagen triple helix at the site where collagen is destroyed. Such applications help promote the repair and strengthening of damaged or potentially damaged sites, such as wounds, diseases, structural abnormalities or disorders (e.g., scars, wrinkle formation, etc.) involving skin, tendons, ligaments, cartilage, bones and other collagen-containing structures and organs. The CMPs described herein are also used to provide biocompatible coatings for certain medical devices to promote healing of injuries and disorders in body regions, where such devices are used to treat or prevent certain diseases, disorders, and structural abnormalities or injuries in humans and veterinary animals, particularly those body regions where such diseases, disorders, and structural abnormalities or injuries involve the destruction of collagen and / or collagen-containing structures. The CMPs described herein are also used to provide unique delivery vehicles suitable for delivering various therapeutic compounds, compositions, and drugs to disease, disorder, and structural abnormality or injury sites in humans and veterinary animals, particularly for treating, preventing, or ameliorating diseases, disorders, medical conditions, and structural abnormalities or injuries caused by collagen destruction, associated with or co-localized with disease, disorder, and structural abnormality or injury sites. In additional embodiments, the CMPs described herein can be used to provide diagnostic agents suitable for diagnosing or detecting diseases, disorders, structural abnormalities, or injuries in humans and veterinary animals. In certain such aspects, the CMP may be co-formulated or directly or indirectly conjugated with one or more suitable diagnostic compounds, agents, labels, etc. (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, the disclosures of all of which are incorporated herein by reference in their entireties). Other suitable uses of the CMPs described herein and used in certain aspects of the invention will be apparent to the skilled artisan based on the disclosure herein and information readily available in the art.

[0458] In certain embodiments, the CMPs described herein are suitable for forming a film, wafer, membrane, or gel comprising one or more CMPs in a form suitable for introduction or implantation into a human or animal for therapeutic, prophylactic, or diagnostic applications, such as those described herein and other applications familiar to those of ordinary skill in the relevant art. For example, a film, wafer, membrane, sphere, nanoparticle, or gel can be formed from one or more CMP solutions described herein using methods such as those described in U.S. Pat. Nos. 6,197,934, 6,448,378, and 9,289,396; the disclosures of all of these patents are incorporated herein by reference in their entirety. Alternatively, the film, wafer, membrane sphere, nanoparticle or gel can be formed from other materials, such as atelocollagen (see U.S. Pat. Nos. 6,197,934, 6,448,378 and 9,289,396), copolymers of polylactic acid and polyglycolic 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., ed., "Polymer Gels: Perspectives and Applications", ISBN 32901584). 978-981-10-6079-3, Singapore: Springer (2018)), and one or more CMPs can be appropriately incorporated into the process of forming such thin films, wafers, membranes, spheres, nanoparticles, gels, etc. by including the CMP in the solution at a concentration of 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. Based on the teachings of this article and information readily available to those of ordinary skill in the art, it can be readily understood that appropriate other amounts or concentrations of the CMPs described herein that can be appropriately included in the solution during the formation of thin films, wafers, membranes, spheres, nanoparticles, gels, etc. In certain such embodiments, one or more therapeutic compounds described herein and / or one or more CMP-TC conjugates described herein may be suitably incorporated into a solution that is formed into a film, wafer, membrane, sphere, nanoparticle, gel, or the like.Alternatively, in a related aspect, once one or more thin films, wafers, membranes, spheres, nanoparticles, gels, etc. are formed as described above, they may be treated or coated with one or more CMPs and / or CMP-TC conjugates described herein by immersing the film, wafer, membrane, sphere, nanoparticle, gel, etc. in a solution, particularly a buffered aqueous solution, containing a suitable amount or concentration (such as those described herein) of one or more CMPs or CMP-TC conjugates described herein, and then drying the film, wafer, membrane, etc. prior to use in a therapeutic, prophylactic, or diagnostic method (e.g., those described herein).

[0459] Attachment / conjugation of CMP

[0460] In certain embodiments of the present invention, the CMPs described herein are suitably linked or conjugated to one or more therapeutic or diagnostic compounds to produce CMP conjugate compounds. In such embodiments of the present invention, the CMP-therapeutic compound or CMP-diagnostic compound conjugate compound can then be introduced into the body of a human or veterinary animal in a method of treating and / or preventing and / or diagnosing certain diseases, disorders and structural abnormalities in humans or veterinary animals. Therefore, in certain embodiments, the present invention also provides the use of linking or conjugating the CMPs described herein to one or more therapeutic compounds to produce conjugated CMPs, compositions comprising such conjugated 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 to treat, prevent and diagnose various diseases, disorders and medical conditions in humans and veterinary animals.

[0461] According to this aspect of the invention, a conjugate of a CMP and at least one therapeutic compound (described herein as a "CMP-TC conjugate") will comprise at least one CMP described herein linked to at least one therapeutic compound to form a CMP-TC conjugate. CMPs suitable for use in these aspects of the invention include any CMP described herein, including a CMP having an amino acid sequence corresponding to any one of SEQ ID NOs: 1-387, particularly wherein the CMP 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 and 397-416, and more particularly 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 and 397-416. Based on the teachings contained herein, other suitable CMP sequences will be immediately apparent to those of ordinary skill in the art. For example, CMPs having at least one, in some cases more than one, cysteine, methionine or lysine residue substituted for at least one, in some cases more than one, proline, hydroxyproline, fluoroproline or chloroproline residue in SEQ ID NOs: 1-9 will be particularly suitable for producing the CMP-TC conjugates provided and used in the present invention. Examples of such suitable CMPs include CMPs having amino acid sequences corresponding to SEQ ID NOs: 10-27, 81-94, 122-135, 207-220, 248-261, 333-346, 374-388, 397-416 and 453-470.

[0462] In other such embodiments, the CMP may be linked to one or more other peptides or proteins via one or more peptide bonds at the C and / or N termini of the CMP, thereby producing a CMP-TC conjugate, which is a peptide or protein comprising the CMP. Any peptide or protein, whether or not such peptide or protein is itself a therapeutic peptide or protein, may advantageously be linked or bound to the CMP via one or more peptide bonds, thereby producing a new compound that is a combination of the CMP and the peptide or protein, and the new compound may have a biological activity resulting from a combination of the structure and function of the CMP and the protein or peptide to which it is conjugated. For example, a CMP that has been conjugated to the Fc or Fab portion of an antibody (e.g., a polyclonal antibody or a monoclonal antibody) may exhibit the biological activity of both the CMP and the antibody portion, thereby providing a unique compound with multiple functions that may enhance the therapeutic and / or diagnostic utility of the compound over that of a single CMP or antibody fragment, or may allow for direct delivery of therapy or diagnosis to specific cells, tissues or organ types when introduced into an animal (particularly a human or veterinary animal) for use in a variety of therapeutic and / or diagnostic methods, such as those described elsewhere herein. According to this aspect of the invention, other peptides or proteins that have therapeutic and / or diagnostic uses themselves may also be advantageously linked or conjugated to the CMP. Such peptides or proteins include peptides or proteins of certain pharmacological classes, including but not limited to antithrombin, fibrinolytic peptides / proteins, enzymes, anti-tumor agents, hormones, fertility agents, immunosuppressants (including anti-inflammatory agents), bone-related peptides / proteins, anti-diabetic agents, and antibodies. More specific examples of peptides / proteins belonging to these classes include those that have been approved by the U.S. Food and Drug Administration as therapeutic and / or diagnostic agents, such as those listed in the real-time THPdb database of FDA-approved therapeutic peptides and proteins, which is available at https: / / webs.iiitd.edu.in / raghava / thpdb / category.php Referenced in and first published in Usmani, SS et al., PLoS ONE 12(7):e0181748 (2017), https: / / doi.org / 10.1371 / journal.pone .0181748, which database and publication are incorporated herein by reference in their entirety. In view of the teachings herein and readily available information in the relevant art, one of ordinary skill in the art will be familiar with other suitable peptides and proteins and fragments thereof that can be advantageously conjugated or linked to the CMPs described herein.

[0463] Based on the teachings herein and information readily available in the art, one of ordinary skill in the art will be familiar with the methods for preparing CMP and CMP-TC described herein and provided and used by the present invention. 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 the techniques described in U.S. Patent Publication No. US2007 / 0275897 A1, the disclosure of which is incorporated herein by reference in its entirety. Synthesis of CMP can also be achieved by purchasing commercially produced custom synthetic CMP, such as those produced by Bachem (Torrance, CA, USA) and RS Synthesis (Louisville, KY, USA). In other embodiments, synthesis of CMP can be achieved using genetic engineering and recombinant expression of CMP from a prokaryotic or eukaryotic expression system (see, e.g., Buechter, DD et al., J. Biol. Chem. 278 (1): 645-650 (2003)).

[0464] When synthesizing the peptides described herein, in certain embodiments it is preferred to use certain stereochemistries for amino acid substitutions, particularly if hydroxyproline, fluoroproline, or chloroproline is used:

[0465] (1) If hydroxyproline replaces the proline at the Xaa position of the above Xaa-Yaa-Gly trimer, in certain embodiments, the hydroxyproline has a (2R, 4S) stereochemistry, either cis or trans, preferably cis stereochemistry;

[0466] (2) If hydroxyproline replaces the proline at the Yaa position of the above Xaa-Yaa-Gly trimer, in certain embodiments, the hydroxyproline has a (2R, 4S) stereochemistry, either cis or trans, preferably cis stereochemistry;

[0467] (3) If fluoroproline replaces the proline at the Yaa position of the above Xaa-Yaa-Gly trimer, in certain embodiments, the hydroxyproline has a (2R, 4S) stereochemistry, either cis or trans, preferably cis stereochemistry;

[0468] (4) If chloroproline replaces the proline at the Yaa position of the above Xaa-Yaa-Gly trimer, in certain embodiments, the hydroxyproline has a (2R, 4S) stereochemistry, either cis or trans, preferably cis.

[0469] Other suitable stereochemistries can be determined empirically without resorting to undue experimentation and will be immediately apparent to one of ordinary skill in the art. As described above, certain CMPs provided and used herein may 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 polymer. Such substitutions may be suitably achieved by adding these residues to the growing CMP peptide chain during the synthesis process using standard peptide synthesis methods, such as those described elsewhere herein and known in the art.

[0470] Once the CMPs are prepared, they are suitable for use in producing the CMP-TCs of the present invention, i.e., therapeutic or diagnostic compositions of the present invention, by attaching one or more therapeutic compounds to the CMPs. In certain embodiments, the CMP-TCs of the present invention can be prepared by a method comprising (a) providing a collagen mimetic peptide having an amino acid sequence corresponding to any one of SEQ ID NOs: 1-470, in particular 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, and more particularly a CMP having an amino acid sequence corresponding to any one of SEQ ID NOs: NO: 10-27, 81-94, 122-135, 207-220, 248-261, 333-346, 374-388, 397-416 and 453-470; (b) providing at least one therapeutic or diagnostic compound suitable for conjugation to the CMP; and (c) directly or indirectly linking the therapeutic or diagnostic compound to the CMP. In some cases, particularly when the therapeutic compound is a small peptide biological compound, the therapeutic compound can be directly linked to the CMP via a peptide bond, for example by simply extending the synthesis of the peptide beyond the carboxyl terminus of the CMP and linking the amino terminal amino acid of the therapeutic compound to the carboxyl terminal amino acid of the CMP via a peptide bond. An example of such a CMP-TC is a peptide conjugate in which a wound healing peptide called substance P having an amino acid sequence of Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met (SEQ ID NO: 471) is linked to the CMP described herein. Examples of such conjugates include, for example:

[0471] 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);

[0472] Hyp-Pro-Gly-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);

[0473] 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);

[0474] Flp-Hyp-Gly-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);

[0475] 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);

[0476] Pro-Flp-Gly-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(SEQID NO:477); and

[0477] Pro-Clp-Gly-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).

[0478] In other methods of the invention, one or more therapeutic or diagnostic compounds are suitably conjugated or linked to the CMP via covalent bonds other than peptide bonds (see, e.g., U.S. Pat. Nos. 3,283,414 and 3,883,964, which are incorporated herein by reference in their entirety). For example, the therapeutic compound may be directly linked to a cysteine ​​or methionine residue on a CMP described herein by covalently bonding a hydroxyl or amino group on an amino acid residue (e.g., a lysine residue) on the therapeutic or diagnostic compound (if it is a biomolecule) to a sulfhydryl group on a cysteine ​​or methionine residue of the CMP. Alternatively, if the CMP does not contain a cysteine ​​or methionine residue, one or more therapeutic or diagnostic compounds may be linked or conjugated to the CMP via a reaction between a hydroxyl or amino group on the CMP and a sulfhydryl group on an amino acid residue (e.g., at a cysteine ​​or methionine residue) on the therapeutic or diagnostic compound (if it is a biomolecule). In another alternative conjugation method, the therapeutic compound can be directly linked to a lysine residue on the CMP described herein by covalently binding the therapeutic compound to the amino group on the lysine, for example, using NHS ester conjugation (see, e.g., Mattson, G., et al., Molec. Biol. Rep. 17:167-183 (1993); Grabarek, Z. and Gergely, J., Anal. Biochem. 185:131-135 (1990); Staros, JV et al., Anal. Biochem. 156:220-2 (1986); Timkovich, R., Anal. Biochem. 79:135-43 (1977)). This direct covalent linking or conjugation between the CMP and the therapeutic / diagnostic compound can be achieved using standard reaction techniques familiar to those of ordinary skill in the art of organic chemistry.

[0479] In other embodiments, particularly in which the therapeutic or diagnostic compound is not a biologic (and therefore does not have a peptide structure or an amino acid residue with a group that can be appropriately attached to a cysteine, methionine, lysine, or other residue on a CMP), such as a small molecule organic or inorganic therapeutic or diagnostic compound, at least one therapeutic or diagnostic compound is indirectly attached to the collagen mimetic peptide by using a linking means. In such embodiments, the linking means has two connectable ends, one of which is attached to an amino acid residue of the CMP and is appropriately attached to a sulfhydryl group on a cysteine ​​or methionine residue or an amino group on a lysine residue, and the other end is attached to a hydroxyl or amino group on the therapeutic or diagnostic compound. For example, in certain such embodiments, the linking means includes at least one polymer chain having a first end and a second end, and the first end of the polymer chain is bound to a sulfhydryl group on a cysteine ​​or methionine residue or an amino group on a lysine residue on the collagen mimetic peptide, and the opposite end or second end of the polymer chain is bound to an amino group or hydroxyl group on the therapeutic compound. In embodiments where the therapeutic or diagnostic compound is a biological agent that is not suitable for direct connection by peptide synthesis described elsewhere herein, the second end of the connecting device can be connected to an amino group on an amino acid residue (such as a lysine residue) on the biological therapeutic or diagnostic compound. Suitable such connection methods are well known to those of ordinary skill in the art. For example, a connection method suitable for use according to this aspect of the invention includes a polymer chain portion, one end of the polymer chain (particularly the CMP binding end) contains a thiol binding group, such as maleimide, and the other end (particularly the treatment or diagnosis composite binding end) contains an amino binding group, such as N-hydroxysuccinimide. In certain such embodiments, the polymer chain is a linear polyethylene glycol chain, which contains at least four ethylene glycol monomers, such as four to fifty ethylene glycol monomers, ten to forty ethylene glycol monomers, fifteen to thirty ethylene glycol monomers, fifteen to twenty-five ethylene glycol monomers, twenty to twenty-five ethylene glycol monomers, particularly four, six, eight, twelve, twenty, twenty-two, twenty-three, twenty-four or twenty-five ethylene glycol monomers. Such linking devices suitable for attaching one or more therapeutic or diagnostic compounds to a CMP by the methods described herein are commercially available, for example, 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 bioavailability and sustainability of the therapeutic or diagnostic compound in vivo can be adjusted - using a longer polymer chain, such as a polymer containing 24 ethylene glycol monomers, will increase the bioavailability of the compound after CMP-TC enters the human or veterinary animal body, while using a shorter polymer chain, such as a polymer containing six ethylene glycol monomers, will reduce the bioavailability, thereby increasing the sustainability of the therapeutic or diagnostic compound (in other words, will result in delayed release or sustained release). Other conjugates using linear or star-shaped PEG moieties that can be appropriately 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 incorporated herein by reference in their entirety. Therefore, according to certain aspects of the present invention, at least one therapeutic compound comprises at least one reactive hydroxyl group that can be cross-linked with a collagen mimetic peptide using a polymer linker.

[0480] According to the present invention, other indirect connection methods for conjugating one or more therapeutic or diagnostic compounds to or on CMP are also appropriately used. For example, at least one therapeutic or diagnostic compound can be encapsulated in at least one nanoparticle, which is connected to the collagen mimetic peptide by a connection method such as described herein. Alternatively, the collagen mimetic peptide can appropriately include at least one biotin moiety, and the therapeutic molecule can appropriately include at least one avidin or streptavidin moiety, and the biotin moiety on the collagen mimetic peptide will be combined with the avidin or streptavidin moiety on the therapeutic or diagnostic compound, thereby connecting the collagen mimetic peptide to the therapeutic or diagnostic compound. Of course, alternatives are also applicable, wherein the collagen mimetic peptide can appropriately include at least one avidin or streptavidin moiety, and the therapeutic or diagnostic compound can appropriately include at least one biotin moiety, and the biotin moiety on at least one therapeutic or diagnostic compound will be combined with the avidin or streptavidin moiety on the collagen mimetic peptide, thereby connecting the collagen mimetic peptide to the therapeutic compound.

[0481] Thus, according to certain embodiments of the present invention, the therapeutic or diagnostic compound may be suitably directly linked to the CMP described herein. In other embodiments of the present invention, one or more therapeutic or diagnostic compounds may be indirectly linked to the CMP described herein, for example by using a spacer, linker or bridge moiety. It should be understood that whether one or more therapeutic compounds are directly or indirectly linked to the CMP, such linkage will result in a conjugate of the CMP and the one or more therapeutic compounds, which may be defined herein as a CMP-TC conjugate.

[0482] Therapeutic or diagnostic compounds suitable for attachment or conjugation to a CMP to produce a CMP-TC of the present invention include any compound that has been shown to have specific therapeutic or prophylactic properties against one or more diseases, disorders, physical conditions or ailments when introduced into a human or veterinary animal suffering from or susceptible to such disease, disorder, physical condition or ailment. Any therapeutic or diagnostic compound may be used in the conjugates, compositions and methods of the present invention, provided that the therapeutic or diagnostic compound can be conjugated or attached to at least one CMP according to the teachings herein. Suitable such therapeutic compounds may be biological or non-biological (e.g., so-called "small molecule") therapeutic compounds. Compounds suitable for use include, but are not limited to, steroidal anti-inflammatory drugs (e.g., prednisolone or a pharmaceutically acceptable salt thereof, such as prednisolone acetate), nonsteroidal 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.; see, e.g., U.S. Pat. No. 7,601,874, which is incorporated herein by reference in its entirety). other indene derivatives used as active pharmaceutical ingredients) and their pharmaceutically acceptable salts, esters and derivatives), local anesthetics (e.g. tetracaine, lidocaine, oxybuprocaine, proparacaine, etc.), vitamins or vitamin derivatives or vitamin precursors (e.g. retinol, retinoic acid, retinal, carotene and other retinoids and retinoid derivatives or precursors; folic acid; α-tocopherol; calciferol; phylloquinone, menaquinone and other vitamin K forms, precursors or derivatives, ascorbic acid;etc.), therapeutic enzymes or therapeutic fragments thereof (e.g., collagenases and serine proteases, or therapeutically effective fragments thereof), antibiotics (e.g., aminoglycoside antibiotics (e.g., gentamicin, tobramycin, paromomycin, kanamycin, neomycin and amikacin, and pharmaceutically acceptable salts or esters thereof, such as tobramycin sulfate), fluoroquinolone antibiotics (e.g., moxifloxacin, gatifloxacin, levofloxacin, gemifloxacin, ciprofloxacin, norfloxacin and ofloxacin, and pharmaceutically acceptable salts, esters or derivatives thereof, such as moxifloxacin hydrochloride, ciprofloxacin hydrochloride and gatifloxacin hydrochloride), sulfonamide antibiotics (e.g., sulfacetamide, sulfadiazine, sulfadiazine, sulfisoxazole (sulfadiazine), sulfadiazine, ... isopyrimidine (sulfadimethoxine), sulfadoxine, sulfamethoxazole, sulfathiazole, sulfadimethoxine, sulfamethoxazole, sulfadimethoxine, sulfamethoxazole, sulfapyrazine and terephthalamide, and pharmaceutically acceptable salts, esters or derivatives thereof), 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, ritipenum, carbapenem (e.g., ertapenem, doripenem, imipenem and meropenem, and pharmaceutically acceptable salts, esters or derivatives thereof), cephems (e.g., cefazolin, cephalexin, cephalexin cefoperazone, cefotaxime, cefotaxime, cefpiramide, cefpodoxime, ceftriaxone, ceftazidime, cefoperazone, cefdinir, cefcaprine, cefotaxime, cefotaxime, cefpiramide, cefpodoxime, ceftibuten, cefditoren, cefepime, cefuroxime, cefoloxime, cefuroxime, ceftriaxone, ceftriaxone, cefditoren, cefepime, cefuroline fosamil, cefoloxe, ceftobiprole, ceftiofur, cefquinox and cefovicidin, and pharmaceutically acceptable salts, esters or derivatives thereof), monobactams (e.g. aztreonam or pharmaceutically acceptable salts, esters or derivatives thereof) and β-lactamase inhibitors (e.g. sulbactam, tazobactam, clavulanic acid and avibactam and pharmaceutically acceptable salts, esters or derivatives thereof) or Cyclic peptide antibiotics (e.g., cyclosporine), therapeutic monoclonal antibodies or therapeutic fragments thereof (e.g., adalimumab, atumomab, atezolizumab, atelizumab, bevacizumab, canakinumab, catuximab, certolizumab, cetuximab, clivazumab, edrecolomab, efalizumab, fontolizumab, girentuximab, golimumab, infliximab, labetuzumab, MABp1 (Xilonix; TM), natalizumab, nimotuzumab, nivolumab, oregovomab, panitumumab, pembrolizumab, pemtumomab, pertuzumab, ramucirumab, ranibizumab, rituximab, lulizumab, tracalizumab, tocilizumab, trastuzumab, ustekinumab, vedolizumab, visilizumab, wartolumumab, zalutumumab and zanoflavone, and active fragments, combinations or conjugates thereof), therapeutic fusion proteins (in certain embodiments, recombinant fusion proteins, such as aflibercept (Regeneron), etanercept (Amgen), afacept (Astellas Pharma), abatacept (Bristol-Myers Squibb), rilonacept (Regeneron), romiplostim (Amgen) and belatacept (Bristol-Myers Squibb), prostaglandin analogs (e.g., latanoprost, travoprost, tafluprost, unoprostone, netasudil, tatanoprostene bunod, netasudil and bimatoprost, and pharmaceutically acceptable salts, esters and derivatives thereof), growth factors (e.g., EGF, PDGF, TGF-β, IGF-1, VEGF, FGF-β, IGF-1) or therapeutic or growth promoting (particularly skin growth promoting) fragments thereof, neuropeptides (e.g., substance P (SEQ ID NO: 389), α-adrenergic antagonists (e.g., brinzolamide, clonidine and apraclonidine, and pharmaceutically acceptable salts, esters or derivatives thereof), β-adrenergic antagonists (e.g., timolol, propranolol, atenolol, levobunolol, carteolol, betaxolol, and pharmaceutically acceptable salts, esters and derivatives thereof, such as timolol maleate), cell surface receptor antagonists (e.g., lifitegrast or etanercept), carbonic anhydrase inhibitors (e.g., dorzolamide, brinzolamide, methazolamide and acetazolamide, and pharmaceutically acceptable salts, esters and derivatives thereof, such as dorzolamide hydrochloride), and pharmaceutically acceptable salts, esters and derivatives thereof. For certain such therapeutic compounds, simultaneous administration with the CMP described herein (whether as a CMP-TC conjugate or simply mixed with one or more CMPs and one or more TCs or applied alone) can prevent, attenuate or reduce one or more adverse side effects of the therapeutic compound.For example, it is known that therapeutic administration of certain fluoroquinolone antibiotics may cause damage to collagen and collagen-containing structures (e.g., tendons) in humans or animals that have been treated with fluoroquinolone (see, e.g., "FDA Drug Safety Communication: FDA updates warnings for oral and injectable fluoroquinolone antibiotics due to disabling side effects," accessed on November 6, 2017, at https: / / www.fda.gov / Drugs / DrugSafety / ucm511530.htm). Therefore, simultaneous or co-administration of one or more CMPs described herein with one or more fluoroquinolone antibiotics to humans or animals that need treatment with fluoroquinolone drugs can allow the patient to receive the therapeutic benefits of fluoroquinolone drugs while reducing, ameliorating, or avoiding collagen damage caused by such treatments because CMPs can localize to areas of damaged collagen in the body and repair them.

[0483] Other suitable therapeutic compounds for use with the CMP-TC compounds, compositions and conjugates of the present invention include other non-biological small molecule therapeutic compounds, including but not limited to alkylating agents, anti-tumor antibiotics, antimetabolites, hormone agents, plant alkaloids, angiogenesis inhibitors, GnRH agonists, tyrosine kinase inhibitors, etc. Examples of such non-biological small molecule therapeutic compounds suitable for use according to the present invention include but are not limited to nitrosoureas, lenalidomide, imatinib, benatrexed valerate, bortezomib, abiraterone acetate, everolimus, taxol, docetaxel, paclitaxel, cabazitaxel, mitoxantrone, carboplatin, cisplatin, gemcitabine, doxorubicin, casodex, flutamide, enzalutamide, abiraterone, sipuleucel-T and ketoconazole. Other suitable non-biological small molecule therapeutic compounds that are advantageously used to form the CMP-TC conjugates of the present invention, particularly for use in generating CMP-TC conjugates 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 applications in the treatment and / or prevention of metastasis of certain cancers and solid tumors (see, e.g., 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; see also Erler, JT, et al., Nature 440:1222-1226 (2006); Erler, JT, 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 which are incorporated herein by reference in their entirety). In a related aspect of the invention, CMP-TC conjugates comprising one or more LOX or LOX-like enzyme inhibitors are useful for treating and / or preventing certain fibrotic diseases and conditions mediated by oxidoreductases such as LOX and LOX-like enzymes (e.g., LOXL1 and LOXL2) in humans and veterinary animals. Fibrotic diseases and conditions that are appropriately treated and / or prevented according to this aspect of the invention include, but are not limited to, pulmonary fibrosis, liver cirrhosis, myocardial fibrosis, surgical scars, systemic sclerosis, scleroderma, keloid formation, proliferative vitreoretinopathy, and other fibrotic diseases and conditions familiar to those of ordinary skill in the relevant art.Particularly useful inhibitors of LOX and Lox-like proteins include β-aminopropionitrile and certain derivatives and prodrugs thereof (see, e.g., U.S. Pat. Nos. 5,201,456, 5,120,764, 5,252,608, 8,461,303, 8,680,246, 9,176,139, and 9,255,086; the disclosures of all of which are incorporated herein by reference in their entireties), and antibodies (which may be polyclonal, or preferably monoclonal) and fragments or portions thereof that bind to and inhibit the activity or function of LOX and LOX-like enzymes (see, e.g., U.S. Pat. No. 8,461,303; the disclosure of which is incorporated herein by reference in its entirety).

[0484] In other embodiments, compounds or compositions comprising one or more CMPs and one or more antigens may be prepared, either as a mixture or co-formulated with one or more CMPs and one or more antigens (and optionally with one or more pharmaceutically suitable carriers or excipients), or as other compounds or compositions in which one or more antigens are directly or indirectly linked or conjugated to one or more CMPs. According to certain such aspects, the antigen may be a complete antigen or antigenic determinant or a fragment thereof (e.g., a hapten) that, when presented to the immune system of a human or veterinary animal under appropriate physiological conditions, such as by administering the compound, conjugate or composition to a human or veterinary animal in the form of a vaccine or immunization, is capable of inducing an immune response in the human or veterinary animal. Compounds, conjugates and compositions useful in such embodiments may be prepared by co-formulation or direct or indirect conjugation according to methods described elsewhere herein for co-formulation and conjugation of therapeutic compounds with CMPs. Antigens or portions thereof suitable for use in such compounds, conjugates and compositions and therefore in methods of use thereof include any molecule or particle or portion thereof capable of inducing an immune response in humans or veterinary animals, including but not limited to antigens (e.g., proteins, toxins, lipids and other antigenic portions, molecules or complexes) from or produced by bacteria (wherein the antigen may include the entire bacteria or a portion thereof, such as a cell wall or cell membrane component, a nuclear component or a toxin produced by the bacteria), viruses (wherein the antigen may include the entire viral particle or a portion thereof, such as a coat component (e.g., a protein or lipid or a portion thereof), a nuclear component or an enzyme encoded by or as a part of the viral particle), protists, fungi, plants (which may include plant irritants or allergens, such as pollen grains), animals (wherein the antigen or portion thereof may be an alloantigen or a self-antigen, or a portion thereof), and the like; examples of such antigens or portions thereof are readily familiar to those skilled in the relevant art. Such compounds, compositions or conjugates are suitable for use in methods of treating and / or preventing one or more conditions, diseases and ailments in humans and veterinary animals, such as by generating an immune response in an animal or veterinary by using the compounds, compositions or conjugates. In some such methods, a disease or condition in an animal or veterinary is treated and / or prevented by administering one or more compounds, compositions or conjugates of this aspect of the invention to a human or veterinary animal, such as in the form of a vaccine or immunization. Such vaccines or immunizations are appropriately formulated according to methods well known in the relevant art and are administered in any manner so as to cause an immune response in a human or veterinary animal to the antigen or a portion thereof, thereby treating and / or preventing a disease or condition caused directly or indirectly by the antigen or a portion thereof.Such vaccines or immunizations can be administered to humans or veterinary animals by any suitable route, such as oral, parenteral (including subcutaneous, intradermal, transdermal, intrathecal or intravenous), ocular administration (e.g., in the form of drops, gels, wafers, or by injection, as described elsewhere herein for ocular CMP-TC administration), nasal, and other routes of administration familiar to those skilled in the art. In such embodiments, the compounds, conjugates or compositions of the present invention are appropriately administered to humans or veterinary animals until the human or veterinary animal has developed an immune response sufficient to treat and / or prevent the target disease or condition, and can be re-administered as needed to enhance the immune response and / or ensure continued immunity to the target antigen or portion thereof. Diseases and conditions suitably treated by such methods of the invention include any disease or condition involving or resulting from the action of any exogenous agent on cells, organs, organ systems, body structures or bodies of humans and veterinary animals, including, but not limited to, infectious diseases, cancer, allergies and other immune overreactions (e.g., graft-versus-host disease or host-versus-graft disease), Stevens-Johnson syndrome, mucous membrane pemphigoid, toxic epidermal necrolysis, Behcet's uveitis, birdshot retinochoroidopathy, juvenile idiopathic arthritis (JIA)-associated uveitis, multifocal choroiditis with panuveitis, necrotizing scleritis, serpiginous choroidopathy, sympathetic ophthalmia, Vogt-Koyanagi-Harada (VKH) disease, non-infectious panuveitis, and the like.

[0485] Suitable diagnostic compounds that can be linked or conjugated to CMP to produce the conjugates and compositions of the present invention include, but are not limited to, labeling probes such as fluorescent dyes (e.g., quantum dots, indocyanine green, fluorescein, rhodamine, merocyanine dyes, near-infrared fluorescent dyes, etc.); radioisotopes, nuclides for PET, nuclides for SPECT, in particular each radioisotope, nuclides for PET or SPECT are each selected from 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 8. 82 Rb, 139 Ce, Te-123m,137 Cs, 86 Y. 90 Y. 185 / 187 Re, 186 / 188 Re, 125 I, their complexes and their combinations; and MRI contrast agents, CT contrast agents and magnetic materials, in particular each MRI contrast agent, CT contrast agent and magnetic material is selected from the group consisting of gadolinium, Gd-DTPA, Gd-DTPABMA, Gd-HP-DO3A, iodine, iron, iron oxide, chromium, manganese, their complexes or chelates, and their combinations. According to these aspects of the invention, the CMP and the labeling probe are suitably directly bound to each other physically or chemically, for example, directly conjugated by coordination bonds, covalent bonds, hydrogen bonds, hydrophobic interactions or physical adsorption, or indirectly by using at least one connection mode, such as the connection modes described herein and other connection modes known in the art. Methods for conjugating or linking diagnostic compounds to proteins such as CMPs are known in the art (see, for example, U.S. Published Patent Application US2012 / 0195828 A1, the disclosure of which is incorporated herein by reference in its entirety).

[0486] Use of CMP and CMP-TC conjugates

[0487] Therefore, the present invention provides methods for preparing compositions that can be used to treat, prevent, diagnose or improve diseases, disorders or medical conditions of humans or veterinary animals. In another aspect, the present invention provides methods for using the compositions of the present invention to treat, prevent, diagnose or improve diseases, disorders or medical or physical conditions of humans or veterinary animals.Particularly preferred CMPs for use in these aspects of the invention include CMPs comprising, consisting essentially of, or consisting of a CMP having the amino acid sequence: (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), 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.

[0488] The CMP and CMP-TC conjugates of the present invention include solutions, gels, films, wafers, membranes, spheres, nanoparticles and suspensions, which contain, consist essentially of or consist of the CMP and / or CMP-TC conjugates of the present invention, which are suitable for use as a medicament for treating, preventing or ameliorating various diseases or conditions of humans or veterinary animals in need of treatment or prevention or contained in a medicament for treating, preventing or ameliorating various diseases or conditions of humans or veterinary animals in need of treatment or prevention or in a composition for use as a medicament. Other compositions provided in this aspect of the 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 agents in various tests and assays, particularly in vivo or in situ tests and assays, to diagnose diseases, disorders or physical conditions of humans or veterinary animals. Such pharmaceutical compositions or diagnostic compositions may also include one or more additional therapeutic compounds or pharmaceutically active ingredients (e.g., one or more antibiotics, one or more growth factors, autologous plasma rich in growth factors (PRGF), one or more cytokines, one or more antibody fragments, 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) in addition to CMP, CMP-TC conjugates or CMPs combined with one or more diagnostic compounds or molecules. 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 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 aerosolizers or carriers, one or more desiccants, etc. Other pharmaceutically acceptable carriers or excipients suitable for the compositions of the present invention are readily familiar to those of ordinary skill in the relevant art.

[0489] Without wishing to be bound by theory, it is believed that the CMP provided by the present invention and used in the method of the present invention is particularly suitable for repairing damaged collagen, particularly damaged helical collagen, which is caused by or associated with various diseases, diseases, structural abnormalities, physical conditions and medical conditions in humans and mammals. For example, when the structure of collagen is damaged, it will usually be hydrolyzed in at least one of the three helices that form triple helical collagen, resulting in the disintegration and structural deformation of the triple helix. This destruction and digestion can also cause the collagen to break into many smaller fragments, which remain in the extracellular environment or enter the blood or lymphatic circulatory system. These fragments are ultimately either engulfed or bound by scavenger cells, or bind to cell surface receptors on human or mammalian somatic cells. These receptors, which may include, for example, integrins, discoidin domain receptors, glycoprotein VI, and leukocyte-associated immunoglobulin-like receptor-1 (LAIR-1), control cellular functions such as growth, differentiation, morphogenesis, tissue repair, adhesion, migration, homeostasis, immune function, and wound healing, and are often disrupted or their functions or signaling systems are up- or down-regulated by binding to these free collagen fragments. According to the theory, when CMPs encounter damaged collagen or fragments thereof, they dynamically anneal or bind to the broken collagen triple helix and structurally repair it, thereby (among other things) causing the cellular receptors to resume normal function and signaling activity levels. Thus, the overall result of applying CMPs in this manner to a human or veterinary animal suffering from a disease, disorder, structural abnormality, or injury involving or caused by damaged collagen is the unleashing of an accelerated wound healing process, which in certain physiological contexts includes rapid growth, migration, and adhesion of epithelial, endothelial, or neural cells on the now repaired collagen matrix, resulting in the restoration of normal or near-normal structure and function of such cells and the tissues, organs, and organ systems containing such cells.

[0490] Diseases, disorders, physical conditions and medical conditions that are suitably treated, prevented, ameliorated or diagnosed using the compositions and methods of the present invention include, but are not limited to, ocular diseases or disorders, skin diseases or disorders, cancer, gastrointestinal diseases or disorders, genitourinary 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. For such uses, suitable dosages of the compositions and conjugates of the invention are concentrations of the CMP component of the composition or conjugate of 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 certain such embodiments, the conjugate or composition is suitable for application to the treated tissue, organ or organ system at a dosage equivalent to a CMP concentration of about 25 μg / ml to about 500 μg / ml (e.g., 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 specific such embodiments, concentrations equivalent to CMP concentrations between about 25 μg / ml, 50 μg / ml, 75 μg / ml, or 100 μg / ml are used. Additional concentrations and amounts of the conjugates or compositions of the invention suitable for use 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 resorting to undue experimentation.

[0491] The ocular diseases or conditions that can be treated, prevented, improved or diagnosed using the compositions and methods of the present invention include, but are not limited to, diseases involving the cornea and / or sclera, i.e., corneoscleral diseases, conditions and disorders. Without wishing to be bound by theory, it is believed that the compositions of the present invention, in particular one or more CMPs contained in such compositions, can repair the disordered, disordered or digested collagen found in the extracellular matrix and / or matrix of the cornea and sclera, thereby repairing the collagen matrix / matrix and restoring the steady-state structure and function (including hardening or strengthening) of the cornea and / or sclera, thereby treating or improving such diseases and conditions and their signs / symptoms. In other aspects, the compositions of the present invention, in particular one or more CMPs contained in such compositions, prevent the disintegration and digestion of collagen in the extracellular matrix and / or matrix of the cornea and sclera when damaged or injured, preserve the collagen matrix / matrix in this way, and therefore preserve the steady-state structure and function of the cornea and / or sclera, thereby preventing such diseases and conditions and their signs / symptoms. Examples of corneal diseases, disorders and conditions that may be suitably treated, prevented, ameliorated or diagnosed using the compositions and methods of the present invention include, but are not limited to, myopia, presbyopia, hyperopia, keratitis, episcleritis, scleritis, corneal ulcer, sequelae of corneal ulcer, corneal ectasia, acquired corneal shape abnormalities, keratoconus, corneal astigmatism, spherical cornea, posterior corneal indentation, corneal proptosis, corneal ectasia, Descemet's membrane ectasia, pellucid marginal corneal degeneration, Trion's marginal dystrophy, Mooren's ulcer, central corneal ulcer, marginal corneal ulcer, staph marginal ulceration, Salzman's nodular dystrophy, Nodulardystrophy, age-related peripheral corneal atrophy, geographic ulcer, discoid stromal keratitis, herpetic ulcer, corneal softening, penetrating keratoplasty, incisional wound, anterior membrane dystrophy, stromal dystrophy, ocular mucosal pemphigoid, necrotizing scleritis, scleromalacia, coloboma, scleromalacia induced by scleral buckle, congenital hereditary stromal dystrophy, congenital anterior staphyloma, scleralized cornea, traumatic descemet membrane rupture, corneal keloid, scleral bulge, scleral staphyloma, deep scleritis, necrotizing scleritis, perforating scleromalacia, hyalinization of sclera, paralimbal scleromalacia, ocular graft-versus-host disease and choroideremia. In particular, the compositions and methods of the present invention are suitable for treating, ameliorating, preventing and / or diagnosing myopia, presbyopia and keratoconus. Other corneoscleral 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 of ordinary skill in the art based on information readily available in the literature.

[0492] Other ocular diseases or conditions that can be treated, prevented, ameliorated or diagnosed using the compositions and methods of the invention include anterior segment diseases and conditions, including but not limited to glaucoma, cataracts, vitreous adhesions or floaters, macular degeneration, dry eye syndrome (also known as dry eye disease), keratitis, non-infectious corneal ulcers, non-infectious corneal melts, infected corneal ulcers, infected corneal melts, conjunctivitis, Stevens-Johnson syndrome, iritis, uveitis, vitritis, Behcet's uveitis, shotgun retinitis Choroidopathy, juvenile idiopathic arthritis (JIA)-associated uveitis, multifocal choroiditis with panuveitis, necrotizing scleritis, serpiginous choroidopathy, sympathetic ophthalmia, Vogt-Koyanagi-Harada (VKH) disease, noninfectious panuveitis, ectasia, corneal laceration, corneal erosion, corneal abrasion, acute or chronic corneal pain (particularly pain caused by corneal nerve damage or injury or denervation; see, e.g., 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 periocular pain, extraocular pain and postherpetic neuralgia and postoperative ocular pain caused by ocular surgery. Such postoperative ocular pain caused by ophthalmic surgery can be, for example, pain caused after cataract surgery or glaucoma surgery, especially those that lead to or are postoperative ocular conditions that require drug treatment.

[0493] Other ocular diseases or conditions that may be treated, prevented, ameliorated or diagnosed using the compositions and methods of the invention include, but are not limited to, diseases and conditions of the posterior segment of the eye, particularly those involving the retina, including, but not limited to, macular degeneration (wet, dry and age-related), retinitis pigmentosa, retinal tears or detachments, retinopathy (e.g., diabetic retinopathy), arterial or venous occlusions (e.g., BRAO (branch retinal artery occlusion), CRAO (central retinal artery occlusion), BRVO (branch retinal vein occlusion) and CRVO (central retinal vein occlusion), optic neuritis, optic neuropathy (including, for example, AION (anterior ischemic optic neuropathy) and traumatic optic neuropathy), optic atrophy (e.g., glaucomatous optic atrophy), one or more diseases, conditions or disorders affecting the eye or the area surrounding the eye, including paraocular diseases, conditions or disorders, and extraocular diseases, conditions or disorders, such as cranial nerve palsies including, but not limited to, cranial nerve III palsies, cranial nerve IV palsies, cranial nerve V palsies (e.g., Such as trigeminal neuralgia and postherpetic neuralgia), cranial VI nerve palsy and cranial VII nerve palsy (such as Bell's palsy), and other retinal and posterior segment related disorders and diseases involving the retinal epithelium (especially retinal pigment epithelium, retinal blood vessels and / or retina, cranial nerves or optic nerves). Other eye diseases that can be advantageously treated, improved and / or prevented using the compositions and methods of the present invention include, but are not limited to, refractive eye diseases, including myopia, presbyopia and amblyopia. For example, myopia is known to be associated with axial lengthening, which may be partly related to collagen destruction in the sclera (see, for example, Guo, P. et al., Trans. Vis. Sci. Tech. 9(9): 45 (2020); Zhao, F. et al., Am. J. Pathol. 188: 1754-1767 (2018)), and can be improved by cross-linking or other operations of the scleral connective tissue to strengthen the sclera (see, for example, Backhouse, S. et al., Ann. Eye Sci. 3:5 (2018); Grytz, R. et al., Curr. Opin. Biomed. Eng. 15:40-50 (2020); Garcia, MB et al., Invest. Ophthalmol. Vis. Sci. 58:1875-1886 (2017)).

[0494] According to this aspect of the invention, a method of treating or preventing an ocular disease, disorder or wound in a human or animal suffering from or susceptible to an ocular disease, disorder or wound comprises administering to the eye of the human or animal a composition as described herein, particularly a CMP or CMP-TC conjugate and / or a composition comprising such a conjugate. Without wishing to be bound by theory, the inventors speculate that in the region of the ocular disease or disorder, the extent of damage to type I collagen is sufficiently great that the CMP will specifically target the site of the ocular disease or disorder and insert into the collagen structure, for example by inserting into one or more damaged helices of the helical collagen, thereby directly reforming a functional collagen helix or matrix, or in the case of a CMP conjugated to a therapeutic compound, delivering the therapeutic compound to the site where it must act to treat, prevent or ameliorate the ocular disease or disorder. In certain such anterior segment ocular diseases or disorders such as acute or chronic corneal pain (including but not limited to paraocular pain, extraocular pain and postherpetic neuralgia), the denervated cornea has a poor ability to heal, and therefore topical therapies that can affect nerve regeneration will become a popular therapy in this area. Pain, whether acute or chronic, is caused by damaged corneal nerves (e.g., see 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), so treatments that benefit nerve health would be of clinical value to 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 expected that any cranial nerve will behave in a similar manner. Therefore, the corneal nerves, which are branches of the trigeminal nerve, will benefit from a therapy comprising topical application of one or more CMPs or CMP-TC conjugates described herein to the cornea. As the nerves repair and regenerate, corneal recovery and pain relief will ensue, thereby improving acute or chronic corneal pain.

[0495] The conjugate or composition is appropriately applied to the eye at a dose 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 to improve the disease state or physical condition. If necessary, the conjugate or composition of the present invention is periodically applied to the eye again according to the dosing and treatment schedule and scheme described herein and other schemes familiar to those skilled in the art until the disease, disorder or wound of the eye is cured, prevented or improved. In such embodiments, the conjugate or composition of the present invention for treating anterior segment diseases and disorders can be appropriately applied to the surface of the eye through the conjunctiva or subconjunctiva, in particular by applying the conjugate or composition dropwise to the surface of the eye or the subconjunctival fornix. In other embodiments, the conjugate or composition of the present invention for treating anterior segment diseases and disorders can be appropriately applied to the anterior portion of the eye (including the sclera and vitreous) by instillation (depending on the ability of the CMP-containing preparation to migrate through the surface epithelium) or by injection, such as by intravitreal injection, according to methods well known to those of ordinary skill in the medical and pharmaceutical fields. In other embodiments involving the treatment, prevention, cure or diagnosis of diseases and disorders of the posterior segment of the eye, the conjugates and compositions of the present invention can be administered to the posterior segment of the eye, such as at or near the retina, by mechanical introduction (e.g., by injection using a needle or other suitable device), or by administering the conjugate or composition to the surface of the eye in the form of drops, wherein the conjugate or composition (or its components, such as CMP or CMP-TC conjugate) is transported or migrated to the posterior segment of the eye (e.g., at or near the retina). Administration of the conjugate or composition to the eye can be achieved by any well-known means, including applying the conjugate or composition to the eye in the form of one or more drops 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 (such as those described herein) implanted in the structure of the eye; in the form of a mesh or patch; by connecting the conjugate or composition to or encapsulating it in one or more gels, spheres or nanoparticles and then delivering it to the structure of the eye. Other suitable methods of administering the conjugate or composition to the eye to achieve the therapeutic and diagnostic methods of the present invention will be apparent to those of ordinary skill in the art.

[0496] Skin diseases or conditions that can be treated, prevented, improved or diagnosed using the compositions and methods of the present invention include, but are not limited to, skin wounds, scars, wrinkles, "wrinkled skin", skin cancers (e.g., melanoma, skin cancer, skin sarcoma, histiocytoma) and skin burns, including sunburn. Other skin diseases or conditions that are appropriately treated, prevented, improved or diagnosed according to the present invention include psoriasis and eczema, shingles, irritant contact dermatitis and allergic contact dermatitis (such as ivy, poison oak or poison sumac).

[0497] According to this aspect of the invention, a method of treating or preventing a skin disease, condition or wound in a human or veterinary animal suffering from or susceptible to a skin disease, condition or wound comprises applying the compositions described herein (particularly CMPs and CMP-TC conjugates) and compositions comprising such CMPs and CMP-TC conjugates to the skin of the human or veterinary animal at a site proximal to the site of the lesion associated with or causing the skin disease, wound or condition. Without wishing to be bound by theory, the inventors speculate that in the area of ​​the skin disease or condition, type I collagen is sufficiently damaged that the CMPs will specifically target the site of the skin disease or condition and insert into the collagen structure, thereby directly reforming a functional collagen matrix, or in the case of CMPs conjugated to a therapeutic compound, thereby delivering the CMPs and / or therapeutic compounds to the site where they must act to treat, prevent or ameliorate the skin disease or condition. Alternatively, the disease or condition afflicting the skin may be excised or removed from the skin (e.g., by surgical removal, such as skin cancer), and the skin wound caused by such excision or removal may be treated with one or more compositions of the invention according to the methods described herein. In certain embodiments, one or more CMPs per se, or one or more CMP-TC conjugates, or any combination thereof, may be introduced into the skin in the form of so-called "cosmeceuticals", particularly intraepidermally, intradermally or subcutaneously (see, e.g., Epstein, H., Clin. Dermatol. 27(5):453-460 (2009)). Particularly preferred CMP-TC conjugates or compositions for use in these aspects of the 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:390-396. Further particularly preferred CMP-TC conjugates or compositions for use in these aspects of the invention include those in which the therapeutic compound is retinol or a derivative or precursor thereof. Further preferred compositions include compositions comprising or 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 other compounds well known in dermatology and other related fields. According to this aspect of the invention, the conjugate or composition is appropriately applied to the skin or into the skin in a dose 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 to improve the disease state or physical condition. If necessary, the conjugate or composition of the invention is periodically re-applied to the skin or into the skin according to the dosing and treatment schedules and regimens described herein and other regimens familiar 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 present invention is suitable for topical, intraepidermal, intradermal or subcutaneous administration to or into the skin. Administration of the conjugate or composition to or into the skin can be achieved by any well-known means, including in the form of solutions, ointments, salves, patches, creams, topical solutions and drug eluting wafers. For example, the conjugate or composition can be applied to or introduced into the skin in the following forms: in the form of one or more drops 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; by connecting the conjugate or composition to or encapsulating it in one or more nanoparticles and then delivering it to the skin. Other suitable methods for applying the conjugate or composition to or into the skin to achieve the treatment and diagnostic methods of the present invention will be apparent to those of ordinary skill in the art.

[0498] Cancers that can be treated, prevented, improved or diagnosed using the compositions and methods of the present invention include, but are not limited to, skin cancer (e.g., skin cancer described elsewhere herein), intracavitary cancers, and brain cancers. Intracavitary cancers that are appropriately treated, prevented, diagnosed or improved using the conjugates, compositions and methods of the present invention include, but are not limited to, colorectal cancer, intestinal cancer, duodenal cancer, gastric cancer, pancreatic cancer, esophageal cancer, bladder cancer (e.g., non-muscle-invasive bladder cancer or bladder carcinoma in situ), upper urinary tract cancer (or renal pelvis and also known to those of ordinary skill in the art) (e.g., upper tract urothelial cancer, Wilms tumor and renal cancer), vaginal cancer, cervical cancer, uterine cancer, ovarian cancer, luminal breast cancer and lung cancer. Brain cancers that are suitable for treatment, prevention, diagnosis or improvement using the conjugates, compositions and methods of the present invention include, but are not limited to, gliomas, glioblastomas, meningiomas, pituitary tumors, craniopharyngiomas and hemangioblastomas. Other non-luminal cancers can also be appropriately treated, prevented, diagnosed or ameliorated using the conjugates, compositions and methods of the invention, including but not limited to prostate cancer, testicular cancer, non-luminal breast cancer, bone cancer, head and neck cancer, thyroid cancer, liver cancer, sarcomas (e.g., Kaposi's sarcoma, Ewing's sarcoma, osteosarcoma, soft tissue sarcoma and rhabdomyosarcoma), etc.

[0499] According to this aspect of the invention, a method of treating or preventing cancer in a human or animal suffering from or susceptible to cancer comprises administering the compositions described herein (particularly CMPs and CMPs and / or conjugates) to a site near the cancer or tumor site in an organ lumen of a human or animal, or in the skull, or in or on the brain. Without wishing to be bound by theory, the inventors speculate that in the cancer region, type I collagen is sufficiently destroyed, or in the case of brain cancer type I collagen is upregulated, so that the CMPs will specifically target the cancer site and insert into the collagen structure, thereby directly re-forming a functional collagen matrix, or in the case of CMPs conjugated to therapeutic compounds, thereby delivering the CMPs and / or therapeutic compounds to the site where they must act to treat, prevent or ameliorate cancer. Particularly preferred conjugates or compositions for use in this aspect of the invention include 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. Additional preferred compositions include compositions that also include 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 and other compounds well known in dermatology and other related fields. According to this aspect of the invention, the conjugate or composition is appropriately administered to the organ cavity or skull or brain or in a dose sufficient to treat, prevent or improve cancer, and then the progress, remission or stagnation of cancer in humans or animals is monitored over time to improve the cancer disease state (e.g., tumor shrinkage or at least cancer does not progress or remission). If necessary, the conjugate or composition of the present invention is periodically administered again to the organ cavity, skull or brain or brain according to the dosing and treatment schedule and scheme described herein and other schemes familiar to those skilled in the art until the cancer is cured, prevented or improved, or enters a permanent remission period. In such embodiments, the conjugate or composition of the present invention is administered to the organ cavity or brain or in a parenteral manner or by directly applying to the tumor site appropriately, or in the case of excision or removal of the tumor, by directly applying to the tumor bed or the wound left after excision or removal of the tumor. Parenteral administration of the conjugate or composition of the invention can be achieved by a route selected from the group consisting of subcutaneous injection, intravenous infusion, intra-arterial infusion, transdermal diffusion, implantation of a drug eluting wafer or film, sublingually, orally, by aerosol inhalation, intravaginally, rectally or intracranially. In certain such embodiments, the conjugate or composition can be parenterally administered to a human or veterinary animal in the form of a mesh, film, wafer, sphere, nanoparticle, gel or patch implanted in a human or veterinary animal at or near the site of cancer.In other such embodiments, particularly in embodiments where the cancer is intracavitary, the conjugate or composition of the invention can be administered to the lumen of a cancerous organ of a human or veterinary animal using a medical device suitable for this purpose, such as an endoscope, a bronchoscope (e.g., via bronchial lavage for the treatment, prevention or diagnosis of lung cancers, such as bronchial cancer or lung cancer), a rectoscope, a colonoscope, a cystoscope (e.g., via cystoscopic lavage into the bladder or upper urinary tract), a gastroscope and a laparoscope, or other suitable surgical / medical devices capable of delivering a dose of a drug (e.g., a conjugate and composition of the invention) to the cancer site of a human or veterinary animal. In certain such embodiments, the conjugate or composition can be administered after surgical resection or removal of a solid tumor or removal or aspiration of tumor ascites (e.g., removal of abdominal ascites using a trocar inserted into the abdomen). In such embodiments, the conjugate or composition of the invention (along with optional one or more additional therapeutic agents) can be introduced directly into the surgical resection site or ascites area, for example, by any of the above instruments or devices.

[0500] In other embodiments, the conjugate or composition is applied to the organ cavity or brain or can be achieved by any well-known means, including in the form of a solution, ointment, salves, patches, creams, topical solutions and drug eluting wafers. For example, the conjugate or composition can be applied to or introduced into the organ cavity or brain or brain in the following forms: in the form of one or more drops 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 organ cavity or brain; in the form of a mesh or patch; by connecting the conjugate or composition to or encapsulating it in one or more nanoparticles and then delivering it to the organ cavity or brain. For those of ordinary skill in the art, other suitable methods for applying the conjugate or composition to the organ cavity or brain or to achieve the treatment and diagnostic methods of the present invention will be apparent.

[0501] Gastrointestinal diseases or disorders that may be treated, prevented, ameliorated or diagnosed using the compositions and methods of the present invention include, but are not limited to, irritable bowel syndrome, Crohn's disease, ulcers, ulcerative colitis, esophagitis, Barrett's esophagitis, gastritis, and proctitis.

[0502] According to this aspect of the invention, a method of treating or preventing a gastrointestinal disease or condition in a human or veterinary animal suffering from or susceptible to a gastrointestinal disease or condition comprises administering a composition as described herein (particularly CMP and CMP-TC conjugates and compositions comprising such CMP and / or conjugates) to the gastrointestinal tract of the human or veterinary animal at a site proximal to the site of a lesion associated with or causing the gastrointestinal disease or condition. Without wishing to be bound by theory, the inventors speculate that in areas of certain gastrointestinal diseases and conditions, type I collagen is sufficiently disrupted that the CMP will specifically target the site of the gastrointestinal disease or condition and insert into the collagen structure, thereby directly reforming a functional collagen matrix, or in the case of a CMP conjugated to a therapeutic compound, thereby delivering the CMP and / or therapeutic compound to the site where it must act to treat, prevent or ameliorate the gastrointestinal disease or condition. Particularly preferred conjugates or compositions for use in this aspect of the invention include 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 invention, the conjugate or composition is appropriately administered to the gastrointestinal tract or the gastrointestinal tract in a dose sufficient to treat, prevent or improve a gastrointestinal disease or condition, and then the progress, relief or stagnation of the gastrointestinal disease or condition of the human or veterinary animal is monitored over time to improve the disease or condition state. If necessary, the conjugate or composition of the present invention is periodically re-administered to the gastrointestinal tract according to the dosing and treatment schedule and scheme described herein and other schemes familiar to those skilled in the art until the gastrointestinal disease or condition is cured, prevented or improved. In such embodiments, the conjugate or composition of the present invention is appropriately administered to the gastrointestinal tract or the gastrointestinal tract in a parenteral or topical manner. Parenteral administration is achieved by any administration route known in the art for gastrointestinal treatment, for example, by a route selected from the group consisting of: subcutaneous injection, intravenous infusion, intra-arterial infusion, transdermal diffusion, drug eluting wafer implantation, sublingual, oral or rectal. In such methods, the composition is appropriately administered to a human or veterinary animal parenterally 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 at or near the site of the disease or condition in the gastrointestinal tract. In other such embodiments, particularly in embodiments where the disease or condition is located in the lumen of the gastrointestinal tract, the conjugate or composition of the invention may be administered to the lumen of the gastrointestinal organs of a human or veterinary animal using a medical device suitable for this purpose, such as a proctoscope, a colonoscope, a cystoscope (e.g., through a cystoscope into the bladder or upper urinary tract), a gastroscope and a laparoscope, or other suitable surgical / medical devices capable of delivering a dose of a drug (e.g., a conjugate and composition of the invention) to the site of a gastrointestinal disease or condition in a human or veterinary animal.

[0503] In other embodiments, administration of the conjugate or composition to or within the gastrointestinal tract can be achieved by any well-known means, including in the form of solutions, ointments, salves, patches, creams, topical solutions, and drug eluting wafers. For example, the conjugate or composition can be applied to or introduced into the gastrointestinal tract in the following forms: in the form of one or more drops of a solution or suspension containing the composition or conjugate; by injection; in the form of a solid material coating implanted in the gastrointestinal tract; in the form of a mesh or patch; by connecting or encapsulating the conjugate or composition in one or more nanoparticles and then delivering it to the gastrointestinal tract. For those of ordinary skill in the art, other suitable methods for administering the conjugate or composition to or within the gastrointestinal tract to achieve the therapeutic and diagnostic methods of the present invention will be apparent.

[0504] Genitourinary 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, female urinary incontinence, cystitis, interstitial cystitis, irritable bladder syndrome, ureteritis and vaginitis.

[0505] According to this aspect of the invention, a method of treating or preventing a urogenital tract disease or condition in a human or veterinary animal suffering from or susceptible to a gastrointestinal disease or condition comprises administering the compositions described herein (particularly CMPs and CMP-TC conjugates and compositions comprising such CMPs and / or conjugates) to the urogenital tract of the human or veterinary animal at a site proximal to the site of a lesion associated with the gastrointestinal disease or condition or causing the urogenital tract or condition. Without wishing to be bound by theory, the inventors speculate that in the area of ​​certain urogenital diseases or conditions, type I collagen is sufficiently disrupted that the CMPs will specifically target the site of the urogenital disease or condition and insert into the collagen structure, thereby directly reforming a functional collagen matrix, or in the case of a CMP conjugated to a therapeutic compound, thereby delivering the CMP and / or therapeutic compound to the site where it must act to treat, prevent or ameliorate the urogenital disease or condition. According to this aspect of the invention, the conjugate or composition is appropriately applied to the urogenital system or the urogenital system at a dose sufficient to treat, prevent or improve the urogenital disease or condition, and then the progress, remission or stagnation of the urogenital disease or condition of the human or veterinary animal is monitored over time to improve the disease or condition state. If necessary, the conjugate or composition of the present invention is then periodically re-applied to the urogenital tract according to the dosing and treatment schedule and regimen described herein and other regimens familiar to ordinary technicians until the urogenital disease or condition is cured, prevented or improved. In such embodiments, the conjugate or composition of the present invention is appropriately administered to the urogenital tract or the urogenital tract parenterally or topically. Parenteral administration is achieved by any gastrointestinal administration route known in the art, for example, by a route selected from the group consisting of: subcutaneous injection, intravenous infusion, intra-arterial infusion, transdermal diffusion, drug eluting wafer implantation, sublingual, oral, vaginal or rectal. In such methods, the composition is suitably administered parenterally 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 at or near the site of the urogenital tract disease or disorder. In other such embodiments, particularly those in which the disease or disorder is within the lumen of the gastrointestinal tract, the conjugate or composition of the invention may be administered to the lumen of a urogenital organ of a human or veterinary animal using a medical device suitable for this purpose, such as an endoscope, colposcope and laparoscope, or other surgical / medical device capable of delivering a dose of a drug, such as the conjugate and composition of the invention, to the human or veterinary animal at the site of the urogenital disease or disorder.

[0506] In other embodiments, administration of the conjugate or composition to or within the urogenital tract can be achieved by any well-known means, including solutions, ointments, salves, patches, wafers, films, gels, spheres, nanoparticles, creams, topical solutions, and drug eluting wafers. For example, the conjugate or composition can be applied to or introduced into the urogenital tract in the following forms: in the form of one or more drops of a solution or suspension containing the composition or conjugate; by injection; in the form of a coating of a solid material implanted in the urogenital tract; in the form of a mesh or patch; by connecting or encapsulating the conjugate or composition in one or more nanoparticles and then delivering it to the urogenital tract. Other suitable methods of administering the conjugate or composition to or within the urogenital tract to achieve the therapeutic and diagnostic methods of the present invention will be apparent to the skilled person.

[0507] Fibrotic diseases or conditions that can be treated, prevented, improved or diagnosed using the compositions and methods of the present invention include, but are not limited to, pulmonary fibrosis, liver cirrhosis, myocardial fibrosis, surgical scars, systemic sclerosis, scleroderma, keloid formation, proliferative vitreoretinopathy, and the like.

[0508] According to this aspect of the invention, a method of treating or preventing a fibrotic disease or condition in a human or veterinary animal suffering from or susceptible to a fibrotic disease or condition comprises administering the compositions described herein (particularly CMPs and CMP-TC conjugates and compositions comprising such CMPs and / or conjugates) to one or more tissues, organs or organ systems of the human or veterinary animal in or near a site proximal to the site of a fibrotic lesion associated with or causing the fibrotic disease or condition. Without wishing to be bound by theory, the inventors speculate that in areas of certain fibrotic diseases or conditions, type I collagen is sufficiently disrupted that the CMPs will specifically target the site of the fibrotic disease or condition and insert into the collagen structure, thereby directly reforming a functional collagen matrix, or in the case of a CMP conjugated to a therapeutic compound, thereby delivering the therapeutic compound to the site where it must act to treat, prevent or ameliorate the fibrotic disease or condition. According to this aspect of the invention, the conjugate or composition is appropriately administered to, near or within a tissue, organ or organ system at a dose sufficient to treat, prevent or improve a fibrotic disease or condition, and then the progression, alleviation or stagnation of the fibrotic disease or condition of a human or veterinary animal is monitored over time to improve the disease or condition state. If necessary, the conjugate or composition of the invention is periodically re-administered to, near or above one or more tissues, organs or organ systems according to the dosing and treatment schedules and regimens described herein and the regimens familiar to those of ordinary skill in the art until the fibrotic disease or condition is cured, prevented or improved. In such embodiments, the conjugate or composition of the invention is appropriately administered to, near, above or within a tissue, organ or organ system in a parenteral or local manner. Parenteral administration is achieved by any administration route known in the art for the treatment of tissues, organs or organ systems, such as by a route selected from the group consisting of: subcutaneous injection, intravenous infusion, intra-arterial infusion, endoscopic application, transdermal diffusion, implantation of drug eluting wafers, films, gels or putties, sublingual, oral or rectal. In such methods, the composition is suitably administered parenterally 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, putty or patch implanted near, on or within fibrotic tissue, an organ or organ system at or near the site of the disease or disorder.

[0509] In other embodiments, the conjugate or composition is applied to, near or within a tissue, organ or organ system by any well-known means, including in the form of a solution, ointment, salve, patch, film, gel, sphere, nanoparticle, putty, cream, topical solution, and drug eluting wafer. For example, the conjugate or composition can be applied to or near a tissue, organ or organ system or introduced into a tissue, organ or organ system in the following forms: in the form of one or more drops of a solution or suspension containing the composition or conjugate; by injection; in the form of a coating on a solid material implanted in, near or on a tissue, organ or organ system; in the form of a mesh or patch; by attaching or encapsulating the conjugate or composition in one or more nanoparticles, and then delivering the nanoparticles to, near or on a tissue, organ or organ system. Other suitable methods for applying the conjugate or composition to, on, near or within a tissue, organ or organ system to achieve the treatment and diagnostic methods of the present invention are obvious to ordinary technicians.

[0510] Cardiovascular diseases or conditions that can be treated, prevented, improved or diagnosed using the compositions and methods of the present invention include, but are not limited to, myocardial infarction, heart failure, heart valve disease, atherosclerosis, cardiomyopathy, arrhythmia, congenital heart disease, coronary artery disease, pericardial disease, vascular occlusive disease (e.g., affecting the carotid artery, aorta, renal artery, femoral artery, pulmonary artery and other large and small blood vessels, which can be arteries, arterioles, veins, venules, etc.), Marfan syndrome, etc.

[0511] According to this aspect of the invention, a method of treating or preventing a cardiovascular disease or condition in a human or animal suffering from or susceptible to a cardiovascular disease or condition comprises administering a composition as described herein (particularly a CMP and / or CMP-TC conjugate and a composition comprising such a CMP and / or conjugate) to the vascular system of a human or animal suffering from or susceptible to such a disease or condition. Without wishing to be bound by theory, the inventors speculate that in certain areas of cardiovascular disease or condition, type I collagen is sufficiently damaged that a CMP introduced into the subject's vascular system will specifically target the site of the cardiovascular disease or condition and embed into the collagen structure, thereby directly reforming a functional collagen matrix, or in the case of a CMP conjugated to a therapeutic compound, thereby delivering the CMP and / or therapeutic compound to the site where it must act to treat, prevent or ameliorate the cardiovascular disease or condition. According to this aspect of the invention, the conjugate or composition is appropriately administered to or within the vascular system at a dose sufficient to treat, prevent or ameliorate the cardiovascular disease or condition, and then the progression, remission or stagnation of the cardiovascular disease or condition in the human or animal is monitored over time to improve the disease or condition state. If necessary, the conjugate or composition of the present invention is periodically re-administered into the vascular system according to the dosing and treatment schedules and regimens described herein and other regimens familiar to those skilled in the art until the cardiovascular disease, disorder or wound is cured, prevented or improved. In such embodiments, the conjugate or composition of the present invention is suitable for parenteral or topical administration to or within the heart, pericardium, blood vessels or other related components of the vascular system. Parenteral administration is achieved by any administration route known in the art for the treatment of the vascular system, such as by a route selected from the group consisting of: subcutaneous injection, intravenous infusion, intra-arterial infusion, transdermal diffusion, catheter insertion, embolization, implantation of drug eluting wafers or films, sublingual, oral, rectal. In such methods, the composition is suitable for parenteral administration to humans or animals in the form of pills, capsules, solutions, suspensions or powders for ingestion by humans or animals, or in the form of meshes, wafers, films, gels, putties, spheres, nanoparticles or patches implanted in the heart, pericardium, blood vessels or other related components of the vascular system at or near the site of cardiovascular disease or disorder.

[0512] In other embodiments, the application of the conjugate or composition to the vascular system or into the vascular system can be achieved by any well-known means, including solutions, ointments, salves, patches, films, gels, spheres, nanoparticles, creams, topical solutions, and drug eluting wafers. For example, the conjugate or composition can be applied to or introduced into the heart, pericardium, blood vessels, or other relevant components of the vascular system in the following forms: in the form of one or more drops of a solution or suspension containing the composition or conjugate; by injection; implanted into the heart, pericardium, blood vessels, or other relevant components of the vascular system in the form of a coating on a solid material; in the form of a mesh or patch; by connecting the conjugate or composition to or encapsulating it in one or more nanoparticles, and then delivering the nanoparticles to the heart, pericardium, blood vessels, or other relevant components of the vascular system. For those of ordinary skill in the art, other suitable methods for applying the conjugate or composition to the vascular system or into the vascular system to achieve the treatment and diagnostic methods of the present invention will be obvious.

[0513] Bone diseases or conditions that can be treated, prevented, improved 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, rickets, osteomalacia, acromegaly, and the like.

[0514] According to this aspect of the invention, a method of treating or preventing a bone disease or condition in a human or animal suffering from or susceptible to a bone disease or condition comprises administering a composition as described herein (particularly CMP and CMP-TC conjugates and compositions comprising such CMP and / or conjugates) to one or more bones of the human or animal at a site proximal to the site of a lesion associated with or causing the bone disease or condition. Without wishing to be bound by theory, the inventors speculate that in certain areas of bone disease or condition, type I collagen is sufficiently damaged that the CMP will specifically target the site of the bone disease or condition and insert into the collagen structure, thereby directly reforming a functional collagen matrix, or in the case of a CMP conjugated to a therapeutic compound, thereby delivering the therapeutic compound to the site where it must act to treat, prevent or ameliorate the bone disease or condition. According to this aspect of the invention, the conjugate or composition is appropriately administered to, near or within the bone at a dose sufficient to treat, prevent or ameliorate the bone disease or condition, and then the progression, remission or stagnation of the bone disease or condition of the human or animal is monitored over time to improve the disease or condition state. If necessary, the conjugate or composition of the invention is periodically re-administered into, near or on one or more bones according to the dosing and treatment schedules and regimens described herein and other regimens familiar to those of ordinary skill in the art until the bone disease or condition is cured, prevented or improved. In such embodiments, the conjugate or composition of the invention is suitable for parenteral or topical administration to, near, on or within a bone. Parenteral administration is achieved by any route of administration known in the art for bone treatment, such as by a route selected from the group consisting of: subcutaneous injection, intravenous infusion, intra-arterial infusion, endoscopic application, transdermal diffusion, implantation of drug eluting wafers, films, gels or putties, sublingual, oral or rectal. In such methods, the composition is appropriately administered to a human or veterinary animal parenterally in the form of a pill, capsule, solution, suspension or powder for ingestion by a human or veterinary animal, or in the form of a mesh, film, wafer, gel, sphere, nanoparticle, putty or patch implanted near, on or within a bone at or near the site of the disease or condition.

[0515] In other embodiments, the conjugate or composition is applied to the bone, near or within the bone by any well-known means, including in the form of a solution, ointment, salves, patches, films, gels, spheres, nanoparticles, putties, creams, topical solutions, and drug eluting wafers. For example, the conjugate or composition can be applied to or near the bone or introduced into the bone in the following forms: in the form of one or more drops of a solution or suspension containing the composition or conjugate; by injection; in the form of a coating on a solid material implanted in, near or above the bone; in the form of a mesh or patch; by attaching or encapsulating the conjugate or composition in one or more nanoparticles, and then delivering the nanoparticles to, near or above the bone. It is obvious to ordinary technicians that other suitable methods for applying the conjugate or composition to, on, near or within the bone to achieve the treatment and diagnostic methods of the present invention.

[0516] Rheumatic diseases or conditions 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), bursitis, rubs, spondylosis, scleroderma, polymyalgia rheumatica and arthritic syndromes.

[0517] According to this aspect of the invention, a method of treating or preventing a rheumatic disease or condition in a human or veterinary animal suffering from or susceptible to a rheumatic disease or condition comprises administering the compositions described herein (particularly CMPs and CMP-TC conjugates and compositions comprising such CMPs and / or conjugates) to the human or veterinary animal at a site proximal to the site of a lesion associated with or causing the rheumatic disease or condition. Without wishing to be bound by theory, the inventors speculate that in certain areas of rheumatic disease or condition, type I collagen is sufficiently disrupted that the CMPs will specifically target the site of the rheumatic disease or condition and insert into the collagen structure, thereby directly reforming a functional collagen matrix, or in the case of a CMP conjugated to a therapeutic compound, thereby delivering the therapeutic compound to the site where it must act to treat, prevent or ameliorate the rheumatic disease or condition. According to this aspect of the invention, the conjugate or composition is appropriately applied to a human or animal or human or animal in a dose sufficient to treat, prevent or improve rheumatic diseases or conditions, and then the progress, relief or stagnation of the rheumatic diseases or conditions of the human or animal is monitored over time to improve the disease or condition state. If necessary, the conjugate or composition of the present invention is periodically re-applied to the human or animal according to the dosing and treatment schedule and scheme described herein and other schemes familiar to those skilled in the art until the rheumatic disease or condition is cured, prevented or improved. In such embodiments, the conjugate or composition of the present invention is appropriately administered to a human or animal or human or animal parenterally or topically. Parenteral administration is achieved by any therapeutic administration route known in the art designed to treat, prevent or improve rheumatic diseases or conditions, such as by a route selected from the group consisting of: subcutaneous injection, intravenous infusion, intra-arterial infusion, transdermal diffusion, drug eluting wafer implantation, sublingual, oral, vaginal or rectal. In such methods, the composition is suitably administered to a human or veterinary animal parenterally 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 at or near the site of the disease or condition in the human or veterinary animal. In other such embodiments, particularly those in which the rheumatic disease or condition is located in or near the bone, tendon, cartilage, ligament, capsule, joint or related structure, the composition or conjugate of the invention is suitably administered to the human or animal using a medical device suitable for this purpose, such as a laparoscope, or other suitable surgical / medical device capable of delivering a dose of a drug, such as the conjugate and composition of the invention, to the site of the disease or condition of the urogenital system of the human or animal.

[0518] In other embodiments, the administration of the conjugate or composition to or into a human or animal can be achieved by any well-known means, including in the form of a solution, ointment, salves, patches, creams, topical solutions, and drug eluting wafers. For example, the conjugate or composition can be applied to or introduced into a human or animal in the following forms: in the form of one or more drops of a solution or suspension containing the composition or conjugate; by injection; in the form of a coating on a solid material implanted in a human or animal; in the form of a mesh or patch; by connecting the conjugate or composition to one or more nanoparticles or encapsulating it in one or more nanoparticles and then delivering it to the human or animal body. It is obvious to those of ordinary skill in the art that other suitable methods of administering the conjugate or composition to or into a human or animal to achieve the treatment and diagnostic methods of the present invention are administered to humans or animals.

[0519] Nervous or nervous system (including central nervous system ("CNS") and peripheral nervous system ("PNS") diseases or conditions that can be treated, prevented, ameliorated or diagnosed using the compositions and methods of the present invention include, but are not limited to, damage to one or more nerves or neurites (including axons, dendrites and neurons or neuronal bodies, ganglia, nerve bundles, etc.), neurodegeneration (in many different physiological or disease contexts, such as multiple sclerosis, amyotrophic lateral sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, traumatic encephalopathy, non-Alzheimer's dementia, encephalitis, meningitis, etc.), conditions involving peripheral nerves (such as diabetic peripheral neuropathy, nutritional neuropathy and alcohol-induced neuropathy), The invention relates to diseases and conditions involving or affecting the corneal nerves, retinal nerves and optic nerves, including, but not limited to, glaucoma, macular degeneration (wet and / or dry, which may or may not be age-related), neurotrophic keratitis, retinopathy (which may include diabetic retinopathy, ischemic retinopathy, proliferative retinopathy, geographic atrophy and other inherited retinal diseases or conditions known in the art), injury or inflammation of one or more corneal nerves (which may be caused by external disease or trauma / injury to the eye, including severance, crushing or twisting of nerves or neurites), corneal pain (which may be acute or Chronic, which can be caused by damage or injury to the corneal nerves or corneal denervation, such as paraocular pain, extraocular pain, and postherpetic neuralgia), encephalopathy (e.g., traumatic encephalopathy, such as concussion, encephalitis, meningitis), etc. In certain such embodiments, the compositions and methods of the present invention can be used to induce nerve repair or regeneration (e.g., through nerve regeneration), particularly in cranial nerves, including but not limited to optic nerves, retinal nerves, auditory nerves, or spinal nerves. In other such embodiments, the compositions and methods of the present invention can be used to protect certain nerves from degeneration or from further or continued degeneration (i.e., provide neuroprotective function), which can, for example, be used to prevent, reduce, or slow the progression of peripheral nerve degeneration to prevent And / or treat diabetic peripheral neuropathy, nutritional neuropathy and alcohol-induced peripheral neuropathy, and the degeneration of corneal nerves, optic nerves and / or retinal nerves to prevent and / or treat corneal pain (e.g., acute corneal pain or chronic corneal pain, including but not limited to paraocular pain, extraocular pain and postherpetic neuralgia), glaucoma, inherited retinal diseases or conditions, and genetically based retinopathy (e.g., diabetic retinopathy). Based on the guidance provided herein and in view of the information readily available in the relevant field, the ordinary technician will be familiar with other beneficial uses of the compositions and methods of the present invention in the treatment, prevention, improvement or diagnosis of neurological and nervous system diseases or conditions.

[0520] According to this aspect of the invention, a method of treating or preventing a neurological or nervous system disease or condition in a human or veterinary animal suffering from or susceptible to a neurological or nervous system disease or condition comprises administering a composition as described herein (particularly CMPs and CMP-TC conjugates and compositions comprising such CMPs and / or conjugates) to or near one or more tissues, organs or organ systems of a human or veterinary animal at a site proximal to the site of a neurological or nervous system lesion associated with or causing a neurological or nervous system disease or condition. Without wishing to be bound by theory, the inventors speculate that in the area of ​​certain neurological or nervous system diseases and conditions, collagen I (and possibly other components of the local extracellular matrix) is sufficiently disrupted that the CMPs will specifically target the site of the neurological or nervous system disease or condition and insert into the collagen structure, thereby inducing nerve regeneration and / or neuroprotection directly through the re-formation of a functional collagen matrix, or in the case of a CMP carrying a therapeutic compound, delivering the therapeutic compound to the site where it must act to treat, prevent or ameliorate the neurological or nervous system disease or condition. According to this aspect of the invention, the conjugate or composition is appropriately applied to a tissue, organ or organ system, near or within a dose sufficient to treat, prevent or improve a nervous or nervous system disease or condition, and then the progress, relief or stagnation of the nervous or nervous system disease or condition of a human or mammal is monitored over time to improve the disease or condition state. A person of ordinary skill in the art can easily determine the other concentrations and amounts of the conjugate or composition of the present invention suitable for such methods based on the information contained herein and available in the art without resorting to excessive experiments. If necessary, the conjugate or composition of the present invention is periodically applied again to one or more tissues, organs or organ systems, near or above, according to the dosing and treatment schedules and schemes described herein and the schemes familiar to a person of ordinary skill in the art, until a nervous or nervous system disease or condition is cured, prevented or improved. In such embodiments, the conjugate or composition of the present invention is appropriately applied to a tissue, organ or organ system, near, above or within in a parenteral or local manner. Parenteral administration is achieved by any route of administration known in the art for treatment of tissues, organs or organ systems, such as by a route selected from the group consisting of: subcutaneous injection, intradermal injection, intramuscular injection, intracranial injection, intraspinal injection, or injection into any tissue, organ or organ system in which a neurological or nervous system disease or disorder occurs; intravenous infusion; intraarterial infusion; endoscopic application; transdermal diffusion; implantation of a drug eluting wafer, film, gel or putty; sublingual; oral; or rectal.In some such methods, the composition is administered parenterally to a human or veterinary animal in the form of an injectable solution or paste, pill, capsule, solution, suspension or powder for inhalation or ingestion by a human or veterinary animal, or in the form of a mesh, film, wafer, gel, sphere, nanoparticle, paste, putty or patch implanted near, on or within a tissue, organ or organ system at or near a site of a neural or nervous system disease or disorder. In some such embodiments, one or more compounds, compositions or conjugates of the invention may be coated on or within a mesh or "sleeve" material such that the mesh or sleeve material is impregnated with one or more compounds, compositions or compositions of the invention, and then the mesh or sleeve is applied to an injured (e.g., transected) or damaged nerve, neurite or nerve bundle.

[0521] In other embodiments, the conjugate or composition is applied to, near or within a tissue, organ or organ system by any well-known means, including in the form of a solution, ointment, salve, patch, film, gel, paste, sphere, nanoparticle, putty, cream, topical solution and drug eluting wafer. For example, the conjugate or composition can be applied to or near a tissue, organ or organ system or introduced into a tissue, organ or organ system in the following form: in the form of one or more drops of a solution or suspension containing the composition or conjugate (e.g., for the back of the eye, in the form of topical eye drops); by injection; in the form of a coating on a solid material implanted in, near or on a tissue, organ or organ system; in the form of a mesh or patch; by attaching or encapsulating the conjugate or composition in one or more nanoparticles, and then delivering the nanoparticles to, near or on a tissue, organ or organ system. It is obvious to ordinary technicians that other suitable methods for applying the conjugate or composition to, on, near or within a tissue, organ or organ system to achieve the treatment and diagnostic methods of the present invention.

[0522] In a related embodiment, the present invention provides a device, particularly a medical device, suitable for treating or preventing a disease, disorder or medical condition of a human or animal suffering from or susceptible to a disease, disorder or medical condition. Such a device will suitably comprise at least one composition of the present invention, in the form of a coating on the device or a composition embedded in the device, so that once implanted in a human or animal, it will be released or eluted from the device. Suitable such devices include, but are not limited to, artificial joints, stents, catheters, sutures, bone screws, bone plates, prostheses (e.g., artificial prostheses, body structures, organs, etc.), absorbable or non-absorbable meshes, absorbable or non-absorbable patches, drug release wafers, brain nerve stimulators (e.g., deep brain nerve stimulators), gastric stimulators, cochlear implants, cardiac defibrillators, cardiac pacemakers, insulin pumps, internal infusion pumps, etc. Other suitable devices useful according to this aspect of the present invention are obvious to those of ordinary skill in the art.

[0523] The devices provided in this aspect of the invention can be used to treat, prevent, ameliorate or diagnose a disease, disorder or medical condition in a human or veterinary animal suffering from or susceptible to such a disease, disorder or medical condition. According to the method of this aspect, one or more medical devices of the invention are implanted in the human or veterinary animal and the medical condition of the human or veterinary animal is monitored until the disease, disorder or medical condition of the human or veterinary animal is cured, ameliorated or prevented. Suitable diseases, disorders and medical conditions that can be cured, treated, ameliorated or prevented using the devices and methods of the invention include cancer (e.g., cancers described elsewhere herein), and diseases or disorders affecting human or veterinary organ systems, including the integumentary system (particularly skin diseases or disorders, such as those described in detail herein), the muscular system, the skeletal system (particularly bone, joint, cartilage, tendon or ligament diseases or disorders, such as those described in detail herein), the nervous system (particularly the nervous system of the brain or eye (e.g., anterior segment ocular diseases and disorders, including but not limited to diseases and disorders involving the corneal nerves (e.g., corneal pain pain (which may be acute or chronic), including but not limited to conditions caused by corneal nerve damage or injury or denervation, such as periocular pain, extraocular pain, and postherpetic neuralgia), glaucoma, cataracts, vitreous adhesions or floaters, macular degeneration, dry eye disease, keratitis, non-infectious corneal ulcers, non-infectious corneal melts, infected corneal ulcers, infected corneal melts, conjunctivitis, Stevens-Johnson syndrome, scleritis, episcleritis, iritis, uveitis, vitritis, Behcet's uveitis, shotgun retinochoroidopathy, juvenile idiopathic arthritis (JIA)-associated uveitis, panarthritis, uveitis, multifocal choroiditis, necrotizing scleritis, serpiginous choroidopathy, sympathetic ophthalmia, Vogt-Koyanagi-Harada (VKH) disease, non-infectious panuveitis, corneal ectasia, keratoconus, corneal lacerations, corneal erosions, corneal abrasions, and postoperative ocular diseases following ophthalmic surgery as a postoperative state of cataract surgery requiring medication or a postoperative state of glaucoma surgery requiring medication, or posterior segment diseases, such as diseases involving the retina, retinal epithelium (particularly retinal pigment epithelium), retinal vasculature, retinal nerves, or optic nerve, including but not limited to macular degeneration (wet, dry, and age-related), retinitis pigmentosa , retinal tears and detachments, retinopathy (e.g., diabetic retinopathy), retinal artery or vein occlusions (e.g., BRAO (branch retinal artery occlusion), CRAO (central retinal artery occlusion), BRVO (branch retinal vein occlusion), and CRVO (central retinal vein occlusion), optic neuritis, optic neuropathies (including, for example, AION (anterior ischemic optic neuropathy), traumatic optic neuropathy, and optic atrophy (e.g., glaucomatous optic atrophy)), and other neuropathies affecting the eye or the area surrounding the eye, including paraocular diseases, disorders, and medical conditions as well as extraocular diseases, disorders, and medical conditions,For example, cranial nerve palsies, including but not limited to cranial III nerve palsies, cranial IV nerve palsies, cranial V nerve palsies (e.g., trigeminal neuralgia and postherpetic neuralgia), cranial VI nerve palsies, and cranial VII nerve palsies (e.g., Bell's palsy), the circulatory system, the lymphatic system, the respiratory system (including diseases or conditions affecting the epiglottis, trachea, bronchi, bronchioles, or lungs of a human or veterinary animal, particularly the diseases and conditions described in detail herein), the endocrine system, the urinary / excretory system (including diseases or conditions affecting the kidneys, ureters, bladder, upper urinary tract (i.e., renal pelvis), the ureters or urethra, especially those diseases and conditions detailed herein), reproductive system (including diseases and conditions affecting the testicles, prostate, penis, vagina, cervix, uterus, fallopian tubes or ovaries of the human or veterinary animal, especially those diseases and conditions detailed herein), digestive system (including those diseases or conditions affecting the esophagus, stomach, small intestine, colon or rectum of the human or veterinary animal, especially those diseases and conditions detailed herein), and nervous or nervous system (including peripheral nervous system and central nervous system, especially those nervous or nervous system conditions, diseases and injuries detailed herein). Suitable methods for implanting one or more devices provided by this aspect of the invention into a human or veterinary animal to achieve treatment, prevention, amelioration or diagnosis of a disease, condition or medical or physical condition of the human or veterinary animal are familiar to those of ordinary skill in the relevant medical and surgical fields. ,

[0524] According to the method of the present invention, the concentration of CMP or CMP-TC conjugate for treating, preventing, improving or diagnosing one or more diseases or conditions is obvious to those of ordinary skill in the pharmaceutical and medical fields. For unconjugated CMP, the appropriate amount or concentration of CMP to be administered to a subject (particularly a human or animal), the appropriate amount or concentration of CMP to be used include those described above. According to the guidance provided herein, a person of ordinary skill in the medical, pharmaceutical and / or pharmacological fields can determine the appropriate amount of the conjugate and composition of the present invention used per kilogram (kg) of human or animal body weight. For conjugated CMP-TC, the same amount or concentration of CMP described herein, whether it is concentration (e.g., ng / ml or μg / ml) or amount (e.g., mg / kg body weight), is suitable for administration to a subject, and the amount of active pharmaceutical ingredient or biologic is calculated during the conjugation process to deliver a therapeutically effective amount of the desired active pharmaceutical ingredient or biologic, which specifically depends on the disease or condition to be treated, prevented, improved or diagnosed in a human or animal. Appropriate amounts or concentrations of active pharmaceutical ingredients or biologics for use in accordance with this aspect of the invention are familiar to those of ordinary skill in the art and can be readily determined based on the information contained herein and other information available in the relevant art.

[0525] It will be apparent to those skilled in the art that other suitable modifications and adaptations may be made to the methods and applications described herein without departing from the scope of the invention or any embodiment thereof. Now that the invention has been described in detail, the invention will be more clearly understood by reference to the following examples, which are included herein for illustrative purposes only and are not intended to limit the invention.

[0526] Example

[0527] Example 1: Effects of CMP and CMP-TC conjugates in treating myopia

[0528] In order to examine the possible therapeutic effects of the CMPs of the present invention in treating myopia, a study was designed to test certain CMP conjugates in an in vivo environment - treating and possibly reversing myopia in experimental animals such as mice and rats. In such a study, the animals were anesthetized and the eyes were treated dropwise for 1-3 days with a matrix of 60 nM human metalloproteinase 1 (MMP-1; Biolegend, San Diego, CA), which had been pre-activated with 2 mM 4-aminophenylmercuric acetate (APMA, Sigma, St. Louis, MO), as previously described (Ribeiro, M. et al., Int. J. Mol. Sci. 23: 7004 (2022)). Negative control animals were treated with vehicle (PBS) only. After MMP treatment, animals were treated with 25 μg / ml or 50 μg / ml CMP (particularly SEQ ID NO: 1 or SEQ ID NO: 6) daily for up to 3 weeks, while vehicles (PBS) were used for negative control animals. After these treatments, axial length was measured using standard optometric techniques, and the structure of the scleral collagen matrix was determined using a variety of microscopy techniques including confocal microscopy, second harmonic microscopy (Guo, P. et al., Trans. Vis. Sci. Tech. 9 (9): 45 (2020)). The results of these studies link increased collagen breakdown and disintegration to increased axial length, indicating that the collagen matrix in the sclera is involved in maintaining optimal eye structure and shape, and that destruction of the collagen matrix is ​​associated with decreased vision and the development of myopia. In addition, the results of these studies showed that animals treated with the CMP-containing compositions of the present invention showed increased levels of collagen tissue and restoration of the underlying collagen matrix structure in the sclera, resulting in a decrease in axial length, which can be used to indicate the treatment of myopic symptoms and / or signs. Therefore, the CMP and CMP-TC conjugates of the present invention and compositions containing them can be used to promote the reduction of axial length in animals as a model for a variety of human and animal ocular diseases (including myopia and presbyopia).

[0529] Example 2: Activity of CMP in restoring the structure and function of the peripapillary sclera collagen matrix in mouse eyes

[0530] The sclera of mammalian eyes is rich in collagen, which, along with elastin, makes up the majority of the sclera (Guo, P. et al., Trans. Vis. Sci. Tech. 9: 45 (2020)). Collagen in the sclera appears to regulate scleral hardness, thereby affecting the shape of human and mammalian eyes (Schultz, DS et al., Invest. Ophthalmol. Vis. Sci. 49: 4232-4236 (2008)). Numerous studies have shown that changes in collagen structure, including thinning of collagen bundles and reduction in the size of individual collagen bundles in the corneosclera, can lead to reduced scleral hardness. This reduction in scleral stiffness in turn increases corneal permeability and affects the shape of the eye, leading to axial elongation of the eyeball and the development of myopia (Jonas, JB 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, CC, 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, CF, Prog. Mol. Biol. Transl. Sci 134:241-248 (2015)). Some studies have found that increased expression of matrix metalloproteinases (MMPs) in the scleral stroma and the accompanying destruction of the scleral collagen matrix, which can be caused by genetic, environmental or inflammatory causes, can lead to 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)). This effect on the corneal scleral stroma may also lead to other ocular diseases and conditions, such as glaucoma, cataracts, staphylomas and retinal complications (Wang, B., et al., PLoS ONE 12:e0175913, https: / / doi.org / 10.1371 / journal.pone.0175913 (2017)).

[0531] Efforts to treat or prevent myopia by strengthening the sclera have achieved varying degrees of success. For example, treating myopic eyes with atropine can slow the progression of myopia (Upadhyay, A. and Beuerman, RW, 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)), apparently by 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 stroma were hardened by chemical or light-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, MB et al., Invest. Ophthalmol. Vis. Sci. 58:1875-1886 (2017); Elsheikh, A., and Phillipa, JR, Ophthalmic Physiol. Opt. 33:385-389 (2013); Wang, W.-Y. et al., Biomed. Pharmacother. 133:111092 (2021)). However, one disadvantage of these methods for treating or preventing myopia is that artificial connective tissue remodeling (such as described in the above literature) may increase the risk of glaucoma in patients receiving such treatments (Grytz, R., et al., Curr. Opin. Biomed. Eng. 15:40-50 (2020)).

[0532] Therefore, the inventors infer that a hardening method that makes the corneoscleral stroma closer to native collagen repair, such as that occurring during treatment of mammalian eyes with a formulation comprising one or more collagen mimetic peptides (CMPs), including the collagen mimetic peptides of the present invention, can treat myopia and prevent its progression by restoring the structure and function of the collagen matrix in the corneosclera. Therefore, this method can be used to treat or prevent various corneoscleral diseases and conditions, including myopia, presbyopia, scleritis, episcleritis, and keratoconus, among others.

[0533] Therefore, in order to examine the possible therapeutic effects of the CMPs of the present invention in treating myopia, we designed studies to test the effects of certain CMP conjugates in an in vivo environment model - in vitro studies of the collagen matrix in the peripapillary sclera of mouse eyes. For these studies, mouse eyes were removed and sliced, and sections of the peripapillary sclera (the area of ​​sclera adjacent to the optic nerve head) were examined using atomic force microscopy (AFM). Figure 1 The morphology of the peripapillary sclera in a representative sample of such sections is shown. Figure 1 A (low power view) and Figure 1 The arrow in B (high power view of the same slice) shows the area targeted by the AFM probe, which can measure the Young's modulus of that tissue area, as a determinant of the stiffness or elasticity of the structure at the measured point (e.g., see Girard, MJ et al., J. Biomech. Eng. 131:051012, doi:10.1115 / 1.3113683 (2009)). Specifically, a higher Young's modulus at a given point measured by AFM indicates that the sclera is less elastic or stiffer and more resistant to deformation than an area where a lower Young's modulus is measured.

[0534] To examine the effect of matrix metalloproteinase (MMP) treatment (whether or not followed by CMP treatment) on the stiffness of mouse peripapillary scleral explants, samples were treated with MMP (50 μg / ml, 30 minutes) and then rinsed with PBS or treated with the CMP-containing formulation of the present invention for 60 minutes. AFM was then used to measure the Young's modulus at multiple different locations. Figure 2 As shown in . Baseline (i.e., untreated) explant samples showed that, as expected, the hardness modulus varied across the scleral surface, since the hardness of the sclera varies from point to point in normal and myopic eyes (Grytz, R., et al., Curr. Opin. Biomed. Eng. 15:40-50 (2020); Jonas, JB and Xu, I., Eye 28:113-117 (2014)). Treatment of scleral explants with MMP significantly reduced scleral hardness (represented by a reduction in Young's modulus), almost uniformly and well below baseline; this result is consistent with the manifestation of advanced myopia in humans and other animals. In contrast, after 60 minutes of treatment with a preparation containing CMP3 (SEQID NO: 1) of the present invention, the degree of scleral hardening was significantly higher than that of samples treated with MMP, indicating that CMP treatment can at least partially reverse the destruction of the scleral matrix caused by MMP. Similar results were observed 30 minutes after treatment of the MMP-treated samples with a preparation containing CMP3 ( Figure 3 A-3B, 4A-4B, 5A-5B, 6A-6B), although in some samples, treatment with CMP for 60 min ( Figure 3B-3C, 5B-5C) provided stronger restoration of scleral stiffness. When these results were plotted as a scatter plot ( Figure 7 ), it was apparent that treatment of MMP-treated scleral explants with a CMP-containing formulation for as little as 30 minutes resulted in significant hardening of the scleral matrix, whereas extending the CMP treatment time to 60 minutes appeared to enhance the therapeutic effect to a degree that exceeded that of a 30-minute treatment.

[0535] To increase the statistical significance of these studies, Young's modulus was measured at a large number of points at multiple individual locations in a given peripapillary sclera sample using AFM. As described above, samples were either untreated (baseline), or treated with 50 μg / ml MMP1 for 30 minutes, followed by treatment with a CMP-containing formulation of the invention (CMP3, i.e., SEQ ID NO: 1 or CMP13, i.e., SEQ ID NO: 6) for 60 minutes, and then Young's modulus was measured by AFM at multiple points at multiple locations. The results are shown in Table 1. Figure 8 and 9 Shown in.

[0536] like Figure 8 As shown in the previous figure, treatment of scleral explants with MMP1 resulted in a significant decrease in the Young's modulus of the samples compared to the untreated (baseline) samples. However, after treatment with the formulation containing CMP3, the scleral stiffness increased rapidly ( Figure 8 A), with very tight statistical significance between the groups (ANOVA p<0.001) ( Figure 8 B). Similar results were observed when the peripapillary sclera samples were treated with the CMP13-containing formulation of the present invention ( Fig. 9 A, 9B). Indeed, treatment with CMP13 (SEQ ID NO: 6) appeared to enhance the stiffness of the peripapillary sclera beyond that observed in untreated baseline samples.

[0537] Taken together, these results indicate that the CMP-containing formulations of the invention can reverse the destruction of the collagen matrix, thereby restoring (or at least partially restoring) the strength and stiffness of the peripapillary sclera in mouse eye explants. Because CMPs are, by definition, mimics of naturally occurring collagen chains, these results indicate that the CMP-containing formulations of the invention and methods of using such formulations can be used to treat ocular diseases and conditions characterized by scleral structural destruction and stiffness with fewer side effects than more traditional treatments (such as atropine or collagen cross-linking).

[0538] Example 3: Activity of CMP in restoring collagen matrix structure and function in the glial layer of mouse eyes

[0539] Based on the studies detailed in Example 2 herein, the inventors reasoned that since CMPs appear to be useful for remodeling the collagen fibril bundle structure in the mouse peripapillary sclera, thereby strengthening the scleral matrix, such CMP-containing formulations may similarly be used to strengthen the collagen structure in the adjacent areas of the peripapillary sclera - particularly the glial layer of the optic nerve head. To conduct these studies, mouse eyes were removed and thinly sectioned as described in Example 2 above, and sections of the glial layer and peripapillary sclera were then examined using atomic force microscopy (AFM). Fig.10 The morphology of the peripapillary sclera and glial layers in three representative samples of such sections is shown, with arrows indicating the region where the AFM probe was directed to enable measurement of Young's modulus for this region of tissue. Fig.10 A is the untreated sample, Fig.10 B is the sample treated with 5 μg / ml MMP1 for 30 minutes. Fig.10 C is a sample treated with 5 μg / ml MMP1 for 30 minutes and then treated with the CMP formulation of the present invention (comprising SEQ ID NO: 6 or "CMP13") for 30 minutes. It can be easily observed from these micrographs that there seems to be no observable difference in microscopic morphology between these samples. However, as Fig.11 As shown, measurement of the Young's modulus of the glial layer of these three samples revealed significant differences in tissue stiffness, with MMPs adversely affecting the stiffness of the glial layer in a manner reminiscent of that seen in peripapillary sclera samples ( Fig.11 A-11C). In contrast, the CMP-containing formulation of the present invention restores tissue stiffness to a value closer to ( Fig.11 A) and in some cases even exceeds ( Fig.11 B) Tissue stiffness observed for untreated baseline samples. To ensure that this effect was not simply due to washout of the MMPs upon treatment with the CMP-containing formulation, the MMP-treated samples were treated with vehicle (PBS); this treatment did not restore the stiffness of the glial layer, which was close to that of the MMP-treated samples ( Fig.11 C).

[0540] To increase the statistical significance of these studies, Young's modulus measurements were performed using AFM at a large number of points at multiple individual locations in a given glial layer sample, as was done for the peripapillary sclera in Example 2. Samples were either untreated (baseline), or treated with 5 μg / ml MMP1 for 30 minutes, followed by treatment with a CMP-containing formulation of the invention (CMP3, i.e., SEQ ID NO: 1) for 60 minutes, and then Young's modulus was measured by AFM at multiple points at multiple locations. The results are shown in Table 1. Fig.12 As observed in the peripapillary sclera and Fig.11As seen in the smaller number of glial layer samples in the glial layer, treatment of the glial layer with MMP1 resulted in a significant decrease in the Young's modulus of the samples compared to the untreated (baseline) samples. However, treatment with the formulation containing CMP3 rapidly increased the stiffness of the glial layer ( Fig.12 A), with very tight statistical significance between the groups (ANOVA p<0.001) ( Fig.12 B).

[0541] To examine the distribution of disrupted and intact collagen in such explants, the samples prepared above were treated with DAPI (to locate cell nuclei), a fluorescently labeled antibody against type I collagen ("Col1"), and a Cy3-labeled collagen hybrid peptide ("RCHP") that binds only to disrupted collagen regions. Fig.13 AFM examination of the morphology of these samples is reminiscent of that described above and Example 2 ( Fig.13 a) and allows the discrimination of the glial layer ("A") and peripapillary sclera ("B") in such samples. Fluorescence microscopy of various markers showed that the glial layer ( Fig.13 b) and peripapillary sclera ( Fig.13 d) and there was a lot of damaged collagen, and there was almost no intact collagen in the glial layer slices ( Fig.13 b). In contrast, samples treated with CMP3 (i.e., SEQ ID NO: 1) showed a decrease in the glial layer ( Fig.13 c) or peripapillary sclera ( Fig.13 e) showed little disruption of collagen; in fact, the glial layer had recovered a stronger, more intact collagen network within 60 minutes ( Fig.13 c) These results indicate that when the CMP-containing formulation of the invention is used in the method of the invention, it is able to rapidly restore the collagen network in mouse eye explants, particularly in the sclera and glial layers, thereby reversing the effects of matrix metalloproteinase degradation of the collagen matrix.

[0542] Together with the results of Example 2, these results indicate that the CMP-containing formulations of the present invention can reverse the destruction of the collagen matrix, thereby restoring (or at least partially restoring) the strength and stiffness of the peripapillary sclera and glial layer in mouse eye explants, where the structure and function of the collagen matrix has been destroyed. Because this destruction of the collagen matrix is ​​a hallmark of certain corneoscleral diseases and conditions, such as myopia, presbyopia, keratoconus, etc., these formulations and methods of the present invention should prove useful in treating ocular diseases and conditions characterized by destruction of the structure and function of the corneosclera and optic nerve, with fewer side effects than more traditional treatments such as atropine or collagen cross-linking.

[0543] Example 4: Activity of CMP in restoring collagen structure: Molecular analysis

[0544] To further examine the effects of CMP-containing formulations on collagen structure and function at the molecular level, samples of type I collagen plated on the matrix 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 matrix at a concentration of 10 μg / ml in PBS, allowed to air dry, and then either left untreated or treated with MMP1 (60 ng / ml) for 30 minutes. The samples were then examined by scanning electron microscopy (SEM); the results were presented in Fig.14 The untreated collagen sample showed extensive fiber and fibril formation ( Fig.14 A, 14C), at low magnification ( Fig.14 A) and high power ( Fig.14 C) Extensive network formation was observed. In contrast, MMP treatment of the matrix resulted in readily observable disruption of collagen fibers, fibrils, and networks ( Fig.14 B), at a higher magnification ( Fig.14 D) It can be seen that it also contains a large number of collagen fragments and, in some cases, single-chain collagen. Thus, MMP treatment of the collagen matrix results in rapid disintegration of the collagen structure and a large amount of destroyed collagen, which is reminiscent of earlier studies by the same inventors (see, e.g., U.S. Pat. No. 11,389,513, the disclosure of which is incorporated herein by reference).

[0545] Examination of these same matrices by AFM, but also including samples treated for 30 minutes with both 100 ng / ml MMP1 and 1 μg / ml of a formulation of the invention containing CMP13 (SEQ ID NO: 6), demonstrated the effect of the formulation of the invention containing CMP in preventing the collagen structural disruption seen on the matrices. The results of these studies are shown in Fig.15 In the untreated (baseline) sample, an extensive and multilayered network of collagen fibers, fibrils, and bundles can be readily observed ( Fig.15 A, 15B). However, the MMP-treated samples showed a large amount of disordered collagen and little residual fiber / fibril formation ( Fig.15 C, 15D). However, the inclusion of CMPs together with MMPs appears to prevent the effects of MMPs on the collagen network on the matrix, as extensive collagen fiber / fibril formation could be observed in these samples ( Fig.15 E), and long fiber bundles and networks spread across the matrix surface ( Fig.15F). In summary, these studies demonstrate that the CMP-containing formulations of the present invention are not only useful for treating and reversing the collagen-destroying effects of MMPs that lead to corneal and scleral defects in certain ocular diseases and conditions, but such formulations are also useful for prevention Thus, the CMP-containing formulations provided herein and methods of using such formulations should prove useful in treating and preventing certain ocular diseases and conditions characterized by loss of corneal and scleral rigidity and strength, including but not limited to myopia, presbyopia, and keratoconus.

[0546] The present invention has been described above with the aid of functional building blocks that illustrate the implementation of specific functions and their relationships. For ease of description, any definition of the boundaries of these functional building blocks has been made herein. As long as the specific functions and their relationships are appropriately performed, alternative boundaries can be defined. For example, a statement of a numerical range (such as a range of dosages or dosing concentrations) should be understood to include the values ​​at the beginning and end of the range, as well as each value between the beginning and end values. To illustrate this concept, the range of "about 25ng / ml to about 250ng / ml" should be interpreted as including the values ​​of "about 25ng / ml", "about 250ng / ml" and each individual concentration value between these two values. The term "about" when used in conjunction with a numerical value generally represents a value of ±10% of the actual value.

[0547] The foregoing description of specific embodiments will fully reveal the general nature of the present invention, so that others can easily modify and / or adapt such specific embodiments for various applications by applying knowledge within the technical scope of the art without departing from the general concept of the present invention. Therefore, in addition to the embodiments specifically described herein, based on the foregoing description and examples and the knowledge generally available in the relevant field, other suitable embodiments of the present invention will be apparent to those of ordinary skill in the art. Therefore, based on the teaching content and the guidance content presented herein, such adaptations and modifications are intended to be within the meaning and scope of the equivalents of the disclosed embodiments. It should be understood that the wording or terminology herein is intended to illustrate rather than to limit, so the technical staff will interpret the terms or wording of this specification according to the teaching content and the guidance content.

[0548] The breadth and scope of the present invention should not be limited by any of the above-described exemplary embodiments, but should be defined only in accordance with the following claims and their equivalents.

[0549] All references cited herein, including U.S. patents and published patent applications, international patents and patent applications, and journal references or other publicly available documents, are incorporated by reference in their entirety to the same extent as if each reference were specifically cited for that part or parts of that reference that are relevant to this application.

Claims

1. A composition suitable for use in a pharmaceutical for treating or preventing a corneal or scleral disease, disorder or condition in a human or veterinary animal in need of such treatment or prevention, the composition comprising (a) at least one collagen mimetic peptide (CMP), having, and (b) one or more pharmaceutically suitable carriers.

2. The composition of claim 1, wherein the corneal diseases, disorders and conditions are selected from the group consisting of keratitis, episcleritis, scleritis, corneal ulcer, corneal ulcer sequelae, corneal ectasia, acquired corneal shape abnormalities, keratoconus, corneal astigmatism, spherical cornea, posterior corneal indentation, corneal proptosis, corneal ectasia, Descemet's membrane ectasia, pellucid marginal corneal degeneration, Trion's marginal dystrophy, Mooren's ulcer, central corneal ulcer, marginal corneal ulcer, staphylococcal marginal ulcer, Salzmann's nodular dystrophy, age-related peripheral corneal atrophy, geographic ulcer, discoid ulcer, Stromal keratitis, herpetic ulcer, keratomalacia, post-penetrating keratoplasty, incisional wounds, anterior membrane dystrophy, stromal dystrophy, ocular mucosal pemphigoid, necrotizing scleritis, scleromalacia, ocular tissue loss, myopia, presbyopia, hyperopia, scleromalacia induced by scleral buckle, congenital hereditary stromal dystrophy, congenital anterior staphyloma, scleralized keratitis, traumatic desmoplasia, corneal keloid, scleral ectasia, scleral staphyloma, deep scleritis, necrotizing scleritis, perforating scleromalacia, hyalinization of the sclera, paralimbal scleromalacia, ocular graft-versus-host disease, and choroideremia.

3. The composition of claim 1, wherein the corneoscleral disease, disorder or condition is myopia, presbyopia or keratoconus.

4. The composition of claim 1, wherein the at least one CMP is linked to at least one therapeutic compound (TC) to form a CMP-TC conjugate.

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

6. The composition of claim 1, wherein the at least one collagen mimetic 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 composition of claim 1, wherein the at least one collagen mimetic peptide has an amino acid sequence corresponding to SEQ ID NO:

1.

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

6.

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

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

11. The composition of claim 1, wherein the at least one collagen mimetic 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.

12. A method for treating or preventing a corneal disease, disorder or condition in a human or animal in need of treatment or prevention, the method comprising administering to the eye of the human or animal a composition of claim 5 in an amount sufficient to treat or prevent the myopia, keratoconus or presbyopia, monitoring the eye condition of the human or animal over time, and re-administering the composition to the eye until the corneal disease, disorder or condition is cured, prevented or improved.

13. The method of claim 12, wherein the corneal diseases, disorders and conditions are selected from the group consisting of keratitis, episcleritis, scleritis, corneal ulcer, corneal ulcer sequelae, corneal ectasia, acquired corneal shape abnormalities, keratoconus, corneal astigmatism, spherical cornea, posterior corneal indentation, corneal proptosis, corneal ectasia, Descemet's membrane ectasia, pellucid marginal corneal degeneration, Trion's marginal dystrophy, Mooren's ulcer, central corneal ulcer, marginal corneal ulcer, staphylococcal marginal ulcer, Salzmann's nodular dystrophy, age-related peripheral corneal atrophy, geographic ulcer, discoid ulcer, Stromal keratitis, herpetic ulcer, keratomalacia, post-penetrating keratoplasty, incisional wounds, anterior membrane dystrophy, stromal dystrophy, ocular mucosal pemphigoid, necrotizing scleritis, scleromalacia, ocular tissue loss, myopia, presbyopia, hyperopia, scleromalacia induced by scleral buckle, congenital hereditary stromal dystrophy, congenital anterior staphyloma, scleralized keratitis, traumatic desmoplasia, corneal keloid, scleral ectasia, scleral staphyloma, deep scleritis, necrotizing scleritis, perforating scleromalacia, hyalinization of the sclera, paralimbal scleromalacia, ocular graft-versus-host disease, and choroideremia.

14. The method of claim 12, wherein the corneoscleral disease, disorder or condition is myopia, keratoconus or presbyopia.

15. The method of claim 12, wherein the method is used to treat or prevent myopia.

16. The method of claim 12, wherein the method is used to treat or prevent presbyopia.

17. The method of claim 12, wherein the composition is administered to the eye transconjunctivally or subconjunctivally.

18. The method of claim 12, wherein the composition is administered to the eye in the form of one or more drops of a solution or suspension containing the composition.

19. The method of claim 12, wherein the composition is administered to the eye by injection.

20. The method of claim 19, wherein the injection is an intravitreal injection.

21. The method of claim 12, wherein the composition is administered to the eye as a coating on a solid material implanted in an ocular structure.

22. The method of claim 12, wherein the composition is applied to the eye in the form of a wafer, film, gel, mesh, or patch.

23. The method of claim 12, wherein the composition is attached to one or more spheroids or nanoparticles that are delivered to or within an ocular structure.

24. A medical device suitable for treating or preventing a corneoscleral disease, disorder or condition in a human or veterinary animal in need of such treatment or prevention, wherein the device comprises the composition of claim 5.

25. The medical device of claim 24, wherein the device is selected from the group consisting of a stent, a shunt, a suture, an absorbable mesh, an absorbable patch, a drug releasing wafer, a membrane, and an internal infusion pump.

26. A method for treating, improving or preventing myopia or presbyopia in a human or animal in need of treatment or prevention, the method comprising implanting the medical device of claim 24 into the eye of the human or animal, and monitoring the medical condition of the human or animal until the myopia, keratoconus or presbyopia is cured, improved or prevented.

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