Facile Modification of Collagen Directed by Collagen Mimetic Peptides

Wang, Allen Y.; Mo, Xinxin; Chen, Christopher; Yu, S. Michael

doi:10.1021/ja0431915

Cited by 132 publications

(159 citation statements)

References 18 publications

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“…Binding was observed only when CMPs [ðProHypGlyÞ x , x ¼ 6, 7, and 10] in a thermally melted, single-strand form and not in folded trimeric form were allowed to fold by cooling in the presence of type I collagen fibers (9,10). Although we observed apparent CMP binding to collagens at temperatures below collagen's T m , the binding was significantly enhanced when hot CMP solution (typically above 70°C) was applied to the collagen film.…”

mentioning

confidence: 64%

“…Previously, we discovered that small collagen mimetic peptides (CMPs, molecular weight: 2-3 kDa) capable of reversibly forming collagen triple helices are able to bind to type I collagen (8)(9)(10)(11). Binding was observed only when CMPs [ðProHypGlyÞ x , x ¼ 6, 7, and 10] in a thermally melted, single-strand form and not in folded trimeric form were allowed to fold by cooling in the presence of type I collagen fibers (9,10).…”

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confidence: 99%

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Targeting collagen strands by photo-triggered triple-helix hybridization

Foss

Summerfield

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

175

246

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Collagen remodeling is an integral part of tissue development, maintenance, and regeneration, but excessive remodeling is associated with various pathologic conditions. The ability to target collagens undergoing remodeling could lead to new diagnostics and therapeutics as well as applications in regenerative medicine; however, such collagens are often degraded and denatured, making them difficult to target with conventional approaches. Here, we present caged collagen mimetic peptides (CMPs) that can be phototriggered to fold into triple helix and bind to collagens denatured by heat or by matrix metalloproteinase (MMP) digestion. Peptidebinding assays indicate that the binding is primarily driven by stereo-selective triple-helical hybridization between monomeric CMPs of high triple-helical propensity and denatured collagen strands. Photo-triggered hybridization allows specific staining of collagen chains in protein gels as well as photo-patterning of collagen and gelatin substrates. In vivo experiments demonstrate that systemically delivered CMPs can bind to collagens in bones, as well as prominently in articular cartilages and tumors characterized by high MMP activity. We further show that CMP-based probes can detect abnormal bone growth activity in a mouse model of Marfan syndrome. This is an entirely new way to target the microenvironment of abnormal tissues and could lead to new opportunities for management of numerous pathologic conditions associated with collagen remodeling and high MMP activity.A s the most abundant protein in mammals, collagens play a crucial role in tissue development and regeneration, and their structural or metabolic abnormalities are associated with debilitating genetic diseases and various pathologic conditions. Although collagen remodeling occurs during development and normal tissue maintenance, particularly for renewing tissues (e.g., bones), excess remodeling activity is commonly seen in tumors, arthritis, and many other chronic wounds. During collagen remodeling, large portions of collagens are degraded and denatured by proteolytic enzymes, which can be explored for diagnostic and therapeutic purposes. Since unstructured proteins are not ideal targets for rational drug design, library approaches have been employed to develop monoclonal antibody (1, 2) and peptide probes (3) that specifically bind to cryptic sites in collagen strands that become exposed when denatured. However, these probes suffer from poor pharmacokinetics (4), and/or low specificity, and binding affinity (5).We envisioned that triple helix, the hallmark structural feature of collagen, could provide a unique targeting mechanism for the denatured collagens. The triple helix is nearly exclusively seen in collagens except as small subdomains in a few noncollagen proteins (6). Considering its striking structural similarity to the DNA double helix in terms of multiplex formation by periodic interchain hydrogen bonds along the polymer backbone (6), we thought that a small peptide sequence with strong triple-helix prope...

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mentioning

confidence: 64%

mentioning

confidence: 99%

Targeting collagen strands by photo-triggered triple-helix hybridization

Foss

Summerfield

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

175

246

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“…11,16 Synthetic collagen model systems, also known as collagen mimetic peptides (CMPs), have been useful in elucidating collagen structure and factors responsible for the stabilization of the triple helix. 9,[17][18][19] CMPs form a triple helical structure almost identical to that of natural collagens; however, unlike collagen molecules, CMPs are small (<3 KDa) and, therefore, exhibit reversible melting behaviors. 11,13,17 CMPs based on ProProGly or ProHypGly trimers have been widely studied and their melting temperatures (T m ) vary from 21 to 75 °C, depending on the molecular weight and amino acid composition.…”

Section: Introductionmentioning

confidence: 99%

“…11,13,17 CMPs based on ProProGly or ProHypGly trimers have been widely studied and their melting temperatures (T m ) vary from 21 to 75 °C, depending on the molecular weight and amino acid composition. 9,[11][12][13][18][19][20] Considering the rare occurrence of triple helical protein structure in nature outside of collagen, we thought that the associative interactions between collagen strands in forming the triple helix can be explored as a unique physical conjugation tool for attaching exogenous molecules to natural collagens. Physical interactions, such as hydrogen bonding, hydrophobic, and ionic interactions and biological affinity interactions, provide a much more convenient and natural way of conjugating agents to proteins and other macromolecules as opposed to covalent chemical attachment.…”

Section: Introductionmentioning

confidence: 99%

Spatio-Temporal Modification of Collagen Scaffolds Mediated by Triple Helical Propensity

et al. 2008

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Functionalized collagen that incorporates exogenous compounds may offer new and improved biomaterials applications, especially in drug-delivery, multifunctional implants, and tissue engineering. To that end, we developed a specific and reversible collagen modification technique utilizing associative chain interactions between synthetic collagen mimetic peptide (CMP) [(ProHypGly) x ; Hyp = hydroxyproline] and type I collagen. Here we show temperature-dependent collagen binding and subsequent release of a series of CMPs with varying chain lengths indicating a triple helical propensity driven binding mechanism. The binding took place when melted, singlestrand CMPs were allowed to fold while in contact with reconstituted type I collagens. The binding affinity is highly specific to collagen as labeled CMP bound to nanometer scale periodic positions on type I collagen fibers and could be used to selectively image collagens in ex vivo human liver tissue. When heated to physiological temperature, bound CMPs discharged from the collagen at a sustained rate that correlated with CMP's triple helical propensity, suggesting that sustainability is mediated by dynamic collagen-CMP interactions. We also report on the spatially defined modification of collagen film with linear and multi-arm poly(ethylene glycol)-CMP conjugates; at 37 °C, these PEG-CMP conjugates exhibited temporary cell repelling activity lasting up to 9 days. These results demonstrate new opportunities for targeting pathologic collagens for diagnostic or therapeutic applications and for fabricating multifunctional collagen coatings and scaffolds that can temporally and spatially control the behavior of cells associated with the collagen matrices.

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“…The folding of (XaaYaaGly) nՅ10 peptides into blunt-ended triple helices has been investigated thoroughly (7). Although such triple helices are biomaterial candidates (9)(10)(11)(12), they are limited to the length of a synthetic peptide (Ͻ10 nm), which is much shorter than natural collagen (Ϸ300 nm). The polymerization of (XaaYaaGly) 10 peptides has afforded long strands that adopt triple-helical structure but have high polydispersity (13).…”

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confidence: 99%

Self-assembly of synthetic collagen triple helices

Kotch

Raines

2006

Proc. Natl. Acad. Sci. U.S.A.

285

232

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Collagen is the most abundant protein in animals and the major component of connective tissues. Although collagen isolated from natural sources has long served as the basis for some biomaterials, natural collagen is difficult to modify and can engender pathogenic and immunological side effects. Collagen comprises a helix of three strands. Triple helices derived from synthetic peptides are much shorter (<10 nm) than natural collagen (Ϸ300 nm), limiting their utility. Here, we describe the synthesis of short collagen fragments in which the three strands are held in a staggered array by disulfide bonds. Data from CD spectroscopy, dynamic light scattering, analytical ultracentrifugation, atomic force microscopy, and transmission electron microscopy indicate that these ''sticky-ended'' fragments self-assemble via intermolecular triple-helix formation. The resulting fibrils resemble natural collagen, and some are longer (>400 nm) than any known collagen. We anticipate that our self-assembly strategy can provide synthetic collagen-mimetic materials for a variety of applications.biomaterial ͉ coiled-coil ͉ nanotechnology ͉ cystine knot ͉ peptide C ollagen constitutes one-third of the human proteome, including three-quarters of the dry weight of human skin. Its high natural abundance and intrinsic plasticity have spurred the development of collagen as a biomaterial (1, 2). The most common source of clinical collagen is now Bos taurus, the domestic cow. Unfortunately, bovine collagen can illicit deleterious pathological and immunological effects when transplanted into humans (3-5). Moreover, the preparation of enriched solutions of natural collagen is problematic (6), and its sitespecific covalent modification is not feasible. We suspected that synthetic chemistry could offer a solution to these problems.The quaternary structure of collagen comprises three strands that wrap around one another to form a triple helix (7). Each strand has the repeating sequence XaaYaaGly, with the most abundant triplet being ProHypGly [Hyp ϭ (2 S,4R)-4-hydroxyproline] (8). The folding of (XaaYaaGly) nՅ10 peptides into blunt-ended triple helices has been investigated thoroughly (7). Although such triple helices are biomaterial candidates (9-12), they are limited to the length of a synthetic peptide (Ͻ10 nm), which is much shorter than natural collagen (Ϸ300 nm). The polymerization of (XaaYaaGly) 10 peptides has afforded long strands that adopt triple-helical structure but have high polydispersity (13).Molecular self-assembly underlies the ''bottom-up'' approach to macromolecular design, wherein a desirable structure forms spontaneously through noncovalent interactions (14, 15). Selfassembling peptides and proteins have been designed to serve as materials for biological and nanotechnological applications (16,17). Using the self-assembly approach, Woolfson and coworkers (18,19) have produced fibers with a design based on a dimeric coiled-coil structure. Likewise, fibrous peptides based on the natural protein elastin (20) and de novo building b...

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Facile Modification of Collagen Directed by Collagen Mimetic Peptides

Cited by 132 publications

References 18 publications

Targeting collagen strands by photo-triggered triple-helix hybridization

Targeting collagen strands by photo-triggered triple-helix hybridization

Spatio-Temporal Modification of Collagen Scaffolds Mediated by Triple Helical Propensity

Self-assembly of synthetic collagen triple helices

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