Collagen is the most abundant protein in humans, comprising 1/3 of the total protein and 3/4 of the dry weight of skin. Collagen abnormalities are associated with many human diseases, including arthritis. The overall objective of the proposed research is to reveal the chemical basis for the unique triple-helical structure of collagen, and t devise new therapies based on that knowledge.
Specific Aims : The four Specific Aims of this research proposal apply methods and ideas from physical organic chemistry, peptide chemistry, molecular self-assembly, chemical enzymology, and matrix biology.
Aim 1 is to discern whether enhancing a newly appreciated physicochemical force-the n->?* interaction-can increase triple-helix stability.
Aim 2 is to create collagen mimetic peptides that self-assemble into human-scale triple helices that are useful for biomedical applications.
Aim 3 is to gain insight into the mechanism of catalysis by human prolyl 4-hydroxylase, which is the enzyme that installs the prevalent and important 4-hydroxyproline residues in collagen strands and is a target for the treatment of fibrotic diseases. Finally, Aim 4 is to use extant knowledge of collagen to create peptide conjugates to assess and heal wounds in mice. Significance: The results of the research proposed herein will provide fundamental insights into the structure and conformational stability of the collagen triple helix, and will use those insights to create transformative molecular therapies for wound care, which now accounts for up to $15B annually in US health care costs, and other indications.
This research project is focused on collagen, which is the most abundant protein in humans. Collagen abnormalities are associated with a variety of human diseases, including arthritis. The goal of the project is to obtain insights into the relationship between the amino acid sequence of collagen and its biological function (or dysfunction), as well as to create novel collagen-like proteins of therapeutic use in wound healing and other indications.
| Ellison, Aubrey J; Raines, Ronald T (2018) A pendant peptide endows a sunscreen with water-resistance. Org Biomol Chem 16:7139-7142 |
| Vasta, James D; Raines, Ronald T (2018) Collagen Prolyl 4-Hydroxylase as a Therapeutic Target. J Med Chem : |
| Newberry, Robert W; Raines, Ronald T (2017) The n??* Interaction. Acc Chem Res 50:1838-1846 |
| Newberry, Robert W; Raines, Ronald T (2017) 4-Fluoroprolines: Conformational Analysis and Effects on the Stability and Folding of Peptides and Proteins. Top Heterocycl Chem 48:1-25 |
| Vasta, James D; Choudhary, Amit; Jensen, Katrina H et al. (2017) Prolyl 4-Hydroxylase: Substrate Isosteres in Which an (E)- or (Z)-Alkene Replaces the Prolyl Peptide Bond. Biochemistry 56:219-227 |
| Arnold, Ulrich; Raines, Ronald T (2016) Replacing a single atom accelerates the folding of a protein and increases its thermostability. Org Biomol Chem 14:6780-5 |
| Chattopadhyay, Sayani; Guthrie, Kathleen M; Teixeira, Leandro et al. (2016) Anchoring a cytoactive factor in a wound bed promotes healing. J Tissue Eng Regen Med 10:1012-1020 |
| Vasta, James D; Raines, Ronald T (2016) Human Collagen Prolyl 4-Hydroxylase Is Activated by Ligands for Its Iron Center. Biochemistry 55:3224-33 |
| Newberry, Robert W; Orke, Samuel J; Raines, Ronald T (2016) n??* Interactions Are Competitive with Hydrogen Bonds. Org Lett 18:3614-7 |
| Newberry, Robert W; Raines, Ronald T (2016) A prevalent intraresidue hydrogen bond stabilizes proteins. Nat Chem Biol 12:1084-1088 |
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