Project Summary Collagen has been used for biomedical applications for many decades due to its unsurpassed biocompatibility and chemically tunable mechanical properties. There is a growing need for processible collagen due to rapidly developing tissue and organ engineering. The major source of raw collagen is animal tissue; thus, safety and possible contamination are major concerns. Current attempts to make synthetic collagen-like materials start from collagen-like peptides synthesized by classical solid-phase peptide synthesis, and thus, is not suitable for large- scale preparation and has little potential for clinical translation. We propose to develop a new approach to address an unmet need in synthesis of peptide polymers: controlling the polymer sequence and at the same time generating high molecular weight polymers. More specifically, we aim to develop collagen-like polymers by de novo synthesis starting from tripeptide ProHypGly-N-carboxyanhydride (NCA) and by ring opening lead to polymerization via kinetically controlled polycondensation. The ring opening polymerization of NCA is a very well- established method of synthetizing peptide polymers from single amino acids. The polymer synthesis can be controlled to yield high molecular weight homopolymers, block-copolymers, and branched and functional polymers. However, the problem of controlling the sequence of amino acids within the polymer has not been resolved. We outline two synthetic routes to synthesize the monomer N-Boc-ProHyp(OtBu)Gly-NCA for the synthesis of collagen-like polymers. Moreover, we propose the simultaneous deprotection of Boc group in tripeptide NCA revealing an open N-terminus, as well as the initiation of kinetically controlled polycondensation leading to collagen-like polymer. While the monodisperse polymers are viewed as better suited for clinical translation, we postulate that having a polydisperse collagen-like polymer will enable self-assembly into the triple helix conformation that is required for mechanical stability of collagen-like matrix. The helical structure of the collagen-like polymers will be observed with Circular Dichroism Spectroscopy. The biocompatibility of the collagen polymer will be evaluated with Human Dermal Fibroblast cell culture and mechanical characterization will be performed at UC San Diego Materials Research Science and Engineering Center. The proposed synthesis and characterization methods have been evaluated for safety and accessibility, because all experiments and data analysis will be performed by undergraduate and MS graduate students. We envision that the development of this novel approach will open the door to synthesis of many types of polymer peptides with short repeatable peptide sequences (e.g., elastin-like and RGD peptides).