Peptide backbone modifications to enhance and study protein folding and binding

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PROJECT SUMMARY/ABSTRACT The objective in this application is to obtain supplemental funding for an instrument that is vital to carry out the research objectives of NIGMS grant R35 GM142883. The supported research seeks to exploit stereochemi- cally robust thioamides, at any point in the peptide sequence, as biophysical probes to address current barriers in peptide synthesis, folding, and drug discovery. The approach in this proposal is to protect the thioamide, in analogy to the protection of the functional groups of amino acid side chains, in order to preserve the thioamide moiety during peptide elongation. The rationale for this approach is that thioamide protection can be easily in- cluded within the standard SPPS work-flow to enable novel applications in peptide synthesis, backbone modifi- cation, and protein-drug interactions. The research plans of this project will exploit thioamides to probe protein folding and site-selective insertion other chemistries. Thioamides will be employed in previously uncharted se- quence space to address fundamental questions in protein folding. We will also develop methods to transform thioamides into functional groups that will unlock new constrained peptide scaffolds. Peptides with persistent structure hold tremendous promise as therapeutics to bridge the performance gap between small molecules and biologics. Finally, this work will identify strategies to interrogate and target therapeutically relevant protein- protein interfaces. Interactions between hydrogen bond donors and acceptors of the main-chain of a peptide and a protein binding target are underutilized in drug design. Based on structural bioinformatics, new strategies to identify underutilized interactions at protein-protein interfaces (PPIs) will assist in the design of more potent inhibitors. Other work will also develop new tools to interrogate PPIs for which very little structural information may be available to inform future experimental design. The proposed research is innovative because it repre- sents a substantive departure from the status quo by developing and employing new methods to preserve thio- amide stability, which promises to unlock new research horizons. The contribution is significant because it is expected to have broad importance in both the study of protein folding and the development of bioactive mole- cules. The instrumentation described in this application will support all of the activities outlined above and is necessary for their completion.