Project Grant K99GM157551

This Project Grant award from the National Institute of General Medical Sciences (NIGMS) Biomedical Research and Research Training Program (CFDA 93.859) provides $124,767 to develop and test a pipeline for designing "enfold" proteins that can conditionally release cell-penetrating peptides (CPPs) and antimicrobial peptides (AMPs) as therapeutic agents. The project aims to enhance understanding of protein structure-function relationships by engineering de novo proteins that can "unmask" the target peptides in response to specific environmental or disease cues, such as protease cleavage or changes in pH. This will address challenges of poor tissue specificity and stability faced by these promising therapeutic peptides. The research will evaluate different protein design approaches, including parametric design and generative models, and utilize molecular dynamics simulations to optimize the enfold structures. The initial proof-of-concept work in Aims 1 and 2 will characterize the folding, stability, and biological activity of the enfold constructs. Aim 3 will then expand the functionality by incorporating receptor-targeting and endosomal escape mechanisms to improve delivery specificity. This project is being conducted by the Regents of the University of California, San Francisco, a leading academic medical center and research institution, from January 1, 2025 to December 31, 2026.