Developed a robust peptide therapeutics discovery platform based on ~500 venom peptide scaffolds, integrating phage and yeast surface display technologies. Libraries were designed using machine learning (ML) models that predict key residues for peptide foldability. An ML-enabled, rapid, and cost-effective affinity maturation workflow accelerates lead optimization, enabling the efficient identification of potent and stable peptide candidates against diverse therapeutic targets.

Peptide-HLA (pHLA)-directed T cell engagers can target otherwise inaccessible intracellular viral and tumor-associated antigens, but require both high affinity and high specificity for safe and effective clinical use. We present an integrated high-throughput yeast-based platform to rapidly discover, engineer, and de-risk fully human soluble T cell receptors (TCRs) and TCR-mimetic (TCRm) antibodies with high affinity and high selectivity, enabling the development of potent and specific pHLA-targeting therapeutics.

Peripherally administered enzyme replacement therapies (ERTs) to address lysosomal storage disorders have been limited in their ability to target the CNS. Such ERTs are also limited by their instability in serum. To generate enzymes with sustained activity in serum we developed a novel enzyme engineering strategy utilizing both yeast surface display and secretion technologies. We show durable activity with a POC enzyme in serum for many days. By fusing engineered enzymes to a TfR transport vehicle (TV) for delivery across the BBB we also show improved substrate reduction in the brains of a relevant mouse disease model.

We developed a chemical biology platform to engineer protein-small molecule hybrids. Combinatorial libraries of protein variants are displayed on yeast, chemically conjugated in a site-specific manner with pharmacophore, and sorted for strong, selective binders. We engineered hybrids with superior enzymatic inhibitory potency and selectivity relative to either protein or pharmacophore alone. Hybrids were engineered with different conjugation sites, linkers, protein sequences, and targets, which demonstrates the breadth of the approach.