Anthony Silvestri
Head of Chemistry, Unnatural Products
Tales of macrocycle medchem: leveraging peptide discovery and optimization technologies
Abstract
Peptide DNA-encoded libraries (DEL) benefit from superior chemical control relative to ribosome display technologies and can be tailored to yield de novo peptide ligands with favorable physicochemical properties as well as high target affinities. This presentation will discuss a DEL design and workflow that yielded a neutral cyclic peptide with nM affinity to MDM2 and juxtapose it against a separate internal optimization effort of a rationally designed chemical series also targeting MDM2. We took a non-traditional medicinal chemistry approach to lead series optimization and, by leveraging our in-house parallel synthetic and computational platform, were able to make large jumps through scaffold and pharmacophore space. This allowed us to imbue the lead series with the high target affinity and small-molecule-like passive permeability necessary to achieve nM cell activity.
Bio
Tony was born and raised in Southern California and earned a B.S. in Chemistry from Colorado State University. He went on to complete a Ph.D. in Organic Chemistry at Scripps Research with Phil Dawson, where he developed novel organometallic peptide ligation and macrocyclization techniques. Since joining Unnatural Products Inc. in 2019—shortly after its founding—Tony has led the chemical development side of the company's peptide macrocycle optimization platform.