Genetically-Encoded (GE) Chemistry: Late-stage reshaping of GE-landscapes — ASN Events

Genetically-Encoded (GE) Chemistry: Late-stage reshaping of GE-landscapes (#102)

Ratmir Derda 1
  1. University of Alberta, Edmonton, AB, Canada

Genetically-encoded libraries (GEL) and DNA-encoded libraries (DEL) are increasingly used as tools that guide discovery of ligands or drug leads and solve general problems in molecular recognition. Phage display—the platform that inspired modern GEL and DEL—is one of a few technologies that permit discovery of molecular interactions in a complex milieu on the surface of cells and inside living organisms. Chemical upgrade of phage display platform have been practiced by our group and others over a decade [1-5]; such upgraded libraries enable de novo discovery of ligands in vitro and in live organisms in vivo [4-5]. While de novo discovery from chemically-modified peptide libraries is attractive, is does not utilize prior knowledge of receptor-ligand interactions. However, a knowledge of natural peptides that bind to a protein is a powerful starting point for discovery. This talk will describe late-stage remodeling of the space of disulfide peptides selected via phage display into mono and bicyclic motifs displayed on phage. The enabling technology for such late-state remodeling is a C2-symmetric linchpin that allows divergent mono and bi-cyclization as well as installation of desired warheads atop cyclic architectures. There have been tens of thousands of completed disulfide selection campaigns in the history of humanity. Space of linear and disulfide peptide segments as well as peptide loops that interact with natural targets has also been mapped. All of such chemical spaces, in principle, can serve as a starting point for late-stage reshaping and discovery of advanced peptide-derived ligands.   

  1. Ratmir Derda el al., Curr. Op. Chem. Biol., 2019, 50, 128.
  2. Arunika Ekanayake et al., J. Am. Chem. Soc., 2021, 143, 14, 5497.
  3. Jeffrey Y.-K. Wong et al., Chem. Sci., 2021,12, 9694.
  4. Mirat Sojitra et al., Nat. Chem. Biol. 2021, 17, 806.
  5. Chih-Lan Lin et al., Nat. Comm. 2023, 14, 5237.
#AusPeptide2023