Genetically-encoded (GE) libraries revolutionized discovery of “biological” drugs that generat over $200 billion in sales annually. Bridging the power of genetic or DNA encoding with traditional areas of chemistry, we employ natural, GE libraries of 109 polypeptides made of 20 natural amino acids as a “raw material for organic synthesis”. Like canonical feedstock—petroleum-derived starting materials—GE-peptides are readily available and can be transformed to useful structures through multi-step organic synthesis. “Late stage” modification of these GE libraries in water, when optimized, can routinely convert million to billion diverse starting materials to products at once. My talk will focus on recent developments from our group the use of GE-libraries of peptides as a starting material for multi-step organic synthesis to yield GE-libraries of novel macrocylic architectures with unnatural pharmacophores that serve as promising starting point for drug discovery. These libraires are ideally poised for fragment based discovery and evaluation of specificity and potency of the existing fragments / pharmacophores [1-4].
1. Ratmir Derda* and Simon Ng “Genetically-Encoded Fragment-Based Discovery (GE-FBD)”, Current Opinion in Chemical Biology, 2019, 50, 128. 2. Arunika Ekanayake, et al., “Genetically Encoded Fragment-Based Discovery (GE-FBD) from Phage-Displayed Macrocyclic Libraries with Genetically-Encoded Unnatural Pharmacophores“ J. Am. Chem. Soc., 2021, 143, 14, 5497. 3. Sojitra, et al., “Genetically encoded multivalent liquid glycan array displayed on M13 bacteriophage“, Nature Chemical Biology 2021, 17, 806. 4. Wong, et al., “Genetically-Encoded Discovery of Proteolytically Stable Bicyclic Inhibitors of Morphogen NODAL“, Chem. Sci., 2021,12, 9694.
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