Genetically-encoded (GE) libraries of proteins are a major source of discovery of “biological” drugs generating a $200 billion in sales in 2017. In Chemistry, GE libraries of 109 polypeptides made of 20 natural amino acids represent an orthogonal “raw material for organic synthesis”. Like canonical feedstock—petroleum-derived starting materials—GE-peptides are readily available but have limited structural diversity and practical utility. Like petroleum, peptides can be transformed to useful structures through multi-step organic synthesis. Departing from traditional diversification of low-functionality, achiral starting materials, we employ “late stage” modification of polar, functionality-rich, chiral molecules in water. Each transformation, when optimized, can routinely convert billion starting materials to billion products at once. Drug discovery for “undruggable targets” necessitates new chemical scaffolds of large surface area that do not break down in aggressive proteolytic environment encountered in serum or GI-tract. Using GE-libraries of peptides as a starting material for multi-step organic synthesis, we produce GE-libraries of novel bicyclic architectures that exhibit remarkable stability to proteolytic degradation. Their stability, depleted ground state conformational ensemble and amphiphilic nature makes then lucrative candidates for development of cell permeable modalitieis (albeit their barrier penetration efficiency is still under investigation). In this talk, I will describe the steps for synthesis and characterization of bicyclic architectures and bicyclic GE-encoded librairies. I will then share our sucesss in de novo discovery campaigns for bicyclic antagonists of protein NODAL. This extrecellular morphogen is an emerging target in oncology due to its role in controlling the plasticity of stem cells in the microenvironment of melanoma as well as ovarian, breast and pancreatic tumors.

Novel genetically encoded bicyclic architectures: Synthesis, pharmacology, and the success stories in lead discovery

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.