The G protein-coupled receptor (GPCR) signaling pathways provide therapeutic opportunities in Alzheimer’s, metabolic, cardiovascular, neurologic, and oncologic diseases. However, GPCR-targeted therapeutics can be ineffective when multiple receptors with redundant or overlapping functions drive diseases pathogenesis or progression, or mutationally activated Gα subunits drive disease independently of GPCRs. Accordingly, pharmacological inhibitors that directly target Gα or Gβγ subunits are emerging as important leads for drug discovery. Two closely related cyclic depsipeptides, YM-254890 (YM) and FR900359 (FR), isolated from Chromobacterium sp. QS3666 and Ardisia Crenata respectively, potently and selectively inhibit signaling by Gq/11 class G protein α subunit by trapping them in their inactive GDP-bound states. This class of natural products could serve as a wonderful tool to selectively regulate the signalling pathways and give us a better understanding of the pathways. We hope to develop a panel of synthetic, bioavailable inhibitors, each of which targets selected Gα subunits as probes and therapeutic leads. While solid-phase peptide synthesis can be used to generate a series of analogs for screening, we eye animal tests that require larger amounts of the compounds. This requires a scalable solution-phase synthesis. Along these lines, we have successfully prepared multiple simplified analogs used to probe the GPCR signaling pathway. While these analogs are not as potent as YM or FR, they do selectively bind to Gαq. Currently, we are developing the synthesis of a new family of analogs that retain more of the functionality found in the natural products. The analogs have the intact “bottom bridge” moiety that was found to bind with Gαq in crystal structures of the YM- Gαq complex and such change is expected to improve the potency of the analogs. The synthetic gains made with this new approach will be discussed.

Devising a scalable solution-phase synthesis of peptidomimetics to probe the G protein-coupled receptor signaling pathway

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.