Elsevier

Drug Discovery Today

Volume 21, Issue 1, January 2016, Pages 90-96
Drug Discovery Today

Review
Gene-to-screen
Can residence time offer a useful strategy to target agonist drugs for sustained GPCR responses?

https://doi.org/10.1016/j.drudis.2015.07.015Get rights and content
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open access

Highlights

  • G-protein-coupled receptors can signal in a sustained manner.

  • We propose that agonist residence time is important for sustained responses.

  • A long duration of action could be targeted by optimizing binding kinetics.

  • Optimizing agonist residence could offer a valuable drug discovery strategy.

Residence time describes the how long a ligand is bound to its target, and is attracting interest in drug discovery as a potential means of improving clinical efficacy by increasing target coverage. This concept, as originally applied to antagonists, is more complicated for G-protein-coupled receptor (GPCR) agonists because of the transiency of receptor responses (via desensitization and internalization). However, in some cases sustained GPCR agonist responses have been observed, with evidence consistent with a role for slow binding kinetics. We propose a model to explain our understanding of how residence time and rebinding might influence sustained signaling by internalized receptors. We also highlight the anticipated benefit for drug discovery of fully understanding and exploiting these phenomena to target desirable receptor response profiles selectively.

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