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Updated: Oct 15, 2025
07:41
A Kinetic Fluorescence-based Ca2+ Mobilization Assay to Identify G Protein-coupled Receptor Agonists, Antagonists, and Allosteric Modulators
Published on: February 20, 2018
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Allosteric Modulator Leads Hiding in Plain Site: Developing Peptide and Peptidomimetics as GPCR Allosteric Modulators
Keith M Olson1, John R Traynor1,2, Andrew Alt1,3
1Department of Pharmacology and Edward F Domino Research Center, University of Michigan, Ann Arbor, MI, United States.
Frontiers in Chemistry
|October 25, 2021
Summary
Peptide-based allosteric modulators (AMs) offer advantages over traditional drugs. Peptidomimetics combine peptide benefits with improved drug-like properties for G-protein coupled receptor (GPCR) targeting.
Area of Science:
- Pharmacology
- Medicinal Chemistry
- Drug Discovery
Background:
- Allosteric modulators (AMs) of G-protein coupled receptors (GPCRs) offer improved selectivity and fewer side effects compared to orthosteric drugs.
- Peptides and proteins derived from endogenous interactions or libraries are valuable, yet underutilized, sources for identifying AM leads.
- Peptides possess high affinity and bioactivity but face challenges in metabolic stability and bioavailability.
Purpose of the Study:
- To explore novel sources and strategies for identifying peptide and peptidomimetic AMs.
- To outline methods for transforming peptide leads into more drug-like peptidomimetics.
- To critically evaluate the benefits, drawbacks, and future potential of peptidomimetic AMs in drug discovery.
Main Methods:
- Literature review of peptide and protein sources for AM lead identification.
- Analysis of strategies for peptide-to-peptidomimetic conversion.
- Critical assessment of peptidomimetic AM advantages and disadvantages.
Main Results:
- Identified endogenous peptides, protein-protein interactions, and exogenous libraries as key sources for AM leads.
- Detailed strategies for enhancing peptide drug-likeness through peptidomimetic design.
- Highlighted the potential of peptidomimetics to overcome limitations of both peptides and small molecules.
Conclusions:
- Peptidomimetics represent a promising class of therapeutics that can complement or surpass small molecules for specific GPCR targets.
- Further research into peptidomimetic development is warranted to fully exploit their therapeutic potential.
- Peptidomimetics offer a versatile approach to modulating GPCRs with enhanced specificity and reduced side effects.
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