Allosteric Modulator Leads Hiding in Plain Site: Developing Peptide and Peptidomimetics as GPCR Allosteric Modulators

Abstract

Allosteric modulators (AMs) of G-protein coupled receptors (GPCRs) are desirable drug targets because they can produce fewer on-target side effects, improved selectivity, and better biological specificity (e.g., biased signaling or probe dependence) than orthosteric drugs. An underappreciated source for identifying AM leads are peptides and proteins—many of which were evolutionarily selected as AMs—derived from endogenous protein-protein interactions (e.g., transducer/accessory proteins), intramolecular receptor contacts (e.g., pepducins or extracellular domains), endogenous peptides, and exogenous libraries (e.g., nanobodies or conotoxins). Peptides offer distinct advantages over small molecules, including high affinity, good tolerability, and good bioactivity, and specific disadvantages, including relatively poor metabolic stability and bioavailability. Peptidomimetics are molecules that combine the advantages of both peptides and small molecules by mimicking the peptide’s chemical features responsible for bioactivity while improving its druggability. This review 1) discusses sources and strategies to identify peptide/peptidomimetic AMs, 2) overviews strategies to convert a peptide lead into more drug-like “peptidomimetic,” and 3) critically analyzes the advantages, disadvantages, and future directions of peptidomimetic AMs. While small molecules will and should play a vital role in AM drug discovery, peptidomimetics can complement and even exceed the advantages of small molecules, depending on the target, site, lead, and associated factors.

Allosteric Regulation of G-Protein-Coupled Receptors: From Diversity of Molecular Mechanisms to Multiple Allosteric Sites and Their Ligands

“…Along with highly specialized components of GPCR signaling, endogenous allosteric regulators of GPCR include some classes of antibodies produced against extracellular regions of receptors, small proteins, oligopeptides, steroids, fatty acids, amino acids, and even simple ions [91,[94][95][96][97][98][99][100]. Some allosteric regulators specifically affect a particular receptor or closely related GPCRs, while others are non-specific and affect the activity of a large number of GPCRs belonging to different families.…”

Biased, Bitopic, Opioid–Adrenergic Tethered Compounds May Improve Specificity, Lower Dosage and Enhance Agonist or Antagonist Function with Reduced Risk of Tolerance and Addiction

“…Figures 6 and 7 provide examples of possible heterobitopic opioid-adrenergic agonist compounds utilizing morphine or methionine-enkephalin as the opioid agonists and epinephrine as the adrenergic agonist. While peptide opioids, such as the enkephalins, may not themselves be useful as therapeutics, they have been used successfully as components of bitopic compounds [107,141] for investigative purposes, and more stable versions, such as D-Ala2, N-MePhe4, Gly-ol]enkephalin (DAMGO), may provide better medicinal chemistry options.…”

Membrane Hormone Receptors and Their Signaling Pathways as Targets for Endocrine Disruptors

“…The human genome encodes roughly 350 GPCRs, and around half of all modern medicinal drugs target them. Indeed, GPCRs are prominent targets for pharmaceuticals acting either at their orthosteric or allosteric sites [ 36 ]. The existence of allosteric ligands has enriched how the functions of GPCRs can be manipulated with potential new drugs.…”