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.
Highlights
PEPTIDE AND PEPTIDOMIMETICS ARE APPEALING SOURCES FOR ALLOSTERIC MODULATOR DRUG DISCOVERYG-protein coupled receptors are transmembrane signaling proteins targeted by an estimated ∼35% of clinically approved drugs that usually bind to the same conserved “orthosteric site” as the endogenous agonist (Sriram and Insel, 2018) (Figure 1)
Peptides and proteins are a bountiful source for identifying Allosteric modulators (AMs) leads, including those derived from 1) endogenous AM proteins and protein fragments, 2) endogenous bitopic ligands, 3) intramolecular contacts, 4) endogenous protein-protein interactions, 5) nature-derived libraries, 6) synthetic exogenous libraries, and 7) directed evolution (Figure 2)
AM leads from these sources can offer distinct advantages over small molecule HTS hits, including having an established putative binding site with rich structural and pharmacophore information
Summary
PEPTIDE AND PEPTIDOMIMETICS ARE APPEALING SOURCES FOR ALLOSTERIC MODULATOR DRUG DISCOVERY. GPCRs possess discrete "allosteric sites’ whereby ligands, including endogenous peptides and proteins, can modulate the activity of the orthosteric agonist(s) (Figures 1C,D; Table 1). Biased AMs are attractive drug targets to precisely hone and modulate endogenous signals (Slosky et al, 2021) Another way to improve the molecule’s biological specificity is by identifying probe-dependent AMs, which selectively modulate some agonists, but not others (Figure 4B, middle left; Table 1). Dynorphin A (1-13) (6)—the orthosteric agonist at the kappa-opioid receptor (KOR)—is a NAM at the M2 receptor that increases the affinity of M2 antagonist [3H]-methylscopolamine (Hu and el-Fakahany, 1993) It is unclear if these two examples are the exception or the rule; future work looking at known endogenous ligands at “off-target” receptors may reveal more endogenous AMs and drug discovery leads. G-proteins are quintessential PAMs binding to the intracellular receptor face to stabilize a “high-affinity” Ra conformation and increase
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