Wandering beyond small molecules: peptides as allosteric protein modulators

Development of G Protein Peptidomimetics to Stabilize Active State G Protein-Coupled Receptors

“…Since the four last C-terminal amino acids of the key helix were suggested to be crucial residues for interaction with the receptor, point mutations were introduced in the lead peptide, SBL-CM-12. Unexpectedly, the substitution of the penultimate leucine (L 393 ) by a cyclohexylalanine residue (Cha), to give SBL-CM-51, resulted in an extraordinary affinity increase of the agonist for the stabilized receptor (Figure 2), comparable to Cb80, a well-studied allosteric modulator of β2AR [2,5,6].…”

“…Although Cbs have been recognized to be of extreme value in the search for novel therapeutics and in structural biology, the significant costs and time required for the discovery and development of specific Cbs has sparked our interest to develop a new, potentially more generic, technology to stabilize GPCRs to use in drug discovery. To overcome the drawbacks associated to Cbs, we developed an approach to mimic the G protein, an endogenous allosteric modulator of GPCRs, via a peptide mimicry approach [4]. Based on a rational design strategy a set of peptidomimetic ligands, stabilizing the active state conformation of the β2 adrenergic receptor (β2AR), was developed [5,6].…”

“…To overcome the drawbacks associated to Cbs, we developed an approach to mimic the G protein, an endogenous allosteric modulator of GPCRs, via a peptide mimicry approach [4]. Based on a rational design strategy a set of peptidomimetic ligands, stabilizing the active state conformation of the β2 adrenergic receptor (β2AR), was developed [5,6]. Therefore, a previously identified epitope of the Gs protein, the α5 helix (F 376 NDCRDIIQRMHLRQYELL 394 ), that is responsible for most interaction with the β2AR [7], was chosen as template to design the peptidomimetics (Figure 1).…”

Call for Papers for a Virtual Special Issue on GPCR Signaling

“…8 Other peptide-based allosteric modulators have been discovered through screening efforts or by the mimicry of endogenous peptides or protein domains. 9 The above reflects that there is a scientific playground available to further exploit GPCRs as allosteric microprocessors. 6 Recent years have seen the emergence of a new class of GPCR ligands that combine the features of both of these classes; the ligand binds at an allosteric site on the receptor while at the same time exerting pathway-specific effects on receptor signaling.…”

“…So far, one peptide-based allosteric modulator, etelcalcetide (Parsabiv), has been approved for clinical use against secondary hyperparathyroidism in patients with chronic kidney disease . Other peptide-based allosteric modulators have been discovered through screening efforts or by the mimicry of endogenous peptides or protein domains . The above reflects that there is a scientific playground available to further exploit GPCRs as allosteric microprocessors …”