Figure 2. Azapeptide and azasulfurylpeptides induce turns by electronic interactions

Innovating methods for conceiving peptide and peptidomimetic drug candidates in collaborations with biochemists, pharmacologists and physicians, we have significant interest in allosteric modulators (Figure 4). By binding receptors at sites spatially distinct from the native ligand “orthosteric” binding site, allosteric ligands may reduce side effects, due to their potential to act selectivity on a subset of signaling pathways activated by the receptor without disruption of normal rhythms of endogenous ligand release and action.  In collaboration with Professor Sylvain Chemtob (Pharmacology), we are pioneering the design of allosteric modulators of membrane proteins based on their own structures.

For example, by utilizing the protein coupled receptors, we identified peptide leads that modulate the prostaglangin-F2α and vasopressin receptors (FP and V2) by allosteric mechanisms of action. Our methods led to the conception of the peptide PDC31 and small molecule peptidomimetics which delay labour for >24 hours in induced mice. Pursuing drugs to prevent premature birth, an unmet-medical need with the highest per patient cost, PDC31 is ready for phase II clinical trials, after demonstrating to be safe in reducing intrauterine pressure and pain associated with excessive uterine contractility in a phase Ib study of women patients with primary dysmenorrhea. Ongoing study of indolizidinone and related azapeptide peptide mimics of PDC31 has revealed allosteric mechanisms of action that implicate respectively negative and positive modulation of bias signalling on pathways leading to microtubule formation and FP expression in the presence of prostaglandin F2α.extra-cellular loop regions of G

Extending this method to cytokine receptors, we have identified peptides that modulate interleukin receptors. For example, the peptide 101.10A was conceived based on a loop of the accessory protein of the interleukin-1 receptor and shown to negatively modulate the latter by an allosteric mechanism featuring biased signalling. In various studies, 101.10A has exhibited promising anti-inflammatory activity and therapeutic potential for a variety of indications including preterm birth and ischemic retinopathy.  With 101.10A as lead candidate, we are studying methods to convert this peptide into peptidomimetics with improved potency and pharmacokinetic properties.

Modulators are also being studied to regulate the cluster of differentiation 36 receptor (CD36) which is expressed on macrophage plasma membranes and serves key roles in recognition and phagocytosis as a scavenger of multiple-ligands including oxidized long chain fatty acids and oxidized azapeptides are being pursued to ultimately find cures for age-related macular degeneration, the leading cause of adult blindness, and atherosclerosis, the main underlying cause of ischemic heart disease and related cardiovascular complications including acute myocardial infarction and stroke. In collaboration with Professor Huy Ong (Pharmacy), azapeptides have been identified that bind CD36 selectively, diminish oxidized lipid uptake, slow phagocytosis of photoreceptor disks, attenuate production of reactive oxygen species and inflammatory mediators, block hyper-proliferation of choroidal endothelial cells and curb angiogenesis. The azacyclopeptides have distinguished themselves as a next generation of first-in-class candidates because they exhibit unprecedented CD36 binding affinity and activity suppressing nitric oxide production, and pro-inflammatory cytokine and chemokine release induced by Toll-like receptor agonists. low density lipoproteins. Targeting CD36 to regulate macrophage-driven inflammation, selective linear and cyclic

Azapeptides &