Development of allosteric intracellular modulators attenuating chemokine receptor CCR5 signalling

C-C chemokine receptor type 5 (CCR5) plays an important role in the immune system and leads to chemotaxis of dendritic cells, hematopoietic progenitor cells, microglia, lymphocytes as well as monocytes. The receptor is most notorious as one of two co-receptors for HIV entry, but its involvement in pathologies extends to several other pathologies as well, including graft-versus-host disease, cancer metastasis and other immune diseases, potentially including cytokine storms in COVID-19. In these pathologies, the intracellular signalling following activation of the receptor triggers chemotaxis, which can be prevented by pharmaceutical receptor blockade.The only FDA approved CCR5 inhibitor Maraviroc, which binds to an extracellular site, exhibits far from ideal pharmacokinetic properties. Overall, the design of these antagonists has historically been limited by metabolic instability, CYP and hERG inhibition and poor bioavailability. In recent years the intracellular pocket overlapping with the G-protein binding site of GPCRs has emerged as an alternative druggable site. As these compounds consist of radically different chemotypes compared to traditional extracellular ligands, they represent an attractive pathway toward the development of signalling inhibitors with a different, more favourable, PK profile. Recently, we discovered a novel set of allosteric intracellular CCR5 signalling inhibitors and in the current project we describe our strategy combining molecular modelling, structural biophysics, synthetic medicinal chemistry and CCR5 activity profiling (at KU Leuven) with experimental DMPK as well as phenotypic and signalling assays (at UoE) to enable hit-to-lead and lead development of CCR5 signalling inhibitors with an unprecedented mode of action.

Keywords:Medicinal Chemistry, DMPK (Drug metabolism/pharmacokinetics), Drug Design, CCR5 antagonists, GPCR signalling inhibitors

Disciplines:Medicinal chemistry, Drug discovery and development not elsewhere classified, Pharmacokinetics