Abstract

The chemokine G-protein coupled receptor CCR5 is used as an entry gate by CCR5-tropic (R5) and dual- or CCR5/CXCR4-tropic (R5/X4) strains of HIV to enter the human host cells. Thus, CCR5 antagonists (i.e. maraviroc) have proven to be clinically effective by preventing the interaction between the viral gp120 and CCR5 and thus impeding viral entry into host cells. However, the emergence of HIV strains resistant to CCR5 antagonists have been reported in vitro and in vivo, where the virus has adapted to enter the cells via antagonist-bound CCR5. An alternative strategy that should obviate this mode of viral resistance would entail ablation of the CCR5 portal for HIV entry from the cell surface through agonist-induced receptor internalization. While this protective effect has been clearly demonstrated with natural CCR5 ligands, the chemoattractant properties of these chemokines have precluded them from further consideration in terms of drug development. Thus we sought to explore the possibility of developing novel small molecules and selective CCR5 agonists devoid of eliciting chemotaxis. Indeed the CCR5 agonists described herein were found to induce profound down modulation of the CCR5 (and not the CXCR4) receptor from the cell surface, and its sustained sequestration in the intracellular compartment, without inducing chemotaxis in vitro. The bioactivity profile of these novel CCR5 agonists is exemplified by the compound ESN-196 that potently inhibits HIV-1 infection in human PBMCs and macrophages in vitro with potencies comparable to that of maraviroc, and moreover demonstrates full activity against a maraviroc-resistant HIV-1 RU570 strain.