HIV Entry Inhibitors

HIV-1 infection is still a major health issue, despite reduction in morbidity and mortality achieved through highly-active-antiretroviral-therapy. Treatment failure is largely caused by drug toxicity and emergence of drug-resistant strains. Inclusion of entry inhibitors in antiretroviral-based therapeutic and preventive regimens is a promising strategy for increasing both potency and the barrier to resistance.

Small-molecule inhibitors targeting the envelope glycoprotein (Env) have shown promising anti-HIV activity in pre-clinical and clinical testing.  It has been shown that compounds with increased affinity for the CD4bs show improved antiviral potency. CD4bs integrity is essential for initiation of events leading to HIV cell entry. This epitope is highly conserved across virus genetic subtypes and, thus, represents a major target for development of broadly neutralizing entry inhibitors.  Current cell-based approaches, as used by other groups, are hampered by the heavy glycosylation and conformational flexibility of Env, which renders the CD4bs only transiently exposed. Surface-plasmon-resonance (SPR) data from a recent study by Hijazi al. show that DC-SIGN (implicated in dendritic cell-mediated HIV transmission) binding to Env induces changes resulting in increased exposure of the CD4bs.  

Informed by these findings, an SPR assay which allows stable exposure of the CD4bs on ENV is being used to conduct a high-througput fragment screen, as part of a SULSA-funded collaboration with experts in the field of fragment-based drug discovery at the University of Dundee; fragment hits identified by the screen will be developed into leads as part of a drug discovery programme within the KCT medicinal chemistry laboratories.

Project Team: Dr Karolin Hijazi, Dr Iva Hopkins Navratilova, Dr Iain Greig

Funding: SULSA, Knowledge Exchange and Transfer Fund