Research

Closing two doors of viral entry: Intramolecular combination of a coreceptor- and fusion inhibitor of HIV-1

Erhard Kopetzki^1* , Andreas Jekle^2* , Changhua Ji² , Eileen Rao² , Jun Zhang² , Stephan Fischer¹ , Nick Cammack² , Surya Sankuratri² and Gabrielle Heilek²

¹  Pharmaceuticals Division, Roche Penzberg, Penzberg, Germany

²  Virology Diseases Area, Roche Palo Alto, 3431 Hillview Ave., Palo Alto, CA, USA

author email corresponding author email* Contributed equally

Virology Journal 2008, 5:56doi:10.1186/1743-422X-5-56

Published:	1 May 2008

Abstract

We describe a novel strategy in which two inhibitors of HIV viral entry were incorporated into a single molecule. This bifunctional fusion inhibitor consists of an antibody blocking the binding of HIV to its co-receptor CCR5, and a covalently linked peptide which blocks envelope mediated virus-cell fusion. This novel bifunctional molecule is highly active on CCR5- and X4-tropic viruses in a single cycle assay and a reporter cell line with IC₅₀ values of 0.03–0.05 nM. We demonstrated that both inhibitors contribute to the antiviral activity. In the natural host peripheral blood mononuclear cells (PBMC) the inhibition of CXCR4-tropic viruses is dependant on the co-expression of CCR5 and CXCR4 receptors. This bifunctional inhibitor may offer potential for improved pharmacokinetic parameters for a fusion inhibitor in humans and the combination of two active antiviral agents in one molecule may provide better durability in controlling the emergence of resistant viruses.