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

• Main Authors: Cammack Nick, Fischer Stephan, Zhang Jun, Rao Eileen, Ji Changhua, Jekle Andreas, Kopetzki Erhard, Sankuratri Surya, Heilek Gabrielle
• Format: Article
• Language: English
• Published: BMC 2008-05-01
• Series: Virology Journal
• Online Access: http://www.virologyj.com/content/5/1/56
• ISSN: 1743-422X

<p>Abstract</p> <p>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 IC₅₀values 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.</p>