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.
Highlights
Enveloped viruses, such as human immunodeficiency virus type 1 (HIV-1), utilize membrane bound fusion proteins to mediate attachment and entry into specific target host cells
In an attempt to improve the in vivo pharmacokinetic properties a prototypic recombinant antibody-FI fusion protein was generated, in which two T-2635 fusion inhibitors were covalently linked to the C-terminal ends of the two heavy chains of a monoclonal antibody against the insulin-like growth factor-I receptor (IGF-IR)
We suggest that anchoring of the CCR5mAb to the CCR5 receptor is a pre-requisite for bifunctional fusion inhibitor (BFFI) activity against X4 viruses
Summary
Enveloped viruses, such as HIV-1, utilize membrane bound fusion proteins to mediate attachment and entry into specific target host cells. The binding to the co-receptor triggers a conformational change of the viral envelope proteins and allows for the smaller envelope subunit gp to be inserted into the host membrane. This is followed by condensation of two helical regions within gp, resulting in formation of a six helix bundle, facilitating close contact of the viral and host membranes and followed by fusion of the viral envelope with the cell membrane. Viruses using CCR5 are defined as R5 tropic, viruses using CXCR4 as X4-tropic and viruses being able to use both as dual or mixed tropic [4]
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