Bifunctional Chimera That Coordinately Targets Human Immunodeficiency Virus 1 Envelope gp120 and the Host-Cell CCR5 Coreceptor at the Virus–Cell Interface

To address the urgent
need for new agents to reduce the global
occurrence and spread of AIDS, we investigated the underlying hypothesis
that antagonists of the HIV-1 envelope (Env) gp120 protein and the
host-cell coreceptor (CoR) protein can be covalently joined into bifunctional
synergistic combinations with improved antiviral capabilities. A synthetic
protocol was established to covalently combine a CCR5 small-molecule
antagonist and a gp120 peptide triazole antagonist to form the bifunctional
chimera. Importantly, the chimeric inhibitor preserved the specific
targeting properties of the two separate chimera components and, at
the same time, exhibited low to subnanomolar potencies in inhibiting
cell infection by different pseudoviruses, which were substantially
greater than those of a noncovalent mixture of the individual components.
The results demonstrate that targeting the virus–cell interface
with a single molecule can result in improved potencies and also the
introduction of new phenotypes to the chimeric inhibitor, such as
the irreversible inactivation of HIV-1.