HIV has evolved a target cell entry strategy that utilizes GCPRs CCR5 or CXCR4 as obligatory co-receptors. This process begins with  recognition of the HIV viral envelope glycoprotein gp120 with host cell CD4 followed by binding of this CD4-gp120 complex with chemokine receptors CCR5 or CXCR4. In CCR5, the N-terminus (Nt) and extracellular loops, particularly the second extracellular loop (ECL2), play critical roles in mediating HIV entry. While the interactions between sulfated CCR5 Nt and gp120 has been described at the atomic level, little is known about how ECL2 contacts gp120. To gain insight, we employed a medicinal chemistry approach to delineate the regions on ECL2 responsible for gp120 binding. Results from HIV neutralization assays and NMR studies that unveiled ECL2 derived peptides as inhibitors of not only CCR5 using HIV-1 strains but also CXCR4 using strains will be presented. Together they provide evidence that a common structural motif presented by CCR5 ECL2 can mediate viral infectivity, and inhibition, of R5 and X4 strains.

Insights into interactions of the GCPR CCR5 with the HIV viral envelope

243rd National Meeting (2012)

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