Palmitic Acid Analogs Exhibit Nanomolar Binding Affinity for the HIV-1 CD4 Receptor and Nanomolar Inhibition of gp120-to-CD4 Fusion

BACKGROUND: We recently reported that palmitic acid (PA) is a novel and efficient CD4 fusion inhibitor to HIV-1 entry and infection. In the present report, based on in silico modeling of the novel CD4 pocket that binds PA, we describe discovery of highly potent PA analogs with increased CD4 receptor binding affinities (K(d)) and gp120-to-CD4 inhibition constants (K(i)). The PA analogs were selected to satisfy Lipinski's rule of drug-likeness, increased solubility, and to avoid potential cytotoxicity. PRINCIPAL FINDINGS: PA analog 2-bromopalmitate (2-BP) was most efficacious with K(d) ∼74 nM and K(i) ∼122 nM, ascorbyl palmitate (6-AP) exhibited slightly higher K(d) ∼140 nM and K(i) ∼354 nM, and sucrose palmitate (SP) was least efficacious binding to CD4 with K(d) ∼364 nM and inhibiting gp120-to-CD4 binding with K(i) ∼1486 nM. Importantly, PA and its analogs specifically bound to the CD4 receptor with the one to one stoichiometry. SIGNIFICANCE: Considering observed differences between K(i) and K(d) values indicates clear and rational direction for improving inhibition efficacy to HIV-1 entry and infection. Taken together this report introduces a novel class of natural small molecules fusion inhibitors with nanomolar efficacy of CD4 receptor binding and inhibition of HIV-1 entry.