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.


RESULTS
PA analog 2-bromopalmitate (2-BP) was most efficacious with K(d) approximately 74 nM and K(i) approximately 122 nM, ascorbyl palmitate (6-AP) exhibited slightly higher K(d) approximately 140 nM and K(i) approximately 354 nM, and sucrose palmitate (SP) was least efficacious binding to CD4 with K(d) approximately 364 nM and inhibiting gp120-to-CD4 binding with K(i) approximately 1486 nM. Importantly, PA and its analogs specifically bound to the CD4 receptor with the one to one stoichiometry.


CONCLUSIONS
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.
Paskaleva
Elena E
EE
Center for Immunology and Microbial Disease, Albany Medical College, Albany, New York, USA.
Xue
Jing
J
Lee
David Y-W
DY
Shekhtman
Alexander
A
Canki
Mario
M
D015704:CD4 Antigens / Q000737:chemistry / Q000378:metabolism*; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000378:metabolism*; D023581:HIV Fusion Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D015497:HIV-1; D008958:Models, Molecular; D019308:Palmitic Acid / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D011487:Protein Conformation
D015704:CD4 Antigens; D015699:HIV Envelope Protein gp120; D023581:HIV Fusion Inhibitors; D019308:Palmitic Acid