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. 2003 Sep 16;100(19):11013-8.
doi: 10.1073/pnas.1832214100. Epub 2003 Aug 20.

A small molecule HIV-1 inhibitor that targets the HIV-1 envelope and inhibits CD4 receptor binding

Pin-Fang Lin  1 , Wade Blair, Tao Wang, Timothy Spicer, Qi Guo, Nannan Zhou, Yi-Fei Gong, H-G Heidi Wang, Ronald Rose, Gregory Yamanaka, Brett Robinson, Chang-Ben Li, Robert Fridell, Carol Deminie, Gwendeline Demers, Zheng Yang, Lisa Zadjura, Nicholas Meanwell, Richard Colonno
Affiliations

A small molecule HIV-1 inhibitor that targets the HIV-1 envelope and inhibits CD4 receptor binding

Pin-Fang Lin et al. Proc Natl Acad Sci U S A. .

Abstract

BMS-378806 is a recently discovered small molecule HIV-1 inhibitor that blocks viral entrance to cells. The compound exhibits potent inhibitory activity against a panel of R5-(virus using the CCR5 coreceptor), X4-(virus using the CXCR4 coreceptor), and R5/X4 HIV-1 laboratory and clinical isolates of the B subtype (median EC50 of 0.04 microM) in culture assays. BMS-378806 is selective for HIV-1 and inactive against HIV-2, SIV and a panel of other viruses, and exhibits no significant cytotoxicity in the 14 cell types tested (concentration for 50% reduction of cell growth, >225 microM). Mechanism of action studies demonstrated that BMS-378806 binds to gp120 and inhibits the interactions of the HIV-1 envelope protein to cellular CD4 receptors. Further confirmation that BMS-378806 targets the envelope in infected cells was obtained through the isolation of resistant variants and the mapping of resistance substitutions to the HIV-1 envelope. In particular, two substitutions, M426L and M475I, are situated in the CD4 binding pocket of gp120. Recombinant HIV-1 carrying these two substitutions demonstrated significantly reduced susceptibility to compound inhibition. BMS-378806 displays many favorable pharmacological traits, such as low protein binding, minimal human serum effect on anti-HIV-1 potency, good oral bioavailability in animal species, and a clean safety profile in initial animal toxicology studies. Together, the data show that BMS-378806 is a representative of a new class of HIV inhibitors that has the potential to become a valued addition to our current armamentarium of antiretroviral drugs.

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Figures

Fig. 1.
Fig. 1.
(A) The structure of BMS-378806. (B) Time-of-addition assay. HeLa CD4 CCR5 cells were infected with HIV-1JRFL pseudotyped virions, encoding a luciferase reporter gene. At the times indicated, either 50 nM BMS-378806 (▪) or 1 μM nevirapine (▴) (10× EC50) was added. At 4 h, the virus was removed and only the media and compounds were put back. Antiviral activity was measured after 48 h by monitoring the luciferase activity.
Fig. 2.
Fig. 2.
Mode-of-action studies on BMS-378806. (A) Inhibition of gp120/CD4 binding by BMS-378806. The dose-dependent inhibition of sCD4 binding to gp120 by BMS-378806 gave an IC50 of ≈100 nM, indicating that the compound interferes with gp120/CD4 binding. (B and C) Gel filtration analysis of [3H]BMS-378806 binding to gp120. [3H]BMS-378806 was mixed with the proteins shown and then centrifuged through a Micro BioSpin 6 gel filtration column. Protein-bound radiolabel was quantitated in the eluent by liquid scintillation counting. (B) Samples contained no protein (Blank), 500 nM gp120, 3 μM CD4, 500 nM gp120 and 3 μM CD4, or 25 μM BSA. (C) Samples contained 0–500 nM gp120. The amount of [3H]BMS-378806 bound was proportional to the amount of gp120 added.
Fig. 3.
Fig. 3.
Susceptibility histogram for subtype B clinical isolates and laboratory strains. BMS-378806 susceptibility was plotted against 42 clinical isolates and 11 laboratory strains of the HIV-1 B subtype. The x axis indicates EC50 (in μM), with the left boundary of each bar listing the lower limit and the right boundary showing the upper limit of EC50. The y axis represents the number of isolates that falls within a particular range of EC50. The median EC50 is 0.04 μM.
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Comment in

  • Blocking the docking of HIV-1.
    McKnight A, Weiss RA. McKnight A, et al. Proc Natl Acad Sci U S A. 2003 Sep 16;100(19):10581-2. doi: 10.1073/pnas.2035071100. Epub 2003 Sep 8. Proc Natl Acad Sci U S A. 2003. PMID: 12963807 Free PMC article. No abstract available.

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