MK-8591 (4'-Ethynyl-2-Fluoro-2'-Deoxyadenosine) Exhibits Potent Activity against HIV-2 Isolates and Drug-Resistant HIV-2 Mutants in Culture

Abstract

There is a pressing need to identify more effective antiretroviral drugs for HIV-2 treatment. Here, we show that the investigational compound MK-8591 (4'-ethynyl-2-fluoro-2'-deoxyadenosine [EFdA]) is highly active against group A and B isolates of HIV-2; 50% effective concentrations [EC₅₀] for HIV-2 were, on average, 4.8-fold lower than those observed for HIV-1. MK-8591 also retains potent activity against multinucleoside-resistant HIV-2 mutants (EC₅₀ ≤ 11 nM). These data suggest that MK-8591 may have antiviral activity in HIV-2-infected individuals.

Keywords: 4′-ethynyl-2-fluoro-2′-deoxyadenosine; EFdA; HIV-1; HIV-2; MK-8591; NRTI; antiretroviral therapy; drug resistance.

FIG 1

Chemical structures of 2′-deoxyadenosine (dA), MK-8591 (4′-ethynyl-2-fluoro-2′-deoxyadenosine [EFdA]), and BMS-986001 (2′,3′-didehydro-3′-deoxy-4′-ethynyl-thymidine; also known as festinavir, censavudine, 4′-ethynyl stavudine, 4′-ethynyl-d4T, and OBP-601).

FIG 2

Antiviral activity of MK-8591 against HIV-1_NL4-3 and HIV-2_ROD9. (A) Representative data from a single run of the drug susceptibility assay in MAGIC-5A cells (single-cycle assay) (32). Data points are the percentages of β-galactosidase activity in MK-8591-treated cultures relative to that in solvent-only controls. Each point represents the mean of results from two cultures that were maintained in parallel. Error bars represent ±1 standard deviations and when not visible are smaller than the symbols. The curves were generated using a sigmoidal regression equation (GraphPad Prism 6.0 software). (B) EC₅₀s from 10 independent runs of the single-cycle assay in which HIV-1_NL4-3 and HIV-2_ROD9 were tested head-to-head. Diagonal lines indicate the paired results from a single assay run.

FIG 3

Susceptibility of HIV-1 and HIV-2 isolates from ART-naive individuals to MK-8591. (A) EC₅₀s for 10 HIV-1 and 14 HIV-2 strains. Bars are the means of results from three or more independent single-cycle assays. Error bars are +1 standard deviation. Group/subtype assignments are shown in parentheses. The HIV-2 intergroup recombinant 7312A encodes a group B pol gene (57). (B) Summary for the isolates shown in panel A. Each point represents the mean EC₅₀ for a single isolate. (C) Comparison of EC₅₀s for group A and B isolates of HIV-2. In panels B and C, the horizontal lines are the means from the respective data groups; P values are the results of Welch's t tests.