2′-Deoxy-4′-C-ethynyl-2-fluoroadenosine: A nucleoside reverse transcriptase inhibitor with highly potent activity against all HIV-1 strains, favorable toxic profiles and stability in plasma

Abstract

A working hypothesis to solve the critical problems of existing HAART was proposed. The study based on the hypothesis proved the validity of the hypothesis and resulted in the development of 2'-deoxy-4'-C-ethynyl-2-fluoro-adenosine (4'Ed2FA), a nucleoside reverse transcriptase inhibitor (NRTI) with highly potent activity against all HIV-1 strains, very favourable toxic profiles, and stability in plasma.

Mechanism of Inhibition of HIV-1 Reverse Transcriptase by 4′-Ethynyl-2-fluoro-2′-deoxyadenosine Triphosphate, a Translocation-defective Reverse Transcriptase Inhibitor

“…PBMCs with an EC 50 of 50 pM (Table 2), consistent with previously published data obtained using T-cell lines (12,13), and data published after completion of this work (23). The antiviral potency of EFdA is at least 4 orders of magnitude greater than the clinically used adenine nucleotide analog tenofovir and over 400-fold greater than that of AZT when assessed under the same conditions (Table 2).…”

“…Deoxynucleotide triphosphates and dideoxynucleotide triphosphates were purchased from Fermentas (Glen Burnie, MD). EFdA was synthesized by Yamasa Corp. (Chiba, Japan) as described previously (12). Using EFdA as the starting material, the triphosphate form, EFdA-TP, was synthesized by TriLink BioTechnologies (San Diego, CA).…”

“…Despite their high anti-HIV activity, 4Ј-substituted compounds are susceptible to degradation by adenosine deaminase (11), a property that limits the plasma and intracellular half-life of the drugs. To overcome the adenosine deaminase sensitivity of these 4Ј-ethynyl NRTIs, we developed a second generation of analogs substituted at the 2-position of the adenine ring (12). We recently reported that the 2-halogenated, 4Ј-ethynyl compounds have remarkably improved potency and selectivity indices (CC 50 /EC 50 ) compared with the nonhalogenated analogs and significantly better ones compared with other approved NRTIs.…”

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

“…1) is an investigational nucleoside analog that inhibits HIV-1 replication with 50% effective concentrations (EC 50 s) in the low nanomolar-to-picomolar range (12)(13)(14)(15)(16). Direct comparisons show that MK-8591 is 10-fold more potent than tenofovir disoproxil fumarate (TDF) (15), 10 to100 times more potent than zidovudine (AZT) (12,14), and 1,000 times more potent than emtricitabine (FTC) (16) against HIV-1 in culture.…”

“…MK-8591 also exhibits favorable pharmacokinetic properties, including a long intracellular half-life compared to those of conventional, FDA-approved NRTIs (16)(17)(18). This property is attributable to the fluorine at the 2 position of the adenine base, which renders the compound resistant to degradation by adenosine deaminase (13,14). MK-8591 suppresses HIV-1 and simian immunodeficiency virus (SIV) replication at clinically achievable concentrations in humanized mice and rhesus macaques, respectively (16,(19)(20)(21).…”