2′-Deoxy-4′-C-Ethynyl-2-Fluoroadenosine: A Nucleoside Reverse Transcriptase Inhibitor with Highly Potent Activity Against Wide Spectrum of HIV-1 Strains, Favorable Toxic Profiles, and Stability in Plasma

Abstract

Working hypotheses to solve the critical problems of the existing highly active anti-retroviral therapy were proposed. The study based on the hypotheses proved the validity of the hypotheses and resulted in the development of 2'-deoxy-4'-C-ethynyl-2-fluoroadenosine, a nucleoside reverse transcriptase inhibitor, with highly potent activity against all HIV-1, very favorable toxic profiles, and stability in plasma. The nucleoside will prevent or delay the emergence of drug-resistant HIV-1 variants and be an ideal therapeutic agent for both HIV-1 and HBV infections.

Potent Activity of a Nucleoside Reverse Transcriptase Inhibitor, 4′-Ethynyl-2-Fluoro-2′-Deoxyadenosine, against Human Immunodeficiency Virus Type 1 Infection in a Model Using Human Peripheral Blood Mononuclear Cell-Transplanted NOD/SCID Janus Kinase 3 Knockout Mice

“…By optimization of such 4Ј-E nucleoside analogs, EFdA was found to have potent anti-HIV activity, including activity against highly multidrug-resistant variants, with favorable in vitro cell toxicities (21,24). EFdA shows unique anti-HIV-1 function and characteristics.…”

“…EFdA was synthesized as published elsewhere (21,23,24). Pharmacokinetic analysis of EFdA in BALB/c mice.…”

“…Recently, a new antiviral agent, 4Ј-ethynyl-2-fluoro-2Ј-deoxyadenosine (EFdA), was created ( Fig. 1) (21,23,24). EFdA shows potent antiviral activity (50% effective concentration ϭ 0.004 M) and good activity against NRTI-resistant strains (10).…”

Oral Administration of the Nucleoside EFdA (4′-Ethynyl-2-Fluoro-2′-Deoxyadenosine) Provides Rapid Suppression of HIV Viremia in Humanized Mice and Favorable Pharmacokinetic Properties in Mice and the Rhesus Macaque

“…A new class of 4=-substituted NRTIs has been developed whose members retain the 3=-hydroxyl group and are more potent, with a higher in vitro selectivity index (SI) than any currently licensed NRTI (3-8). The most potent of these analogs, EFdA (4-ethynyl-2-fluoro-2=-deoxyadenosine), also has a halogen substitution at the 2-position of the adenine ring which confers resistance to degradation by adenosine deaminase, resulting in improved intracellular half-lives (3,8,9).The potency of EFdA stems in part from a novel mechanism of action, translocation-defective RT inhibition, described by Michailidis et al (3,10), involving inhibition of primer translocation following EFdA-monophosphate (EFdA-MP) incorporation. HIV RT can use EFdA-5=-triphosphate (EFdA-TP) as a substrate more efficiently than the natural dATP substrate, and, despite the presence of the 3=-hydroxyl group, the incorporated EFdA-MP acts as a de facto terminator of further RT-catalyzed DNA synthesis because of the diffi- Citation Stoddart CA, Galkina SA, Joshi P, Kosikova G, Moreno ME, Rivera JM, Sloan B, Reeve AB, Sarafianos SG, Murphey-Corb M, Parniak MA.…”

HIV pre-exposure prophylaxis for women and infants prevents vaginal and oral HIV transmission in a preclinical model of HIV infection

“…16,17 Importantly, 4 ′ -ethynyl-2-fluoro-2 ′ -deoxyadenosine exhibits low cytotoxicity due to nearly negligible incorporation into human mitochondrial DNA by DNA polymerase g. 14,18,19 Furthermore, 4 ′ -ethynyl-2-fluoro-2 ′ -deoxyadenosine retains significant potency against a broad range of clinically important drug-resistant isolates, including HIV strains containing the K65R RT mutation, which is associated with resistance to tenofovir, an ARV included in all PrEP regimens evaluated in women to date. 18,20 Studies on the in vivo protective efficacy of 4 ′ -ethynyl-2-fluoro-2 ′ -deoxyadenosine PrEP are very limited 21 and it is currently not known if 4 ′ -ethynyl-2-fluoro-2 ′ -deoxyadenosine PrEP can prevent vaginal or oral HIV transmission of clinically relevant HIV-1 strains. In this study, we utilized bone marrow/liver/thymus (BLT) humanized mice 22 -28 individually bioengineered from NOD/ SCID/gc 2/2 (NSG) immunodeficient mice, as a preclinical in vivo model to evaluate the efficacy of 4 ′ -ethynyl-2-fluoro-2 ′ -deoxyadenosine PrEP to prevent vaginal and oral HIV transmission following multiple high-dose challenges with relevant transmitted/ founder (T/F) viruses.…”