4-Ethynyl-2-fluoro-2-deoxyadenosine, MK-8591: a novel HIV-1 reverse transcriptase translocation inhibitor

• Authors: Martin Markowitz, Aaron Diamond AIDS Research Center; Stefan Sarafianos, Emory University
• Journal Title: Current Opinion in HIV and AIDS
• Volume: Volume 13, Number 4
• Publisher: Lippincott, Williams & Wilkins | 2018-07-01, Pages 294-299
• Type of Work: Article | Post-print: After Peer Review
• Publisher DOI: http://doi.org/10.1097/COH.0000000000000467
• Subjects: Chemistry, Biochemistry; Health Sciences, Immunology
• Keywords: Science & Technology; Life Sciences & Biomedicine; Immunology; Infectious Diseases; HIV-1 reverse transcriptase translocation inhibitor; long acting; weekly dosing; IMMUNODEFICIENCY-VIRUS TYPE-1; IN-VITRO; 4'-ETHYNYL-2-FLUORO-2'-DEOXYADENOSINE EFDA; MITOCHONDRIAL TOXICITY; ANTIRETROVIRAL-THERAPY; POTENT ACTIVITY; HIGHLY POTENT; MECHANISM; RESISTANT; VARIANTS

Abstract

Purpose of review 4′-Ethynyl-2-fluoro-2′-deoxyadenosine (EFdA) is a nucleoside reverse transcriptase inhibitor (NRTI) with a novel mechanism of action, unique structure, and amongst NRTIs, unparalleled anti-HIV-1 activity. We will summarize its structure and function, antiviral activity, resistance profile, and potential as an antiretroviral for use in the treatment and preexposure prophylaxis of HIV-1 infection. Recent findings EFdA is active against wild-Type (EC 50 as low as 50-pmol/l) and most highly NRTI-resistant viruses. The active metabolite, EFdA-Triphosphate, has been shown to have a prolonged intracellular half-life in human and rhesus (Rh) blood cells. As a result, single drug doses tested in simian immunodeficiency virus mac 251-infected Rh macaques and HIV-1-infected individuals exhibited robust antiviral activity of 7-10 days duration. Preclinical studies of EFdA as preexposure prophylaxis in the Rh macaque/simian/human immunodeficiency virus low-dose intrarectal challenge model have shown complete protection when given in clinically relevant doses. Summary EFdA is a novel antiretroviral with activity against both wild-Type and NRTI-resistant viruses. As a result of the prolonged intracellular half-life of its active moiety, it is amenable to flexibility in dosing of at least daily to weekly and perhaps longer.