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Review
. 2018 Jul;13(4):294-299.
doi: 10.1097/COH.0000000000000467.

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

Martin Markowitz  1 , Stefan G Sarafianos  2
Affiliations
Review

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

Martin Markowitz et al. Curr Opin HIV AIDS. 2018 Jul.

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 (EC50 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 mac251-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.

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Conflict of interest statement

Conflicts of interest: M.M. is a paid consultant to Merck Research Laboratories. His research program receives grant support from Merck Laboratories. Merck, Sharp, and Dohme has also provided him with honoraria for serving as a plenary speaker at MSD organized symposia. He also receives grant support from Gilead Sciences and GlaxoSmithKline/ViiV. He is also a member of the Gilead Speakers Bureau.

S.G.S. has served as a paid consultant to Merck Research Laboratories.

Figures

Figure 1
Figure 1
Chemical structure of EFdA. Circled in red from left to right are the 4′-ethynyl group, the 3′-OH group, and the 2-fluouro adenosine ring.
Figure 2
Figure 2
Interactions of EFdA-triphosphate (EFdA-TP) at the dNTP binding site of RT shown as Van der Waals surface. The 4′-E group of EFdA-TP interacts with RT residues at a conserved hydrophobic pocket (red) contributing to strong inhibitor binding prior to catalysis. After catalysis and incorporation of EFdA-MP to the primer (primer·EFdA-MP; not shown) the 4′-E of EFdA-MP may decrease RT translocation, a step required for vacating the active site for binding of the next incoming dNTP and further DNA synthesis. This decrease in translocation would manifest itself as immediate chain termination (Figures 2 and 3 was prepared using PDB ID 5J2M crystal structure and PyMOL).
Figure 3
Figure 3
Structural basis of RT inhibition by EFdA acting as a delayed chain terminator. In some cases, after incorporation of EFdA-monophosphate (EFdA-MP, in cyan) into the primer strand (gray sticks), an additional nucleotide can be added. Upon translocation of the extended primer·EFdA-MP·dN-MP substrate, the 4′-E would be expected to sterically clash (red X) with residues of the upstream “primer grip” region of RT, leading to dissociation of the nucleic acid and suppression of further DNA synthesis (Molecular model prepared by superposition of EFdA-MP with the equivalent nucleotide that is present in PDB ID 5J2M crystal structure, as described in (11).
See this image and copyright information in PMC

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