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Cell Chem Biol. 2018 Oct 18;25(10):1268-1278.e3. doi: 10.1016/j.chembiol.2018.07.014. Epub 2018 Aug 30.

The High Genetic Barrier of EFdA/MK-8591 Stems from Strong Interactions with the Active Site of Drug-Resistant HIV-1 Reverse Transcriptase.

Author information

1
Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-1868, USA.
2
Department of Refractory Viral Infection, National Center for Global Health and Medicine Research Institute, 1-21-1 Toyama Shinjuku, Tokyo 162-8655, Japan; Faculty of Pharmaceutical Sciences, Sojo University, Kumamoto 860-0082, Japan.
3
Department of Refractory Viral Infection, National Center for Global Health and Medicine Research Institute, 1-21-1 Toyama Shinjuku, Tokyo 162-8655, Japan.
4
Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-1868, USA; Department of Refractory Viral Infection, National Center for Global Health and Medicine Research Institute, 1-21-1 Toyama Shinjuku, Tokyo 162-8655, Japan.
5
Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30307, USA.
6
Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-1868, USA; Department of Refractory Viral Infection, National Center for Global Health and Medicine Research Institute, 1-21-1 Toyama Shinjuku, Tokyo 162-8655, Japan; Department of Hematology, Rheumatology and Infectious Disease, Kumamoto University Graduate School of Biomedical Sciences, Kumamoto 860-0811, Japan.
7
Experimental Retrovirology Section, HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-1868, USA; Department of Refractory Viral Infection, National Center for Global Health and Medicine Research Institute, 1-21-1 Toyama Shinjuku, Tokyo 162-8655, Japan. Electronic address: kmaeda@ri.ncgm.go.jp.

Abstract

4'-Ethynyl-2-fluoro-2'-deoxyadenosine (EFdA/MK-8591), a nucleoside reverse transcriptase inhibitor (NRTI) under clinical trials, is a potent and promising long-acting anti-HIV type 1 (HIV-1) agent. EFdA and its derivatives possess a modified 4'-moiety and potently inhibit the replication of a wide spectrum of HIV-1 strains resistant to existing NRTIs. Here, we report that EFdA and NRTIs with a 4'-ethynyl- or 4'-cyano-moiety exerted activity against HIV-1 with an M184V mutation and multiple NRTI-resistant HIV-1s, whereas NRTIs with other moieties (e.g., 4'-methyl) did not show this activity. Structural analysis indicated that EFdA and 4'-ethynyl-NRTIs (but not other 4'-modified NRTIs), formed strong van der Waals interactions with critical amino acid residues of reverse transcriptase. Such interactions were maintained even in the presence of a broad resistance-endowing M184V substitution, thus potently inhibiting drug-resistant HIV-1 strains. These findings also explain the mechanism for the potency of EFdA and provide insights for further design of anti-HIV-1 therapeutics.

KEYWORDS:

4ʹ-cyano; 4ʹ-ethynyl; 4′-ethynyl-2-fluoro-2′-deoxyadenosine (EFdA/MK-8591); HIV type 1 (HIV-1); drug resistance; nucleoside reverse transcriptase inhibitor (NRTI); reverse transcriptase

PMID:
30174310
PMCID:
PMC6261781
[Available on 2019-10-18]
DOI:
10.1016/j.chembiol.2018.07.014

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