Mechanistic Insight into Antiretroviral Potency of 2'-Deoxy-2'-β-fluoro-4'-azidocytidine (FNC) with a Long-Lasting Effect on HIV-1 Prevention

Journal of Medicinal Chemistry
Li SunJunbiao Chang

Abstract

In preclinical and phase I and II clinical studies, 2'-deoxy-2'-β-fluoro-4'-azidocytidine (FNC) displays a potent and long-lasting inhibition of HIV-1 infection. To investigate its mechanism of action, we compared it with the well-documented lamivudine (3TC). Pharmacokinetic studies revealed that the intracellular retention of FNC triphosphate in peripheral blood mononuclear cells was markedly longer than that of the 3TC triphosphate. FNC selectively enters and is retained in HIV target cells, where it exerts long-lasting prevention of HIV-1 infection. In addition to inhibition of HIV-1 reverse transcription, FNC also restores A3G expression in CD4+ T cells in FNC-treated HIV-1 patients. FNC binds to the Vif-E3 ubiquitin ligase complex, enabling A3G to avoid Vif-induced ubiquitination and degradation. These data reveal the mechanisms underlying the superior anti-HIV potency and long-lasting action of FNC. Our results also suggest a potential clinical application of FNC as a long-lasting pre-exposure prophylactic agent capable of preventing HIV infection.

References

Apr 20, 2004·Biochemical and Biophysical Research Communications·Jian-Hua WangYong-Tang Zheng
Sep 23, 2008·Nature Biotechnology·Robin NathansTariq M Rana
Apr 29, 2009·Journal of Computational Chemistry·Garrett M MorrisArthur J Olson
Apr 7, 2010·The Journal of Biological Chemistry·Shan CenJian-Dong Jiang
Jul 13, 2011·European Journal of Medicinal Chemistry·Qiang WangJunbiao Chang
Apr 3, 2013·Bioorganic & Medicinal Chemistry·Tali H ReingewertzAssaf Friedler
Mar 1, 2015·The Journal of Biological Chemistry·Erez PeryDana Gabuzda
Jun 7, 2015·The Journal of General Virology·Kasandra Bélanger, Marc-André Langlois
Aug 5, 2016·Proceedings of the National Academy of Sciences of the United States of America·Zhe Li SalieStefan G Sarafianos
Jul 30, 2017·Bioorganic & Medicinal Chemistry Letters·Chunlan PuRui Li
Sep 9, 2017·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Huan ChenYong-Tang Zheng
Nov 21, 2017·Cell Chemical Biology·Margaret E OlsonDaniel A Harki
May 16, 2018·Infectious Diseases and Therapy·Anita ChawlaCorklin Steinhart
Feb 28, 2019·MBio·Mark SharkeyMario Stevenson
Apr 27, 2019·Heliyon·Nazanin MohammadzadehLinda Chelico
Jul 12, 2019·Cell Host & Microbe·D A CollierR K Gupta

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Citations

Oct 12, 2020·Signal Transduction and Targeted Therapy·Bin Yu, Junbiao Chang
Feb 27, 2021·Chemical Reviews·Paramasivam SivaguruXihe Bi

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