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

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

  • J Med Chem. 2020 Aug 13;63(15):8554-8566. doi: 10.1021/acs.jmedchem.0c00940.
Li Sun 1,  Youmei Peng 2,  Wenquan Yu 3,  Yan Zhang 1,  Lan Liang 4,  Chuanjun Song 3,  Jiao Hou 3,  Yan Qiao 3,  Qingduan Wang 2,  Jingyu Chen 1 5,  Mengli Wu 1 5,  Dongwei Zhang 1 5,  Ertong Li 6,  Zhifu Han 6,  Qingxia Zhao 7,  Xia Jin 8,  Bailing Zhang 9,  Zhiwei Huang 9,  Jijie Chai 1 6,  Jian-Hua Wang 5,  Junbiao Chang 1 3 4
Affiliations

Affiliations

  • 1 Henan Key Laboratory of Organic Functional Molecule and Drug Innovation, College of Life Science, Henan Normal University, Xinxiang 453007, China.
  • 2 Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China.
  • 3 College of Chemistry, Zhengzhou University, Zhengzhou 450001, China.
  • 4 College of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang 453007, China.
  • 5 Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.
  • 6 Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing 100084, China.
  • 7 Department of Infection, Zhengzhou Sixth People's Hospital, Zhengzhou 450000, China.
  • 8 Shanghai Public Health Clinical Center Affiliated to Fudan University, Shanghai 201508, China.
  • 9 HIT Center for Life Sciences, School of Life Science and Technology, Harbin Institute of Technology, Harbin 150080, China.
PMID: 32678592 DOI: 10.1021/acs.jmedchem.0c00940
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.

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