2. Academic Validation
  3. Discovery of potential dual-target prodrugs of HIV-1 reverse transcriptase and nucleocapsid protein 7

Discovery of potential dual-target prodrugs of HIV-1 reverse transcriptase and nucleocapsid protein 7

  • Bioorg Med Chem Lett. 2020 Aug 15;30(16):127287. doi: 10.1016/j.bmcl.2020.127287.
Songkai Sun 1,  Boshi Huang 1,  Zhuo Li 1,  Zhao Wang 1,  Lin Sun 1,  Ping Gao 1,  Dongwei Kang 1,  Chin-Ho Chen 2,  Kuo-Hsiung Lee 3,  Dirk Daelemans 4,  Erik De Clercq 4,  Christophe Pannecouque 4,  Peng Zhan 5,  Xinyong Liu 6
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Ji'nan 250012, China.
  • 2 Duke University Medical Center, Box 2926, SORF, Durham, NC 27710, United States.
  • 3 Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599-7568, United States; Chinese Medicine Research and Development Center, China Medical University and Hospital, Taichung 40402, Taiwan, China.
  • 4 Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, K.U.Leuven, Herestraat 49 Postbus 1043 (09.A097), B-3000 Leuven, Belgium.
  • 5 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Ji'nan 250012, China. Electronic address: zhanpeng1982@sdu.edu.cn.
  • 6 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology, Ministry of Education, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Ji'nan 250012, China. Electronic address: xinyongl@sdu.edu.cn.
PMID: 32631509 DOI: 10.1016/j.bmcl.2020.127287
Abstract

In the present work, we described the design, synthesis and biological evaluation of a novel series of potential dual-target prodrugs targeting the HIV-1 Reverse Transcriptase (RT) and nucleocapsid protein 7 (NCp7) simultaneously. Among them, the most effective compound 7c was found to inhibit HIV-1 wild-type (WT) strain at double-digit nanomolar concentration (EC50 = 42 nM) in MT-4 cells, and sub-micromole (EC50 = 0.308 μM) to inhibit HIV-1 NL4-3 strain in TZM-bl cells. This is a significant improvement over the parent drug MT. In addition, it showed moderate inhibitory potency (EC50 = 1.329 μM) against the HIV-1 K103N/Y181C double mutant strain (MT-4 cells). The metabolic stability in human plasma of compound 7c indicated that it can release the active forms of the parent drugs MT and AZT in a linear time-independent manner and turn out to be a potential prodrug.

Keywords

Anti-HIV activity; Dual-target prodrug; HIV-1; Metabolic stability; NCp7; RT.

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