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

Songkai Sun; Boshi Huang; Zhuo Li; Zhao Wang; Lin Sun; Ping Gao; Dongwei Kang; Chin-Ho Chen; Kuo-Hsiung Lee; Dirk Daelemans; Erik De Clercq; Christophe Pannecouque; Peng Zhan; Xinyong Liu

doi:10.1016/j.bmcl.2020.127287

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. Epub 2020 May 26.

Authors

Songkai Sun¹, Boshi Huang¹, Zhuo Li¹, Zhao Wang¹, Lin Sun¹, Ping Gao¹, Dongwei Kang¹, Chin-Ho Chen², Kuo-Hsiung Lee³, Dirk Daelemans⁴, Erik De Clercq⁴, Christophe Pannecouque⁴, Peng Zhan⁵, Xinyong Liu⁶

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: [email protected].
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: [email protected].

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Anti-HIV Agents / chemical synthesis
Anti-HIV Agents / chemistry
Anti-HIV Agents / pharmacology*
Cell Survival / drug effects
Dose-Response Relationship, Drug
Drug Discovery
HIV Reverse Transcriptase / antagonists & inhibitors*
HIV Reverse Transcriptase / metabolism
HIV-1 / drug effects*
Humans
Microbial Sensitivity Tests
Molecular Structure
Prodrugs / chemical synthesis
Prodrugs / chemistry
Prodrugs / pharmacology*
Reverse Transcriptase Inhibitors / chemical synthesis
Reverse Transcriptase Inhibitors / chemistry
Reverse Transcriptase Inhibitors / pharmacology*
Structure-Activity Relationship
Tumor Cells, Cultured
gag Gene Products, Human Immunodeficiency Virus / antagonists & inhibitors*
gag Gene Products, Human Immunodeficiency Virus / metabolism

Substances

Anti-HIV Agents
NCP7 protein, Human immunodeficiency virus 1
Prodrugs
Reverse Transcriptase Inhibitors
gag Gene Products, Human Immunodeficiency Virus
reverse transcriptase, Human immunodeficiency virus 1
HIV Reverse Transcriptase