2. Academic Validation
  3. Design, synthesis, and structure activity relationship analysis of new betulinic acid derivatives as potent HIV inhibitors

Design, synthesis, and structure activity relationship analysis of new betulinic acid derivatives as potent HIV inhibitors

  • Eur J Med Chem. 2021 Apr 5:215:113287. doi: 10.1016/j.ejmech.2021.113287.
Yu Zhao 1,  Chin-Ho Chen 2,  Susan L Morris-Natschke 3,  Kuo-Hsiung Lee 4
Affiliations

Affiliations

  • 1 School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou, 510006, China; Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, 27599-7568, USA. Electronic address: yuzhao@gdut.edu.cn.
  • 2 Duke University Medical Center, Box 2926, Surgical Oncology Research Facility, Durham, NC, 27710, USA.
  • 3 Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, 27599-7568, USA.
  • 4 Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, 27599-7568, USA; Chinese Medicine Research and Development Center, China Medical University and Hospital, Taichung, Taiwan. Electronic address: khlee@unc.edu.
PMID: 33639343 DOI: 10.1016/j.ejmech.2021.113287
Abstract

Prior modification of betulinic acid (1), a natural product lead with promising anti-HIV activity, produced 3-O-(3',3'-dimethylsuccinyl)betulinic acid (bevirimat, 3), the first-in-class HIV maturation inhibitor. After 3-resistant variants were found during Phase I and IIa clinical trials, further modification of 3 produced 4 with improved activity against wild-type and 3-resistant HIV-1. In continued efforts to optimize 1, 63 final products have now been designed, synthesized, and evaluated for anti-HIV-1 replication activity against HIV-1NL4-3 infected MT-4 cell lines. Five known and 21 new derivatives were as or more potent than 3 (EC50 0.065 μM), while eight new derivatives were as or more potent than 4 (EC50 0.019 μM). These derivatives feature expanded structural diversity and chemical space that may improve the Antiviral activity and address the growing resistance crisis. Structure-Activity Relationship (SAR) correlations were thoroughly analyzed, and a 3D Quantitative SAR model with high predictability was constructed to facilitate further rational design and development of new potent derivatives.

Keywords

Anti-HIV inhibitor; Betulinic acid; Quantitative SAR; Structure-activity relationship (SAR).

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