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  3. Design, synthesis and anti-HBV activity study of novel HBV capsid assembly modulators

Design, synthesis and anti-HBV activity study of novel HBV capsid assembly modulators

  • Bioorg Med Chem Lett. 2024 Aug 5:112:129913. doi: 10.1016/j.bmcl.2024.129913.
Minghui Liang 1,  Linyue Liu 2,  Jun Liu 3,  Zechun Yang 1,  Mei Wang 4,  Yong Xie 5,  Yuqing Cai 6,  Peng Xue 6,  Yunfu Chen 7,  Peng Zhan 8,  Haiyong Jia 9
Affiliations

Affiliations

  • 1 School of Pharmacy, Shandong Second Medical University, Weifang, China.
  • 2 School of Pharmacy, Shandong Second Medical University, Weifang, China; Binzhou Hospital of Traditional Chinese Medicine, Binzhou, China.
  • 3 School of Nursing, Shandong Second Medical University, Weifang, China.
  • 4 School of Pharmacy, Shandong Second Medical University, Weifang, China; Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012, Jinan, Shandong, China.
  • 5 State Key Laboratory of Anti-Infective Drug Development (NO. 2015DQ780357), Sunshine Lake Pharma Co., Ltd, Dongguan 523871, China.
  • 6 School of Public Health, Shandong Second Medical University, Weifang, China.
  • 7 State Key Laboratory of Anti-Infective Drug Development (NO. 2015DQ780357), Sunshine Lake Pharma Co., Ltd, Dongguan 523871, China. Electronic address: chenyunfu@HEC.CN.
  • 8 Department of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Shandong University, 44 West Culture Road, 250012, Jinan, Shandong, China. Electronic address: zhanpeng1982@sdu.edu.cn.
  • 9 School of Pharmacy, Shandong Second Medical University, Weifang, China. Electronic address: 502378774@163.com.
PMID: 39111727 DOI: 10.1016/j.bmcl.2024.129913
Abstract

Capsid assembly modulators (CAMs) have the potential to cure chronic hepatitis B, as demonstrated in clinical trials. Lead compounds NVR3-778 and 5a were found to exist in normal and flipped conformations through induced fit docking. Therefore, we designed and synthesized series I and II compounds by interchanging the amide and sulfonamide bonds of 5a to modify both the tolerance region and solvent-opening region. Among them, compound 4a (EC50 = 0.24 ± 0.10 μM, CC50 > 100 μM) exhibited potent anti-HBV activity with low toxicity, surpassing the lead compounds NVR3-778 (EC50 = 0.29 ± 0.03 μM, CC50 = 20.78 ± 2.29 μM) and 5a (EC50 = 0.50 ± 0.07 μM, CC50 = 48.16 ± 9.15 μM) in HepAD38 cells. Additionally, compared with the lead compound, 4a displayed a stronger inhibitory effect on HBV capsid protein assembly. Molecular dynamics (MD) simulations confirmed that the normal conformation of 4a had relatively stable conformation at different frames of binding modes. Furthermore, 4a showed better metabolic stability in human plasma than positive control drugs. Therefore, compound 4a could be further structurally modified as a potent lead compound.

Keywords

Capsid assembly modulators; HBV; HepAD38 cells; Molecular dynamics.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-162795
    HBV衣壳组装调节剂
    HBV
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