Development of sulfamoylbenzamide-based capsid assembly modulators for hepatitis B virus capsid assembly

Eur J Med Chem. 2025 Jun 5:290:117430. doi: 10.1016/j.ejmech.2025.117430.

Syed Azeem Abbas ¹, Hyeon-Min Cha ², Sandesha Nayak ³, Sujin Ahn ⁴, Jayaraj Gowda ⁵, Ilva Lieknina ⁶, Andris Dislers ⁷, In Su Kim ⁸, Inseong Jo ⁹, Meehyein Kim ¹⁰, Hyejin Kim ¹¹, Chunkyu Ko ¹², Soo Bong Han ¹³

Affiliations

1 Infectious Diseases Therapeutic Research Center, Therapeutics and Biotechnology Division, Korea Research Institute of Chemical Technology (KRICT), Daejeon, 34114, Republic of Korea; Department of Medicinal Chemistry and Pharmacology, University of Science and Technology, Daejeon, 34113, Republic of Korea. Electronic address: azeem@krict.re.kr.
2 Infectious Diseases Therapeutic Research Center, Therapeutics and Biotechnology Division, Korea Research Institute of Chemical Technology (KRICT), Daejeon, 34114, Republic of Korea; Graduate School of New Drug Discovery and Development, Chungnam National University, Daejeon, 34134, Republic of Korea. Electronic address: chahm@krict.re.kr.
3 Infectious Diseases Therapeutic Research Center, Therapeutics and Biotechnology Division, Korea Research Institute of Chemical Technology (KRICT), Daejeon, 34114, Republic of Korea; Department of Medicinal Chemistry and Pharmacology, University of Science and Technology, Daejeon, 34113, Republic of Korea. Electronic address: sandesha@krict.re.kr.
4 Infectious Diseases Therapeutic Research Center, Therapeutics and Biotechnology Division, Korea Research Institute of Chemical Technology (KRICT), Daejeon, 34114, Republic of Korea. Electronic address: asujin2443@gmail.com.
5 Infectious Diseases Therapeutic Research Center, Therapeutics and Biotechnology Division, Korea Research Institute of Chemical Technology (KRICT), Daejeon, 34114, Republic of Korea; Department of Medicinal Chemistry and Pharmacology, University of Science and Technology, Daejeon, 34113, Republic of Korea. Electronic address: jayaraj@krict.re.kr.
6 Latvian Biomedical Research and Study Centre, Ratsupites 1, k-1, LV-1067, Riga, Latvia. Electronic address: ilva@biomed.lu.lv.
7 Latvian Biomedical Research and Study Centre, Ratsupites 1, k-1, LV-1067, Riga, Latvia. Electronic address: dishlers@biomed.lu.lv.
8 School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Republic of Korea. Electronic address: insukim@skku.edu.
9 Infectious Diseases Therapeutic Research Center, Therapeutics and Biotechnology Division, Korea Research Institute of Chemical Technology (KRICT), Daejeon, 34114, Republic of Korea. Electronic address: inseong@krict.re.kr.
10 Infectious Diseases Therapeutic Research Center, Therapeutics and Biotechnology Division, Korea Research Institute of Chemical Technology (KRICT), Daejeon, 34114, Republic of Korea; Graduate School of New Drug Discovery and Development, Chungnam National University, Daejeon, 34134, Republic of Korea. Electronic address: mkim@krict.re.kr.
11 Infectious Diseases Therapeutic Research Center, Therapeutics and Biotechnology Division, Korea Research Institute of Chemical Technology (KRICT), Daejeon, 34114, Republic of Korea; Department of Medicinal Chemistry and Pharmacology, University of Science and Technology, Daejeon, 34113, Republic of Korea; School of Pharmacy, Sungkyunkwan University, Suwon, 16419, Republic of Korea. Electronic address: hjinkim@krict.re.kr.
12 Infectious Diseases Therapeutic Research Center, Therapeutics and Biotechnology Division, Korea Research Institute of Chemical Technology (KRICT), Daejeon, 34114, Republic of Korea. Electronic address: ckko@krict.re.kr.
13 Infectious Diseases Therapeutic Research Center, Therapeutics and Biotechnology Division, Korea Research Institute of Chemical Technology (KRICT), Daejeon, 34114, Republic of Korea; Department of Medicinal Chemistry and Pharmacology, University of Science and Technology, Daejeon, 34113, Republic of Korea. Electronic address: sbhan@krict.re.kr.

PMID: 40184774 DOI: 10.1016/j.ejmech.2025.117430

Abstract

Hepatitis B virus (HBV) is a leading cause of chronic hepatitis and remains a significant global public health concern due to the lack of effective treatments. HBV replicates through reverse transcription within the viral capsid, making capsid assembly a promising Antiviral target. However, no approved therapies currently target this process. In our previous study, we optimized the structure-activity relationship (SAR) of NVR 3-778 by modifying the A and B rings, leading to the identification of KR-26556 and Compound 3. In this study, we further synthesized derivatives to modify the C ring, resulting in the discovery of KR019 and KR026. These compounds exhibited over 170-fold higher selectivity than the reference compound while demonstrating potent Antiviral activity in HBV-replicating cells. Mechanistic studies revealed that KR019 binds to the hydrophobic pocket at the core protein dimer-dimer interface, misdirecting capsid assembly into genome-free capsids and thereby inhibiting viral replication. Additionally, pharmacokinetic profiling confirmed favorable stability and safety. These findings highlight the strong Antiviral potential of KR019 and KR026 and provide a foundation for further in vivo investigation.

Keywords

Antivirals; Capsid assembly modulators; Core proteins; Hepatitis B virus; Small molecules; Sulfamoylbenzamides.

Products

Cat. No.

Product Name

Description

Target

Research Area
HY-173121

KR019

HBV Inhibitor

HBV

Infection

Name
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