Discovery of a New Sulfonamide Hepatitis B Capsid Assembly Modulator

Na, Hyo Gyeong; Imran, Ali; Kim, Kyuneun; Han, Hong Sik; Lee, Young Jin; Kim, Myung-Jin; Yun, Chang‐Soo; Jung, Young‐Sik; Lee, Joo‐Youn; Han, Soo Bong

doi:10.1021/acsmedchemlett.9b00550

Cited by 17 publications

(11 citation statements)

References 12 publications

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“…Our prior efforts to improve anti-HBV activity starting from NVR 3-778 and HAP_R01 yielded a structurally related but more potent compound, KR-26556. 22 Despite its cellular potency evidenced by reduced HBV DNA levels in HepAD cells, the present findings in HepG2.2.15 cells (Table 1, entry 15, EC 50 = 0.27 μM and CC 50 = 19.7 μM) revealed the need to develop more HBV-specific antiviral candidates. We aimed to synthesize more KR-26556 derivatives and identify alternative CAMs by investigating structure−antiviral activity relationships (SARs).…”

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confidence: 99%

“…The molecular docking studies with the HBV core protein (PDB code: 5T2P) showed that the proposed binding mode of 3 was similar to those of the cocrystallized ligand and 15 in our previous study (Figure 3). 22 The oxygen of the benzamide in 3 forms a key hydrogen bond with Trp102 (B chain), whereas Thr128 (C chain) forms additional hydrogen bonds with the nitrogen of the benzamide group. In addition, the piperidyl group of 3 points toward the solvent-exposed area.…”

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confidence: 99%

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Sulfamoylbenzamide-based Capsid Assembly Modulators for Selective Inhibition of Hepatitis B Viral Replication

Lee

Cha

Hwang

et al. 2021

ACS Med. Chem. Lett.

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As the spread of infections caused by hepatitis B virus (HBV) threatens public health worldwide, investigations from multiple perspectives and of various mechanisms of action are urgently required to increase the HBV cure rate. Targeting the encapsidation of the nuclear capsid protein (core protein, HBc) has emerged as an attractive strategy for inhibiting the viral assembly process; however, a drug targeting this mechanism has not yet been approved. We synthesized novel sulfamoylbenzamides (SBAs) as capsid assembly modulators of HBV and found that the effects and safety profiles of compounds 3 and 8 have potential therapeutic applicability against HBV. The formation of tubular particles was time-dependent in the presence of 3, indicating a new mode of protein assembly by SBA compounds. Our findings provide a new entity for developing safe and efficient treatments for HBV infection.

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confidence: 99%

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confidence: 99%

Sulfamoylbenzamide-based Capsid Assembly Modulators for Selective Inhibition of Hepatitis B Viral Replication

Lee

Cha

Hwang

et al. 2021

ACS Med. Chem. Lett.

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“…This inhibitor, developed by Roche, showed favorable safety, tolerability, and pharmacokinetics profile and has been classified as suitable for further clinical development [120]. This compound was also further successfully modified by installing functional moieties to increase the inhibitory activity of SBA_R01 as proved for sulfamoylbenzamide-based compound KR-26556 [121] (Table 2). Especially modifications of positions 4 and 6 with fluorine and methoxy group, respectively, resulted in significant improvement of the inhibitor potency.…”

Section: Hepatitis B Virus Assembly Inhibitorsmentioning

confidence: 99%

Targeting the Virus Capsid as a Tool to Fight RNA Viruses

Hozáková

Vokatá

Ruml

et al. 2022

Viruses

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Several strategies have been developed to fight viral infections, not only in humans but also in animals and plants. Some of them are based on the development of efficient vaccines, to target the virus by developed antibodies, others focus on finding antiviral compounds with activities that inhibit selected virus replication steps. Currently, there is an increasing number of antiviral drugs on the market; however, some have unpleasant side effects, are toxic to cells, or the viruses quickly develop resistance to them. As the current situation shows, the combination of multiple antiviral strategies or the combination of the use of various compounds within one strategy is very important. The most desirable are combinations of drugs that inhibit different steps in the virus life cycle. This is an important issue especially for RNA viruses, which replicate their genomes using error-prone RNA polymerases and rapidly develop mutants resistant to applied antiviral compounds. Here, we focus on compounds targeting viral structural capsid proteins, thereby inhibiting virus assembly or disassembly, virus binding to cellular receptors, or acting by inhibiting other virus replication mechanisms. This review is an update of existing papers on a similar topic, by focusing on the most recent advances in the rapidly evolving research of compounds targeting capsid proteins of RNA viruses.

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“…Representative HAPs (Bay 41-4109 and GLS4) and a SBA ENAN-34017 [80] also inhibited de novo synthesis of cccDNA. In recent years, discovery of new CAMs has markedly accelerated [83,[92][93][94]. Indeed, CAMs have been shown to disrupt amplification and formation of cccDNA [95,96].…”

Section: Nucleocapsid Assembly Modulatorsmentioning

confidence: 99%

Targeting Viral cccDNA for Cure of Chronic Hepatitis B

Ligat

Goto

Verrier

2020

Curr Hepatology Rep

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Purpose of Review Chronic hepatitis B (CHB), caused by hepatitis B virus (HBV), is a major cause of advanced liver disease and hepatocellular carcinoma (HCC) worldwide. HBV replication is characterized by the synthesis of covalently closed circular (ccc) DNA which is not targeted by antiviral nucleos(t)ide analogues (NUCs) the key modality of standard of care. While HBV replication is successfully suppressed in treated patients, they remain at risk for developing HCC. While functional cure, characterized by loss of HBsAg, is the first goal of novel antiviral therapies, curative treatments eliminating cccDNA remain the ultimate goal. This review summarizes recent advances in the discovery and development of novel therapeutic strategies and their impact on cccDNA biology. Recent Findings Within the last decade, substantial progress has been made in the understanding of cccDNA biology including the discovery of host dependency factors, epigenetic regulation of cccDNA transcription and immune-mediated degradation. Several approaches targeting cccDNA either in a direct or indirect manner are currently at the stage of discovery, preclinical or early clinical development. Examples include genome-editing approaches, strategies targeting host dependency factors or epigenetic gene regulation, nucleocapsid modulators and immune-mediated degradation. Summary While direct-targeting cccDNA strategies are still largely at the preclinical stage of development, capsid assembly modulators and immune-based approaches have reached the clinical phase. Clinical trials are ongoing to assess their efficacy and safety in patients including their impact on viral cccDNA. Combination therapies provide additional opportunities to overcome current limitations of individual approaches.

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Discovery of a New Sulfonamide Hepatitis B Capsid Assembly Modulator

Cited by 17 publications

References 12 publications

Sulfamoylbenzamide-based Capsid Assembly Modulators for Selective Inhibition of Hepatitis B Viral Replication

Sulfamoylbenzamide-based Capsid Assembly Modulators for Selective Inhibition of Hepatitis B Viral Replication

Targeting the Virus Capsid as a Tool to Fight RNA Viruses

Targeting Viral cccDNA for Cure of Chronic Hepatitis B

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