Benserazide, the first allosteric inhibitor of Coxsackievirus B3 3C protease

Kim, Bokyoung; Cho, Joong-Heui; Jeong, Pyeonghwa; Lee, Youngjin; Lim, Jia Jia; Park, Kyoung Ryoung; Eom, Soo Hyun; Kim, Yong-Chul

doi:10.1016/j.febslet.2015.05.027

Cited by 13 publications

(11 citation statements)

References 31 publications

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“…Thus, exploration of non-covalent inhibitors of picornaviral 3C pro s has already begun. Non-covalent inhibitors of RV 3C pro and CVB3 3C pro have been identified through fragment screening and FRET-based enzyme assay screening [ 136 ]. The chemical modification from water-insolubility to water-solubility shows a positive effect.…”

Section: Treatmentmentioning

confidence: 99%

Roles of the Picornaviral 3C Proteinase in the Viral Life Cycle and Host Cells

Sun

Chen

Cheng

et al. 2016

Viruses

109

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The Picornaviridae family comprises a large group of non-enveloped viruses that have a major impact on human and veterinary health. The viral genome contains one open reading frame encoding a single polyprotein that can be processed by viral proteinases. The crucial 3C proteinases (3Cpros) of picornaviruses share similar spatial structures and it is becoming apparent that 3Cpro plays a significant role in the viral life cycle and virus host interaction. Importantly, the proteinase and RNA-binding activity of 3Cpro are involved in viral polyprotein processing and the initiation of viral RNA synthesis. In addition, 3Cpro can induce the cleavage of certain cellular factors required for transcription, translation and nucleocytoplasmic trafficking to modulate cell physiology for viral replication. Due to interactions between 3Cpro and these essential factors, 3Cpro is also involved in viral pathogenesis to support efficient infection. Furthermore, based on the structural conservation, the development of irreversible inhibitors and discovery of non-covalent inhibitors for 3Cpro are ongoing and a better understanding of the roles played by 3Cpro may provide insights into the development of potential antiviral treatments. In this review, the current knowledge regarding the structural features, multiple functions in the viral life cycle, pathogen host interaction, and development of antiviral compounds for 3Cpro is summarized.

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Section: Treatmentmentioning

confidence: 99%

Roles of the Picornaviral 3C Proteinase in the Viral Life Cycle and Host Cells

Sun

Chen

Cheng

et al. 2016

Viruses

109

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“…CVB3 has been consistently reported as the predominant pathogen causing human viral myocarditis, and current treatment approaches for patients with CVB3-related myocarditis are almost entirely supportive, as there is no vaccine or specific treatment for infections caused by coxsackieviruses [26]. In addition, HADV are the most common infectious cause of ocular disease worldwide, and HADV infections are associated with considerable morbidity and mortality, which could clearly be limited by the availability of effective antiviral drugs.…”

Section: Discussionmentioning

confidence: 99%

Antiviral Effects of Novel 2-Benzoxyl-Phenylpyridine Derivatives

Wang

et al. 2020

Molecules

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Coxsackievirus B3 (CVB3) is the most common cause of acute and chronic viral myocarditis, primarily in children, while human adenovirus infections represent a significant cause of morbidity and mortality worldwide, in people of all ages. A series of novel 2-benzoxyl-phenylpyridine derivatives were evaluated for their potential antiviral activities against CVB3 and adenovirus type 7 (ADV7). Preliminary assays indicated that some of these compounds exhibited excellent antiviral effects on both CVB3 and ADV7 viruses; they could effectively inhibit virus-induced cytopathic effects, reduce viral progeny yields, and had similar or superior antiviral activities compared with the control drug, ribavirin. Further, these compounds targeted the early stages of CVB3 replication in cells, including viral RNA replication and protein synthesis, rather than inactivating the virus directly, inhibiting virus adsorption/entry, or affecting viral release from cells. Our data demonstrate that the tested 2-benzoxyl-phenylpyridine derivatives are effective inhibitors of CVB3 and ADV7, raising the possibility that these compounds might be feasible candidates for anti-viral agents.

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“…Benz was identified as an HK2 inhibitor. Besides targeting the decarboxylase, Benz showed inhibitory effect against Coxsackievirus B3 3C protease [ 35 ]. Recent studies reported that the pretreatment of Benz enhanced the base-excision DNA repair of oxidative DNA damage in the presence of mutant breast cancer susceptibility gene 1 (BRCA1) [ 36 ].…”

Section: Discussionmentioning

confidence: 99%

Benserazide, a dopadecarboxylase inhibitor, suppresses tumor growth by targeting hexokinase 2

Wei

Zheng

et al. 2017

J Exp Clin Cancer Res

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BackgroundHexokinase (HK) is the rate-limiting enzyme in the first reaction of glycolysis. And Hexokinase 2 (HK2) is most closely related to malignant tumor which expresses at higher level compared with normal cells. HK2 plays a pivotal role in tumor initiation and maintenance, which provides a new target for cancer therapy.MethodsStructure-based virtual ligand screening was used in hit identification from ZINC Drug Database. Microscale thermophoresis assay was performed to evaluate the binding affinity. Enzyme inhibition, cytotoxicity, apoptosis, intracellular ATP level, mitochondrial membrane potential (MMP), glucose uptake and lactate production experiments were undertaken in SW480 cells to identify Benz as a HK2 inhibitor. Western blot was used to test protein expression. SW480 cells xenograft mouse models were used for in vivo study. Nano-particles of Benz were prepared to improve the antitumor efficacy and tumor targeting of Benz. HPLC was used to measure the concentration of free Benz in tumor tissues.ResultsBenserazide (Benz), was identified as a selective HK2 inhibitor, could specifically bind to HK2 and significantly inhibit HK2 enzymatic activity in vitro. In addition, Benz reduced glucose uptake, lactate production and intracellular ATP level, and could cause cell apoptosis and an increased loss of MMP as well. In vivo study indicated that intraperitoneal (ip) injection of Benz at 300 and 600 mg/Kg suppressed cancer growth in tumor-bearing mice and no toxicity shown. To further improve the antitumor efficacy and tumor targeting of Benz, nano-particles of Benz was prepared. Liposomal Benz at 100 and 200 mg/Kg performed potent inhibitory effects on tumor-bearing mice, showing reduced dose and better efficacy.ConclusionsOur study provides a new direction for the development of Benz and its analogues as novel antitumor agents for cancer therapy.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-017-0530-4) contains supplementary material, which is available to authorized users.

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Benserazide, the first allosteric inhibitor of Coxsackievirus B3 3C protease

Cited by 13 publications

References 31 publications

Roles of the Picornaviral 3C Proteinase in the Viral Life Cycle and Host Cells

Roles of the Picornaviral 3C Proteinase in the Viral Life Cycle and Host Cells

Antiviral Effects of Novel 2-Benzoxyl-Phenylpyridine Derivatives

Benserazide, a dopadecarboxylase inhibitor, suppresses tumor growth by targeting hexokinase 2

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