An anti-picornaviral strategy based on the crystal structure of foot-and-mouth disease virus 2C protein

Zhang, Chu; Yang, Fan; Wojdyla, Justyna Aleksandra; Qin, Bo; Zhang, Wei; Zheng, Min; Cao, Weijun; Wang, Meitian; Gao, Xiaopan; Zheng, Haixue; Cui, Sheng

doi:10.1016/j.celrep.2022.111030

Cited by 11 publications

(11 citation statements)

References 53 publications

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“…Enteroviruses are a significant health burden globally, but despite over 70 years of research efforts, no licensed small‐molecule anti‐EV therapeutics exist. 2C is highly conserved across the enteroviruses and is involved at multiple critical stages in the viral life cycle [27,31,33,45,46] . These properties make 2C a good target for broad‐spectrum antiviral therapeutics.…”

Section: Discussionmentioning

confidence: 99%

“…2C has ATPase activity when oligomerized into a hexamer [29] and can function in vitro as an AAA+ helicase [30] . Published crystal structures of an N‐terminal truncated 2C lacking the first 115 amino acids of the 329‐long protein from EV‐A71, poliovirus, foot‐and‐mouth‐disease virus, and hepatitis A virus show a conserved pocket [31–34] . This 2C pocket is adjacent to the ATP‐binding site.…”

Section: Introductionmentioning

confidence: 99%

“…[30] Published crystal structures of an N-terminal truncated 2C lacking the first 115 amino acids of the 329-long protein from EV-A71, poliovirus, foot-and-mouth-disease virus, and hepatitis A virus show a conserved pocket. [31][32][33][34] This 2C pocket is adjacent to the ATPbinding site. It is the site of interaction between the C-terminal alpha helix of one 2C subunit and another 2C subunit in the hexameric assembly.…”

Section: Introductionmentioning

confidence: 99%

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Development of Enterovirus Antiviral Agents That Target the Viral 2C Protein

et al. 2023

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The Enterovirus (EV) genus includes several important human and animal pathogens. EV‐A71, EV‐D68, poliovirus (PV), and coxsackievirus (CV) outbreaks have affected millions worldwide, causing a range of upper respiratory, skin, and neuromuscular diseases, including acute flaccid myelitis, and hand‐foot‐and‐mouth disease. There are no FDA‐approved antiviral therapeutics for these enteroviruses. This study describes novel antiviral compounds targeting the conserved non‐structural viral protein 2C with low micromolar to nanomolar IC50 values. The selection of resistant mutants resulted in amino acid substitutions in the viral capsid protein, implying these compounds may play a role in inhibiting the interaction of 2C and the capsid protein. The assembly and encapsidation stages of the viral life cycle still need to be fully understood, and the inhibitors reported here could be useful probes in understanding these processes.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Development of Enterovirus Antiviral Agents That Target the Viral 2C Protein

et al. 2023

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“…Enteroviruses are a major health burden globally but despite over 70 years of research efforts, no licensed small-molecule anti-EV therapeutics exist. 2C is highly conserved across the enteroviruses and is involved at multiple critical stages in the viral life cycle 27,31,33,39,63 . These properties make 2C a good target for broad-spectrum anti-viral therapeutics.…”

Section: Discussionmentioning

confidence: 99%

“…2C has ATPase activity when oligomerized into a hexamer 29 and can function in vitro as a AAA+ helicase 30 . Published crystal structures of an N-terminal truncated 2C lacking the first 115 amino acids of the 329-long protein from EV-A71, poliovirus, foot-and-mouthdisease virus, and hepatitis A virus show a conserved pocket [31][32][33][34] . This 2C pocket is adjacent to the ATP-binding site and is the site of interaction between the C-terminal alpha helix of one 2C subunit and another 2C subunit in the hexameric assembly.…”

Section: Introductionmentioning

confidence: 99%

Development of Enterovirus anti-viral agents that target the viral 2C protein

Kejriwal¹,

Evans²,

Calabrese³

et al. 2022

Preprint

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The enterovirus (EV) genus includes a number of important human and animal pathogens. EV-A71, EV-D68, poliovirus (PV), and coxsackievirus (CV) outbreaks have affected millions worldwide causing a range of upper respiratory, skin, neuromuscular diseases, including acute flaccid myelitis, and hand-foot-and-mouth disease. There are no FDA-approved anti-viral therapeutics for these enteroviruses. In this study, we describe novel broad spectrum anti-viral compounds targeting the conserved non-structural viral protein 2C that have low micro-molar to nanomolar IC50 values. The selection of resistant mutants resulted in amino acid substitutions in the viral capsid protein, implying a role for 2C in capsid assembly, as has been seen in PV. The assembly and encapsidation stages of the viral life cycle are not fully understood and the inhibitors reported here could be useful probes in understanding these processes.

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The interplay between lipid droplets and virus infection

Wang

Xiao

et al. 2023

Journal of Medical Virology

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As an intracellular parasite, the virus usurps cellular machinery and modulates cellular metabolism pathways to replicate itself in cells. Lipid droplets (LDs) are universally conserved energy storage organelles that not only play vital roles in maintaining lipid homeostasis but are also involved in viral replication. Increasing evidence has demonstrated that viruses take advantage of cellular lipid metabolism by targeting the biogenesis, hydrolysis, and lipophagy of LD during viral infection. In this review, we summarize the current knowledge about the modulation of cellular LD by different viruses, with a special emphasis on the Hepatitis C virus, Dengue virus, and SARS-CoV-2.

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An anti-picornaviral strategy based on the crystal structure of foot-and-mouth disease virus 2C protein

Cited by 11 publications

References 53 publications

Development of Enterovirus Antiviral Agents That Target the Viral 2C Protein

Development of Enterovirus Antiviral Agents That Target the Viral 2C Protein

Development of Enterovirus anti-viral agents that target the viral 2C protein

The interplay between lipid droplets and virus infection

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