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

Rishabh Kejriwal; Tristan Evans; Joshua Calabrese; Lea Swistak; Lauren Alexandrescu; Michelle Cohen; Nahian Rahman; Niel Henriksen; Radha Charan Dash; M. Kyle Hadden; Nicola J. Stonehouse; David J. Rowlands; Natalie J. Kingston; Madeline Hartnoll; Samuel J. Dobson; Simon J. White

doi:10.1002/cmdc.202200541

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

Rishabh Kejriwal, Tristan Evans, Joshua Calabrese, Lea Swistak, Lauren Alexandrescu, Michelle Cohen, Nahian Rahman, Niel Henriksen, Radha Charan Dash, M. Kyle Hadden, Nicola J. Stonehouse, David J. Rowlands, Natalie J. Kingston, Madeline Hartnoll, Samuel J. Dobson, Simon J. White

Research output: Contribution to journal › Article › peer-review

Abstract

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.

Original language	English (US)
Article number	e202200541
Journal	ChemMedChem
Volume	18
Issue number	10
DOIs	https://doi.org/10.1002/cmdc.202200541
State	Published - May 16 2023
Externally published	Yes

Keywords

2C protein
ATPase
Antiviral agents
Enteroviruses
Helicase

ASJC Scopus subject areas

Drug Discovery
General Pharmacology, Toxicology and Pharmaceutics
Molecular Medicine
Biochemistry
Pharmacology
Organic Chemistry

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1002/cmdc.202200541

Cite this

Kejriwal, R., Evans, T., Calabrese, J., Swistak, L., Alexandrescu, L., Cohen, M., Rahman, N., Henriksen, N., Charan Dash, R., Hadden, M. K., Stonehouse, N. J., Rowlands, D. J., Kingston, N. J., Hartnoll, M., Dobson, S. J., & White, S. J. (2023). Development of Enterovirus Antiviral Agents That Target the Viral 2C Protein. ChemMedChem, 18(10), Article e202200541. https://doi.org/10.1002/cmdc.202200541

Kejriwal, R, Evans, T, Calabrese, J, Swistak, L, Alexandrescu, L, Cohen, M, Rahman, N, Henriksen, N, Charan Dash, R, Hadden, MK, Stonehouse, NJ, Rowlands, DJ, Kingston, NJ, Hartnoll, M, Dobson, SJ & White, SJ 2023, 'Development of Enterovirus Antiviral Agents That Target the Viral 2C Protein', ChemMedChem, vol. 18, no. 10, e202200541. https://doi.org/10.1002/cmdc.202200541

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abstract = "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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doi = "10.1002/cmdc.202200541",

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AU - Alexandrescu, Lauren

AU - Cohen, Michelle

AU - Rahman, Nahian

AU - Henriksen, Niel

AU - Charan Dash, Radha

AU - Hadden, M. Kyle

AU - Stonehouse, Nicola J.

AU - Rowlands, David J.

AU - Kingston, Natalie J.

AU - Hartnoll, Madeline

AU - Dobson, Samuel J.

AU - White, Simon J.

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N2 - 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.

AB - 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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KW - Helicase

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

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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