Assessing <i>In Vitro</i> Resistance Development in Enterovirus A71 in the Context of Combination Antiviral Treatment

Lanko, Kristina; Shi, Chengying; Patil, Shivaprasad; Matthijnssens, Jelle; Mirabelli, Carmen; Neyts, Johan

doi:10.1021/acsinfecdis.0c00872

Cited by 11 publications

(2 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The picornavirus polymerase has low fidelity, and a single drug tends to induce the production of drug-resistant mutants. Cocktail chemotherapy has been widely used in cancer therapy and similar attempts in the treatment of EV-A71 have been shown to delay the development of drug-resistant mutants [ 142 , 143 ]. Viruses resist drugs by rapidly mutating and as more and more targeted drugs are developed, drug resistance needs to be addressed.…”

Section: Discussionmentioning

confidence: 99%

The multiple roles of viral 3D ^pol protein in picornavirus infections

Nie,

Zhai,

Zhang

et al. 2024

Virulence

View full text Add to dashboard Cite

The Picornaviridae are a large group of positive-sense, single-stranded RNA viruses, and most research has focused on the Enterovirus genus, given they present a severe health risk to humans. Other picornaviruses, such as foot-and-mouth disease virus (FMDV) and senecavirus A (SVA), affect agricultural production with high animal mortality to cause huge economic losses. The 3D pol protein of picornaviruses is widely known to be used for genome replication; however, a growing number of studies have demonstrated its non-polymerase roles, including modulation of host cell biological processes, viral replication complex assembly and localization, autophagy, and innate immune responses. Currently, there is no effective vaccine to control picornavirus diseases widely, and clinical therapeutic strategies have limited efficiency in combating infections. Many efforts have been made to develop different types of drugs to prohibit virus survival; the most important target for drug development is the virus polymerase, a necessary element for virus replication. For picornaviruses, there are also active efforts in targeted 3D pol drug development. This paper reviews the interaction of 3D pol proteins with the host and the progress of drug development targeting 3D pol .

show abstract

Section: Discussionmentioning

confidence: 99%

The multiple roles of viral 3D ^pol protein in picornavirus infections

Nie,

Zhai,

Zhang

et al. 2024

Virulence

View full text Add to dashboard Cite

show abstract

“…Rupintrivir was identified as an inhibitor of rhinovirus 3C protease (40), but has since been shown to inhibit the enzymatic activity of a wide variety of viral 3C and 3C-like proteases (41)(42)(43)(44)(45). It is an efficacious inhibitor of viral growth as well: the reported EC50 for EV-D68 isolates ranges from 2-3 nM (42), while for poliovirus the reported EC50 ranges from 5-40 nM (46).…”

Section: Antivirals Have Varying Efficacy In Inhibiting Intra-molecul...mentioning

confidence: 99%

Differential Inhibition of Intra- and Inter-molecular Protease Cleavages by Antiviral Compounds

Doherty¹,

Kirkegaard

2023

Preprint

View full text Add to dashboard Cite

Enteroviruses encode two protease active sites, in the 2A and 3C coding regions. While they target many host proteins, they first need to be excised from the viral polyprotein in which they are embedded. Polyprotein cleavage can occur either intra-molecularly (in cis) or inter-molecularly (in trans). Previous work suggested that antivirals targeting intra-molecular cleavages could generate inhibitory precursors that suppress the outgrowth of drug-resistant variants. Therefore, we wanted to evaluate enteroviral cleavage patterns to identify such obligate intra-molecular cleavages for drug target selection. Using translation extracts, we show that cis cleavage of the 2A protease N-terminal junction is conserved across three enteroviruses, while the mechanism for the N-terminal junction of 3C varies, with EV-D68 3C cleavage occurring in cis and poliovirus 3C cleavage occurring in trans. Antiviral agents targeting proteases are often identified via their ability to block the cleavage of artificial peptide substrates. Here, we show that antivirals identified for their abilities to block inter-molecular cleavage can sometimes block intra-molecular cleavage of the protease from its polyprotein as well, but with widely varying efficacy. Additionally, we demonstrate that, for three enteroviral species, genomes defective in 2A protease activity suppress the growth of wild-type virus in mixed populations, supporting the hypothesis that preventing intra-molecular cleavage at the VP1·2A junction can create dominantly inhibitory precursors. These data argue that, to reduce the likelihood of drug resistance, protease-targeted antivirals should be evaluated for their ability to block intra-molecular polyprotein cleavages in addition to inter-molecular cleavage of other substrates.

show abstract

Insights into enterovirus a-71 antiviral development: from natural sources to synthetic nanoparticles

Feferbaum-Leite,

Santos,

Grosche

et al. 2023

Arch Microbiol

View full text Add to dashboard Cite

Assessing In Vitro Resistance Development in Enterovirus A71 in the Context of Combination Antiviral Treatment

Cited by 11 publications

References 35 publications

The multiple roles of viral 3D ^pol protein in picornavirus infections

The multiple roles of viral 3D ^pol protein in picornavirus infections

Differential Inhibition of Intra- and Inter-molecular Protease Cleavages by Antiviral Compounds

Insights into enterovirus a-71 antiviral development: from natural sources to synthetic nanoparticles

Contact Info

Product

Resources

About

Assessing In Vitro Resistance Development in Enterovirus A71 in the Context of Combination Antiviral Treatment

Cited by 11 publications

References 35 publications

The multiple roles of viral 3D pol protein in picornavirus infections

The multiple roles of viral 3D pol protein in picornavirus infections

Differential Inhibition of Intra- and Inter-molecular Protease Cleavages by Antiviral Compounds

Insights into enterovirus a-71 antiviral development: from natural sources to synthetic nanoparticles

Contact Info

Product

Resources

About

The multiple roles of viral 3D ^pol protein in picornavirus infections

The multiple roles of viral 3D ^pol protein in picornavirus infections