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Antiviral Res. 2014 Oct;110:1-9. doi: 10.1016/j.antiviral.2014.07.003. Epub 2014 Jul 17.

H1PVAT is a novel and potent early-stage inhibitor of poliovirus replication that targets VP1.

Author information

1
Laboratory of Virology and Chemotherapy, KU Leuven, Leuven, Belgium.
2
Centre for Innovation and Stimulation of Drug Discovery, CISTIM Leuven vzw, Leuven, Belgium.
3
Polio and Picornavirus Lab, Branch Division of Viral Diseases, NCIRD/OID/CDC, Atlanta, USA.
4
Institut für Pharmazie, Abteilung Pharmazeutische Chemie, Universität Innsbruck, Innrain 52a, A-6020 Innsbruck, Austria.
5
Division of Virology, National Institute for Biological Standards and Control, Potters Bar, Hertfordshire, UK.
6
Centre for Drug Design and Discovery, KU Leuven, Leuven, Belgium; Centre for Innovation and Stimulation of Drug Discovery, CISTIM Leuven vzw, Leuven, Belgium.
7
Laboratory of Virology and Chemotherapy, KU Leuven, Leuven, Belgium. Electronic address: johan.neyts@rega.kuleuven.be.

Abstract

A novel small molecule, H1PVAT, was identified as a potent and selective inhibitor of the in vitro replication of all three poliovirus serotypes, whereas no activity was observed against other enteroviruses. Time-of-drug-addition studies revealed that the compound interfered with an early stage of virus replication. Four independently-selected H1PVAT-resistant virus variants uniformly carried the single amino acid substitution I194F in the VP1 capsid protein. Poliovirus type 1 strain Sabin, reverse-engineered to contain this substitution, proved to be completely insensitive to the antiviral effect of H1PVAT and was cross-resistant to the capsid-binding inhibitors V-073 and pirodavir. The VP1 I194F mutant had a smaller plaque phenotype than wild-type virus, and the amino acid substitution rendered the virus more susceptible to heat inactivation. Both for the wild-type and VP1 I194F mutant virus, the presence of H1PVAT increased the temperature at which the virus was inactivated, providing evidence that the compound interacts with the viral capsid, and that capsid stabilization and antiviral activity are not necessarily correlated. Molecular modeling suggested that H1PVAT binds with high affinity in the pocket underneath the floor of the canyon that is involved in receptor binding. Introduction of the I194F substitution in the model of VP1 induced a slight concerted rearrangement of the core β-barrel in this pocket, which disfavors binding of the compound. Taken together, the compound scaffold, to which H1PVAT belongs, may represent another promising class of poliovirus capsid-binding inhibitors next to V-073 and pirodavir. Potent antivirals against poliovirus will be essential in the poliovirus eradication end-game.

KEYWORDS:

Capsid-binder; Picornavirus; Pirodavir; Poliovirus; V-073; VP1

PMID:
25043639
DOI:
10.1016/j.antiviral.2014.07.003
[Indexed for MEDLINE]

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