title: H1PVAT is a novel and potent early-stage inhibitor of poliovirus replication that targets VP1.
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.
authors.affiliation: Laboratory of Virology and Chemotherapy, KU Leuven, Leuven, Belgium.
authors.forename: Aloys
authors.initials: A
authors.lastname: Tijsma
authors.affiliation: Laboratory of Virology and Chemotherapy, KU Leuven, Leuven, Belgium.
authors.forename: Hendrik Jan
authors.initials: HJ
authors.lastname: Thibaut
authors.affiliation: Centre for Innovation and Stimulation of Drug Discovery, CISTIM Leuven vzw, Leuven, Belgium.
authors.forename: Stéphane A H
authors.initials: SA
authors.lastname: Spieser
authors.affiliation: Laboratory of Virology and Chemotherapy, KU Leuven, Leuven, Belgium.
authors.forename: Armando
authors.initials: A
authors.lastname: De Palma
authors.affiliation: Centre for Innovation and Stimulation of Drug Discovery, CISTIM Leuven vzw, Leuven, Belgium.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Koukni
authors.affiliation: Polio and Picornavirus Lab, Branch Division of Viral Diseases, NCIRD/OID/CDC, Atlanta, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Rhoden
authors.affiliation: Polio and Picornavirus Lab, Branch Division of Viral Diseases, NCIRD/OID/CDC, Atlanta, USA.
authors.forename: Steve
authors.initials: S
authors.lastname: Oberste
authors.affiliation: Institut für Pharmazie, Abteilung Pharmazeutische Chemie, Universität Innsbruck, Innrain 52a, A-6020 Innsbruck, Austria.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Pürstinger
authors.affiliation: Centre for Innovation and Stimulation of Drug Discovery, CISTIM Leuven vzw, Leuven, Belgium.
authors.forename: Antonia
authors.initials: A
authors.lastname: Volny-Luraghi
authors.affiliation: Division of Virology, National Institute for Biological Standards and Control, Potters Bar, Hertfordshire, UK.
authors.forename: Javier
authors.initials: J
authors.lastname: Martin
authors.affiliation: Centre for Innovation and Stimulation of Drug Discovery, CISTIM Leuven vzw, Leuven, Belgium.
authors.forename: Arnaud
authors.initials: A
authors.lastname: Marchand
authors.affiliation: Centre for Drug Design and Discovery, KU Leuven, Leuven, Belgium; Centre for Innovation and Stimulation of Drug Discovery, CISTIM Leuven vzw, Leuven, Belgium.
authors.forename: Patrick
authors.initials: P
authors.lastname: Chaltin
authors.affiliation: Laboratory of Virology and Chemotherapy, KU Leuven, Leuven, Belgium. Electronic address: johan.neyts@rega.kuleuven.be.
authors.forename: Johan
authors.initials: J
authors.lastname: Neyts
authors.affiliation: Laboratory of Virology and Chemotherapy, KU Leuven, Leuven, Belgium.
authors.forename: Pieter
authors.initials: P
authors.lastname: Leyssen
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D001483:Base Sequence; D001665:Binding Sites; D002213:Capsid / Q000187:drug effects; D036022:Capsid Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D024882:Drug Resistance, Viral; D006367:HeLa Cells; D006801:Humans; D008958:Models, Molecular; D010880:Piperidines / Q000494:pharmacology; D011051:Poliomyelitis / Q000188:drug therapy*; D017955:Poliovirus / Q000187:drug effects / Q000235:genetics; D011720:Pyrazoles / Q000494:pharmacology*; D011724:Pyridazines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology*; D012367:RNA, Viral / Q000235:genetics; D017423:Sequence Analysis, RNA; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D036022:Capsid Proteins; C000598560:H1PVAT compound; D010880:Piperidines; D011720:Pyrazoles; D011724:Pyridazines; D011743:Pyrimidines; D012367:RNA, Viral; C442540:VP1 protein, Poliovirus; C074589:pirodavir
keywords: Capsid-binder; Picornavirus; Pirodavir; Poliovirus; V-073; VP1