http://www.cnr.it/ontology/cnr/individuo/prodotto/ID188815

Structure-Based Inhibition of Norovirus RNA-Dependent RNA Polymerases (Articolo in rivista)

Type

Prodotto della ricerca (Classe)
Articolo in rivista (Classe)

Label

Structure-Based Inhibition of Norovirus RNA-Dependent RNA Polymerases (Articolo in rivista) (literal)

Anno

2012-01-01T00:00:00+01:00 (literal)

Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#doi

10.1016/j.jmb.2012.03.008 (literal)

Alternative label

Mastrangelo E; Pezzullo M; Tarantino D; Petazzi R; Germani F; Kramer D; Robel I; Rohayem J; Bolognesi M; Milani M (2012)
Structure-Based Inhibition of Norovirus RNA-Dependent RNA Polymerases
in Journal of Molecular Biology; Academic Press Ltd., Elsevier Science Ltd., London (Regno Unito)
(literal)

Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#autori

Mastrangelo E; Pezzullo M; Tarantino D; Petazzi R; Germani F; Kramer D; Robel I; Rohayem J; Bolognesi M; Milani M (literal)

Pagina inizio

198 (literal)

Pagina fine

210 (literal)

Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#url

http://www.sciencedirect.com/science/article/pii/S002228361200263X (literal)

Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#numeroVolume

419 (literal)

Rivista

Journal of Molecular Biology (Rivista)

Note

ISI Web of Science (WOS) (literal)

Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#affiliazioni

Department of Biomolecular Sciences and Biotechnology, University of Milano, Via Celoria 26, I-20133 Milano, Italy; CNR-IBF, Istituto di Biofisica, Via Celoria 26, I-20133 Milano, Italy; Institute of Virology, Dresden University of Technology, Fiedlerstrasse 42, 01307 Dresden, Germany; Riboxx GmbH, Pharmapark Radebeul, Meissner Strasse 191, 01445 Radebeul, Germany (literal)

Titolo

Structure-Based Inhibition of Norovirus RNA-Dependent RNA Polymerases (literal)

Abstract

Caliciviridae are RNA viruses with a single-stranded, positively oriented polyadenylated genome, responsible for a broad spectrum of diseases such as acute gastroenteritis in humans. Recently, analyses on the structures and functionalities of the RNA-dependent RNA polymerase (RdRp) from several Caliciviruses have been reported. The RdRp is predicted to play a key role in genome replication, as well as in synthesis and amplification of additional subgenomic RNA. Starting from the crystal structures of human Norovirus (hNV) RdRp, we performed an in silico docking search to identify synthetic compounds with predicted high affinity for the enzyme active site. The best-ranked candidates were tested in vitro on murine Norovirus (MNV) and hNV RdRps to assay their inhibition of RNA polymerization. The results of such combined computational and experimental screening approach led to the identification of two high-potency inhibitors: Suramin and NF023, both symmetric divalent molecules hosting two naphthalene-trisulfonic acid heads. We report here the crystal structure of MNV RdRp alone and in the presence of the two identified inhibitors. Both inhibitory molecules occupy the same RdRp site, between the fingers and thumb domains, with one inhibitor head close to residue 42 and to the protein active site. To further validate the structural results, we mutated Trp42 to Ala in MNV RdRp and the corresponding residue (i.e., Tyr41 to Ala) in hNV RdRp. Both NF023 and Suramin displayed reduced inhibitory potency versus the mutated hNV RdRp, thus hinting at a conserved inhibitor binding mode in the two polymerases. (literal)

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