2. Academic Validation
  3. Targeting flavivirus RNA dependent RNA polymerase through a pyridobenzothiazole inhibitor

Targeting flavivirus RNA dependent RNA polymerase through a pyridobenzothiazole inhibitor

  • Antiviral Res. 2016 Oct;134:226-235. doi: 10.1016/j.antiviral.2016.09.007.
Delia Tarantino 1,  Rolando Cannalire 2,  Eloise Mastrangelo 1,  Romina Croci 3,  Gilles Querat 4,  Maria Letizia Barreca 2,  Martino Bolognesi 1,  Giuseppe Manfroni 5,  Violetta Cecchetti 2,  Mario Milani 6
Affiliations

Affiliations

  • 1 Dipartimento di Bioscienze, Università di Milano, Via Celoria 26, I-20133, Milano, Italy; CNR-IBF, Istituto di Biofisica, Via Celoria 26, I-20133, Milano, Italy.
  • 2 Dipartimento di Scienze Farmaceutiche, Università degli Studi di Perugia, Perugia, Italy.
  • 3 Dipartimento di Bioscienze, Università di Milano, Via Celoria 26, I-20133, Milano, Italy.
  • 4 UMR "Emergence des Pathologies Virales" (EPV: Aix-Marseille university - IRD 190 - Inserm 1207 - EHESP), & Fondation IHU Méditerranée Infection, APHM Public Hospitals of Marseille, Marseille, France.
  • 5 Dipartimento di Scienze Farmaceutiche, Università degli Studi di Perugia, Perugia, Italy. Electronic address: giuseppe.manfroni@unipg.it.
  • 6 Dipartimento di Bioscienze, Università di Milano, Via Celoria 26, I-20133, Milano, Italy; CNR-IBF, Istituto di Biofisica, Via Celoria 26, I-20133, Milano, Italy. Electronic address: mario.milani@unimi.it.
PMID: 27649989 DOI: 10.1016/j.antiviral.2016.09.007
Abstract

RNA dependent RNA polymerases (RdRp) are essential enzymes for Flavivirus replication. Starting from an in silico docking analysis we identified a pyridobenzothiazole compound, HeE1-2Tyr, able to inhibit West Nile and Dengue RdRps activity in vitro, which proved effective against different flaviviruses in Cell Culture. Crystallographic data show that HeE1-2Tyr binds between the fingers domain and the priming loop of Dengue virus RdRp (Site 1). Conversely, Enzyme kinetics, binding studies and mutational analyses suggest that, during the catalytic cycle and assembly of the RdRp-RNA complex, HeE1-2Tyr might be hosted in a distinct binding site (Site 2). RdRp mutational studies, driven by in silico docking analysis, allowed us to locate the inhibition Site 2 in the thumb domain. Taken together, our results provide innovative concepts for optimization of a new class of anti-flavivirus compounds.

Keywords

Crystal structure; Flavivirus; Non-competitive inhibition; Polymerase mutants; RNA dependent RNA polymerase; Virus inhibition.

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