The VIZIER project: preparedness against pathogenic RNA viruses

Abstract

Life-threatening RNA viruses emerge regularly, and often in an unpredictable manner. Yet, the very few drugs available against known RNA viruses have sometimes required decades of research for development. Can we generate preparedness for outbreaks of the, as yet, unknown viruses? The VIZIER (VIral enZymes InvolvEd in Replication) (http://www.vizier-europe.org/) project has been set-up to develop the scientific foundations for countering this challenge to society. VIZIER studies the most conserved viral enzymes (that of the replication machinery, or replicases) that constitute attractive targets for drug-design. The aim of VIZIER is to determine as many replicase crystal structures as possible from a carefully selected list of viruses in order to comprehensively cover the diversity of the RNA virus universe, and generate critical knowledge that could be efficiently utilized to jump-start research on any emerging RNA virus. VIZIER is a multidisciplinary project involving (i) bioinformatics to define functional domains, (ii) viral genomics to increase the number of characterized viral genomes and prepare defined targets, (iii) proteomics to express, purify, and characterize targets, (iv) structural biology to solve their crystal structures, and (v) pre-lead discovery to propose active scaffolds of antiviral molecules.

Fig. 1

The pipeline organization of the VIZIER project, with its core (large symbols) and satellite labs (smaller symbols) represented by the numbers 1–25; The numbers 1–25 correspond to the a–z author laboratory addresses, respectively.

Fig. 2

The flow of information, material, and activities within the VIZIER pipeline. Viralis: Virus Alignment Suite; VaZyMolO: Viral Enzymes Modular Organization; SFV: Semliki Forest Virus.

Fig. 3

Phylogentic tree and crystal structures available before the start of the VIZIER project and now. The VIZIER contribution is shown in red (letters beside tree), with other contributions in blackI. P: Protease (Nt-NS3), H: Helicase (Ct-NS3), M: Mtase (Nt-NS5), R: RNA polymerase (Ct-NS5), #: crystals only. Only complete genome sequences are represented. In red (tree): sequences determined as part of the VIZIER project. NGOV is a new virus discovered and sequenced in VIZIER (Grard et al., 2006). This figure was prepared by Gilda Grard (Unité des Virus Emergents, Marseille).

Fig. 4

Discovery of a moderate flavivirus MTase inhibitor by virtual screening. (A) Electrostatic surface representation of the dengue virus NS5 MTase domain in complex with a cap analog depicting the cap-binding site during 2′O-methylation and SAH the co-product of the methyltransfer. The blue (positively charged) zone is thought to accommodate the RNA substrate. (B) Close-up of the SAM/SAH binding site showing a superposition of the docked inhibitor with an adamantane scaffold (coloured according to atom type) and SAH (pink). (C) Inhibition of the 2′OMTase activity of NS5MTase_DV by compound 17.