The VIZIER project: Overview; expectations; and achievements

Coutard, Bruno; Canard, Bruno

doi:10.1016/j.antiviral.2010.02.326

Cited by 13 publications

(5 citation statements)

References 51 publications

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“…However, it should be realized that big pharma generally has little interest in emerging RNA viruses, because these typically cause self‐limiting rather than chronic disease. Yet, these viruses potentially pose a big threat to man, as we were impressively taught by the SARS coronavirus , and we are well advised to increase our preparedness in view of the increasing frequency of outbreaks caused by these viruses . Academic institutions have important tasks in these efforts at increasing preparedness, as far as the preclinical discovery phase of the drug development process is concerned .…”

Section: Discussionmentioning

confidence: 99%

From SARS to MERS: crystallographic studies on coronaviral proteases enable antiviral drug design

2014

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This review focuses on the important contributions that macromolecular crystallography has made over the past 12 years to elucidating structures and mechanisms of the essential proteases of coronaviruses, the main protease (M pro ) and the papain-like protease (PL pro ). The role of X-ray crystallography in structure-assisted drug discovery against these targets is discussed. Aspects dealt with in this review include the emergence of the SARS coronavirus in 2002-2003 and of the MERS coronavirus 10 years later and the origins of these viruses. The crystal structure of the free SARS coronavirus M pro and its dependence on pH is discussed, as are efforts to design inhibitors on the basis of these structures. The mechanism of maturation of the enzyme from the viral polyprotein is still a matter of debate. The crystal structure of the SARS coronavirus PL pro and its complex with ubiquitin is also discussed, as is its orthologue from MERS coronavirus. Efforts at predictive structure-based inhibitor development for bat coronavirus M pro s to increase the preparedness against zoonotic transmission to man are described as well. The paper closes with a brief discussion of structure-based discovery of antivirals in an academic setting.

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Section: Discussionmentioning

confidence: 99%

From SARS to MERS: crystallographic studies on coronaviral proteases enable antiviral drug design

2014

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“…Extensive efforts to obtain high-resolution crystal structures of NNS L proteins, or parts there of, have so far proved unsuccessful (12,13). Comparison of evolutionarily divergent NNS L proteins (14) has revealed partitioning of conserved sequences into six distinct blocks, conserved region I (CRI) to CRVI, postulated to be domains with specific functions (Fig.…”

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confidence: 99%

Putative Domain-Domain Interactions in the Vesicular Stomatitis Virus L Polymerase Protein Appendage Region

Ruedas

Perrault

2014

J Virol

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The multidomain polymerase protein (L) of nonsegmented negative-strand (NNS) RNA viruses catalyzes transcription and replication of the virus genome. The N-terminal half of the protein forms a ring-like polymerase structure, while the C-terminal half encoding viral mRNA transcript modifications consists of a flexible appendage with three distinct globular domains. To gain insight into putative transient interactions between L domains during viral RNA synthesis, we exchanged each of the four distinct regions encompassing the appendage region of vesicular stomatitis virus (VSV) Indiana serotype L protein with their counterparts from VSV New Jersey and analyzed effects on virus polymerase activity in a minigenome system. The methyltransferase domain exchange yielded a fully active polymerase protein, which functioned as well as wild-type L in the context of a recombinant virus. Exchange of the downstream C-terminal nonconserved region abolished activity, but coexchanging it with the methyltransferase domain generated a polymerase favoring replicase over transcriptase activity, providing strong evidence of interaction between these two regions. Exchange of the capping enzyme domain or the adjacent nonconserved region thought to function as an "unstructured" linker also abrogated polymerase activity even when either domain was coexchanged with other appendage domains. Further probing of the putative linker segment using in-frame enhanced green fluorescent protein (EGFP) insertions similarly abrogated activity. We discuss the implications of these findings with regard to L protein appendage domain structure and putative domain-domain interactions required for polymerase function. IMPORTANCE NNS viruses include many well-known human pathogens (e.g., rabies, measles, and Ebola viruses), as well as emerging viral threats (e.g., Nipah and Hendra viruses). These viruses all encode a large L polymerase protein similarly organized into multiple domains that work in concert to enable virus genome transcription and replication. But how the unique L protein carries out the multiplicity of individual steps in these two distinct processes is poorly understood. Using two different approaches, i.e., exchanging individual domains in the C-terminal appendage region of the protein between two closely related VSV serotypes and inserting unrelated protein domains, we shed light on requirements for domain-domain interactions and domain contiguity in polymerase function. These findings further our understanding of the conformational dynamics of NNS L polymerase proteins, which play an essential role in the pathogenic properties of these viruses and represent attractive targets for the development of antiviral measures.

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“…Various efforts has been made to develop an effective anti-flavi drugs aiming specific replication, structural, non-structural, and host protein, as well as non-specific targets, etc (Sampath and Padmanabhan, 2009; Bollati et al, 2010; García et al, 2017). To tackle the severity of the RNA viruses, the European Union released VIZIER (Coutard and Canard, 2010) and SILVER 2 projects for drug discovery against viruses. However, various computational efforts would be useful along with the experimental ones to speed up the antiviral drug discovery process.…”

Section: Discussionmentioning

confidence: 99%

Anti-flavi: A Web Platform to Predict Inhibitors of Flaviviruses Using QSAR and Peptidomimetic Approaches

Rajput

Kumar

2018

Front. Microbiol.

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Flaviviruses are arboviruses, which comprises more than 70 viruses, covering broad geographic ranges, and responsible for significant mortality and morbidity globally. Due to the lack of efficient inhibitors targeting flaviviruses, the designing of novel and efficient anti-flavi agents is an important problem. Therefore, in the current study, we have developed a dedicated prediction algorithm anti-flavi, to identify inhibition ability of chemicals and peptides against flaviviruses through quantitative structure–activity relationship based method. We extracted the non-redundant 2168 chemicals and 117 peptides from ChEMBL and AVPpred databases, respectively, with reported IC50 values. The regression based model developed on training/testing datasets of 1952 chemicals and 105 peptides displayed the Pearson’s correlation coefficient (PCC) of 0.87, 0.84, and 0.87, 0.83 using support vector machine and random forest techniques correspondingly. We also explored the peptidomimetics approach, in which the most contributing descriptors of peptides were used to identify chemicals having anti-flavi potential. Conversely, the selected descriptors of chemicals performed well to predict anti-flavi peptides. Moreover, the developed model proved to be highly robust while checked through various approaches like independent validation and decoy datasets. We hope that our web server would prove a useful tool to predict and design the efficient anti-flavi agents. The anti-flavi webserver is freely available at URL http://bioinfo.imtech.res.in/manojk/antiflavi.

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The VIZIER project: Overview; expectations; and achievements

Cited by 13 publications

References 51 publications

From SARS to MERS: crystallographic studies on coronaviral proteases enable antiviral drug design

From SARS to MERS: crystallographic studies on coronaviral proteases enable antiviral drug design

Putative Domain-Domain Interactions in the Vesicular Stomatitis Virus L Polymerase Protein Appendage Region

Anti-flavi: A Web Platform to Predict Inhibitors of Flaviviruses Using QSAR and Peptidomimetic Approaches

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