Targeting flavivirus RNA dependent RNA polymerase through a pyridobenzothiazole inhibitor

Tarantino, Delia; Cannalire, Rolando; Mastrangelo, Eloise; Croci, Romina; Quérat, Gilles; Barreca, Maria Letizia; Bolognesi, Martino; Manfroni, Giuseppe; Cecchetti, Violetta; Milani, Mario

doi:10.1016/j.antiviral.2016.09.007

Cited by 58 publications

(42 citation statements)

References 33 publications

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“…4b). Molecular interactions with amino acids of this binding site are important to generate both potent and pan-serotype active NS5 RdRp inhibitors61213. Therefore, these findings indicate some structural determinants that can be explored for the discovery and development of new antiviral against ZIKV NS5 RdRp.…”

Section: Discussionmentioning

confidence: 95%

Crystal structure of Zika virus NS5 RNA-dependent RNA polymerase

et al. 2017

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The current Zika virus (ZIKV) outbreak became a global health threat of complex epidemiology and devastating neurological impacts, therefore requiring urgent efforts towards the development of novel efficacious and safe antiviral drugs. Due to its central role in RNA viral replication, the non-structural protein 5 (NS5) RNA-dependent RNA-polymerase (RdRp) is a prime target for drug discovery. Here we describe the crystal structure of the recombinant ZIKV NS5 RdRp domain at 1.9 Å resolution as a platform for structure-based drug design strategy. The overall structure is similar to other flaviviral homologues. However, the priming loop target site, which is suitable for non-nucleoside polymerase inhibitor design, shows significant differences in comparison with the dengue virus structures, including a tighter pocket and a modified local charge distribution.

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Section: Discussionmentioning

confidence: 95%

Crystal structure of Zika virus NS5 RNA-dependent RNA polymerase

et al. 2017

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“…The discovery of compounds is highly dependent on the development of reliable inhibition assays amenable to high throughput screenings (HTS) using various compound libraries. The selection of lead molecules with NS5 inhibitory activity employed X-ray crystallography (to identify fragments that bind to the protein [81]), or were based on enzymatic inhibition assay or virtual screenings [82,83]. Both the initiation step and the elongation step [84,85] or capping activity were targeted [86].…”

Section: Antiviral Strategies Against Ns5mentioning

confidence: 99%

Dengue Virus Non-Structural Protein 5

Sahili¹,

Lescar

2017

Viruses

111

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The World Health Organization estimates that the yearly number of dengue cases averages 390 million. This mosquito-borne virus disease is endemic in over 100 countries and will probably continue spreading, given the observed trend in global warming. So far, there is no antiviral drug available against dengue, but a vaccine has been recently marketed. Dengue virus also serves as a prototype for the study of other pathogenic flaviviruses that are emerging, like West Nile virus and Zika virus. Upon viral entry into the host cell and fusion of the viral lipid membrane with the endosomal membrane, the viral RNA is released and expressed as a polyprotein, that is then matured into three structural and seven non-structural (NS) proteins. The envelope, membrane and capsid proteins form the viral particle while NS1-NS2A-NS2B-NS3-NS4A-NS4B and NS5 assemble inside a cellular replication complex, which is embedded in endoplasmic reticulum (ER)-derived vesicles. In addition to their roles in RNA replication within the infected cell, NS proteins help the virus escape the host innate immunity and reshape the host-cell inner structure. This review focuses on recent progress in characterizing the structure and functions of NS5, a protein responsible for the replication and capping of viral RNA that represents a promising drug target.

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“…In this context, Tarantino et al reported the biochemical and crystallographic characterisation of a pyridobenzothiazole lead (9) as an inhibitor of flavivirus RdRp in micromolar range possessing very high selectivity against DENV2. [31] Subsequently, optimisation of a pyridobenzothiazole scaffold by a substituted phenyl ring provided a broad-spectrum antiviral agent 10 (Figure 4). [32] Anti-hepatitis C virus Hepatitis C virus (HCV) infection is a major global health concern.…”

Section: Denv Helicase Inhibitorsmentioning

confidence: 99%

Benzothiazoles as potential antiviral agents

Asiri

Alsayari

Muhsinah

et al. 2020

Journal of Pharmacy and Pharmacology

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Objectives The recent viral pandemic poses a unique challenge for healthcare providers. Despite the remarkable progress, the number of novel antiviral agents in the pipeline is woefully inadequate against the evolving virulence and drug resistance of current viruses. This highlights the urgent need for new and improved vaccines, diagnostics and therapeutic agents to obviate the viral pandemic. Key findings Benzothiazole plays a pivotal role in the design and development of antiviral drugs. This is evident from the fact that it comprises many clinically useful agents. The current review is aimed to provide an insight into the recent development of benzothiazole-based antiviral agents, with a special focus on their structure-activity relationships and lead optimisation. One hundred and five articles were initially identified, and from these studies, 64 potential novel lead molecules and main findings were highlighted in this review. Summary We hope this review will provide a logical perspective on the importance of improving the future designs of novel broad-spectrum benzothiazolebased antiviral agents to be used against emerging viral diseases. Benzothiazoles as antiviral agents Yahya I. Asiri et al.

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Targeting flavivirus RNA dependent RNA polymerase through a pyridobenzothiazole inhibitor

Cited by 58 publications

References 33 publications

Crystal structure of Zika virus NS5 RNA-dependent RNA polymerase

Crystal structure of Zika virus NS5 RNA-dependent RNA polymerase

Dengue Virus Non-Structural Protein 5

Benzothiazoles as potential antiviral agents

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