Tizoxanide Antiviral Activity on Dengue Virus Replication

Yamamoto, Kristie Aimi; Blackburn, Kevin; Goshe, Michael B.; Brown, Dennis T.; Migoswski, Edimilson; Campanhon, Isabele Batista; Moreira, Mônica F.; Ferreira, Davis Fernandes; Soares, Márcia Regina

doi:10.3390/v15030696

Cited by 3 publications

(1 citation statement)

References 64 publications

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“…From the genomics side, EVEs are of interest due to their important roles in physiology and genome evolution [78]. These include roles antiviral immunity [11, 79, 80], and a diverse range of other physiological processes [18, 58, 59, 81–83]. Notably, we identified numerous non-retroviral EVEs encoding ORFs longer than 300aa ( Fig.…”

Section: Discussionmentioning

confidence: 99%

A novel approach to exploring the dark genome and its application to mapping of the vertebrate virus ‘fossil record’

Blanco-Melo,

Campbell,

Zhu

et al. 2023

Preprint

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Background: Genomic regions that remain poorly understood, often referred to as the "dark genome," contain a variety of functionally relevant and biologically informative genome features. These include endogenous viral elements (EVEs) - virus-derived sequences that can dramatically impact host biology and serve as a virus "fossil record". In this study, we introduce a database-integrated genome screening (DIGS) approach to investigating the dark genome in silico, focusing on EVEs found within vertebrate genomes. Results: Using DIGS on 874 vertebrate species genomes, we uncovered approximately 1.1 million EVE sequences, with over 99% originating from endogenous retroviruses or transposable elements that contain EVE DNA. We show that the remaining 6038 sequences represent over a thousand distinct horizontal gene transfer events across ten virus families, including some that have not previously been reported as EVEs. We explore the genomic and phylogenetic characteristics of non-retroviral EVEs and determine their rates of acquisition during vertebrate evolution. Our study uncovers novel virus diversity and broadens our knowledge of virus distribution among vertebrate hosts. It also provides new insights into the long-term evolution of highly pathogenic filoviruses. Conclusions: We comprehensively catalogue and analyse EVEs within 874 vertebrate genomes, shedding light on the distribution, diversity and long-term evolution of viruses, and revealing their extensive impact on vertebrate genome evolution. Our results demonstrate the power of linking a relational database management system to a similarity search-based screening pipeline for in silico exploration of the dark genome.

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Section: Discussionmentioning

confidence: 99%

A novel approach to exploring the dark genome and its application to mapping of the vertebrate virus ‘fossil record’

Blanco-Melo,

Campbell,

Zhu

et al. 2023

Preprint

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The modulation of proteomics and antioxidant stress is involved in the effect of nitazoxanide against Japanese encephalitis virus in vitro

Su,

Wang,

Xiong

et al. 2024

Veterinary Microbiology

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Orthoflaviviral Inhibitors in Clinical Trials, Preclinical In Vivo Efficacy Targeting NS2B-NS3 and Cellular Antiviral Activity via Competitive Protease Inhibition

Cavina,

Bouma,

Gironés

et al. 2024

Molecules

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Orthoflaviviruses, including zika (ZIKV), West Nile (WNV), and dengue (DENV) virus, induce severely debilitating infections and contribute significantly to the global disease burden, yet no clinically approved antiviral treatments exist. This review offers a comprehensive analysis of small-molecule drug development targeting orthoflaviviral infections, with a focus on NS2B-NS3 inhibition. We systematically examined clinical trials, preclinical efficacy studies, and modes of action for various viral replication inhibitors, emphasizing allosteric and orthosteric drugs inhibiting NS2B-NS3 protease with in vivo efficacy and in vitro-tested competitive NS2B-NS3 inhibitors with cellular efficacy. Our findings revealed that several compounds with in vivo preclinical efficacy failed to show clinical antiviral efficacy. NS3-NS4B inhibitors, such as JNJ-64281802 and EYU688, show promise, recently entering clinical trials, underscoring the importance of developing novel viral replication inhibitors targeting viral machinery. To date, the only NS2B-NS3 inhibitor that has undergone clinical trials is doxycycline, however, its mechanism of action and clinical efficacy as viral growth inhibitor require additional investigation. SYC-1307, an allosteric inhibitor, exhibits high in vivo efficacy, while temoporfin and methylene blue represent promising orthosteric non-competitive inhibitors. Compound 71, a competitive NS2B-NS3 inhibitor, emerges as a leading preclinical candidate due to its high cellular antiviral efficacy, minimal cytotoxicity, and favorable in vitro pharmacokinetic parameters. Challenges remain in developing competitive NS2B-NS3 inhibitors, including appropriate biochemical inhibition assays as well as the selectivity and conformational flexibility of the protease, complicating effective antiviral treatment design.

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Tizoxanide Antiviral Activity on Dengue Virus Replication

Cited by 3 publications

References 64 publications

A novel approach to exploring the dark genome and its application to mapping of the vertebrate virus ‘fossil record’

A novel approach to exploring the dark genome and its application to mapping of the vertebrate virus ‘fossil record’

The modulation of proteomics and antioxidant stress is involved in the effect of nitazoxanide against Japanese encephalitis virus in vitro

Orthoflaviviral Inhibitors in Clinical Trials, Preclinical In Vivo Efficacy Targeting NS2B-NS3 and Cellular Antiviral Activity via Competitive Protease Inhibition

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