Acetylation of the NS3 helicase by KAT5γ is essential for flavivirus replication

Serman, Taryn M.; Chiang, Cindy; Liu, Guanqun; Sayyad, Zuberwasim; Pandey, Shanti; Volcic, Meta; Lee, Haejeong; Muppala, Santoshi; Acharya, Dhiraj; Goins, Christopher M.; Stauffer, Shaun R.; Gack, Michaela U.

doi:10.1016/j.chom.2023.06.013

Cited by 3 publications

(1 citation statement)

References 65 publications

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“…It is possible that like HSPA1A a fuller evaluation would show that they are indeed consistent, although the current results fit with our previous study 18 . A David functional annotation clustering ontology analysis (Supplemental Tables S4 and S5 ) indicated that the proteins were collectively associated with the process of cellular and nuclear acetylation, and acetylation of the NS3 helicase domain is known to be essential for flavivirus replication 33 , but again how discordant expression of these proteins affect viral replication remains unclear.…”

Section: Discussionmentioning

confidence: 99%

A 2D-proteomic analysis identifies proteins differentially regulated by two different dengue virus serotypes

Chumchanchira,

Ramphan,

Paemanee

et al. 2024

Sci Rep

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The mosquito transmitted dengue virus (DENV) is a major public health problem in many tropical and sub-tropical countries around the world. Both vaccine development and drug development are complex as the species Dengue virus consist of four distinct viruses (DENV 1 to DENV 4) each of which is composed of multiple lineages and strains. To understand the interaction of DENV with the host cell machinery, several studies have undertaken in vitro proteomic analysis of different cell lines infected with DENV. Invariably, these studies have utilized DENV 2. In this study we sought to define proteins that are differentially regulated by two different DENVs, DENV 2 and DENV 4. A 2-dimensional proteomic analysis identified some 300 protein spots, of which only 11 showed differential expression by both DENVs. Of these, only six were coordinately regulated. One protein, prohibitin 1 (PHB1) was downregulated by infection with both DENVs. Overexpression of PHB1 increased DENV protein expression, level of infection and genome copy number. DENV E protein colocalized with PHB, and there was a direct interaction between DENV 2 E protein and PHB1, but not between DENV 4 E protein and PHB1. The low number of proteins showing coordinate regulation after infection by different DENVs is a cause for concern, particularly in determining new druggable targets, and suggests that studies should routinely investigate multiple DENVs.

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Section: Discussionmentioning

confidence: 99%

A 2D-proteomic analysis identifies proteins differentially regulated by two different dengue virus serotypes

Chumchanchira,

Ramphan,

Paemanee

et al. 2024

Sci Rep

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ADAM9 promotes type I interferon-mediated innate immunity during encephalomyocarditis virus infection

Bazzone,

Zhu,

King

et al. 2024

Nat Commun

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Viral myocarditis, an inflammatory disease of the heart, causes significant morbidity and mortality. Type I interferon (IFN)-mediated antiviral responses protect against myocarditis, but the mechanisms are poorly understood. We previously identified A Disintegrin And Metalloproteinase domain 9 (ADAM9) as an important factor in viral pathogenesis. ADAM9 is implicated in a range of human diseases, including inflammatory diseases; however, its role in viral infection is unknown. Here, we demonstrate that mice lacking ADAM9 are more susceptible to encephalomyocarditis virus (EMCV)-induced death and fail to mount a characteristic type I IFN response. This defect in type I IFN induction is specific to positive-sense, single-stranded RNA (+ ssRNA) viruses and involves melanoma differentiation-associated protein 5 (MDA5)—a key receptor for +ssRNA viruses. Mechanistically, ADAM9 binds to MDA5 and promotes its oligomerization and thereby downstream mitochondrial antiviral-signaling protein (MAVS) activation in response to EMCV RNA stimulation. Our findings identify a role for ADAM9 in the innate antiviral response, specifically MDA5-mediated IFN production, which protects against virus-induced cardiac damage, and provide a potential therapeutic target for treatment of viral myocarditis.

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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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Acetylation of the NS3 helicase by KAT5γ is essential for flavivirus replication

Cited by 3 publications

References 65 publications

A 2D-proteomic analysis identifies proteins differentially regulated by two different dengue virus serotypes

A 2D-proteomic analysis identifies proteins differentially regulated by two different dengue virus serotypes

ADAM9 promotes type I interferon-mediated innate immunity during encephalomyocarditis virus infection

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

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