Intrinsic molecular activities of the interferon-induced 2-5A-dependent RNase.

Dong, Bin; Xu, Lulu; Zhou, Aimin; Hassel, Bret A.; Lee, Xavier; Torrence, Paul F.; Silverman, Robert H.

doi:10.1016/s0021-9258(17)36767-4

Cited by 147 publications

(30 citation statements)

References 43 publications

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“…Additionally, it has been shown that indole alkaloids such as arbidol and homoharringtonine are capable of activating the type I IFN response [ 56 , 57 ] and that Vero is a cell line that lacks IFN-alpha genes, a fundamental component in the innate antiviral response. IFN is induced in response to the presence and identification of viral or double-stranded RNA within the cell and subsequently activates INF-stimulated genes, such as PKR, 2′-5′ oligoadenylate synthetases, and RNase L, among others [ 58 ], which could degrade viral RNA [ 59 ]. Taking the above into account, this could be the reason for the difference found in the inhibition of the genome between Vero cells and human cell lines U937 and A549.…”

Section: Discussionmentioning

confidence: 99%

Indole alkaloids inhibit zika and chikungunya virus infection in different cell lines

Monsalve-Escudero

Loaiza-Cano

Pájaro-González

et al. 2021

BMC Complement Med Ther

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Background In recent years, an increase in the occurrence of illnesses caused by two clinically- important arboviruses has been reported: Zika virus (ZIKV) and Chikungunya virus (CHIKV). There is no licensed antiviral treatment for either of the two abovementioned viruses. Bearing in mind that the antiviral effect of indole alkaloids has been reported for other arboviral models, the present study proposed to evaluate the antiviral in vitro and in silico effects of four indole alkaloids on infections by these two viruses in different cell lines. Methods The antiviral effects of voacangine (VOAC), voacangine-7-hydroxyindolenine (VOAC-OH), rupicoline and 3-oxo voacangine (OXO-VOAC) were evaluated in Vero, U937 and A549 cells using different experimental strategies (Pre, Trans, Post and combined treatment). Viral infection was quantified by different methodologies, including infectious viral particles by plating, viral genome by RT-qPCR, and viral protein by cell ELISA. Moreover, molecular docking was used to evaluate the possible interactions between structural and nonstructural viral proteins and the compounds. The results obtained from the antiviral strategies for each experimental condition were compared in all cases with the untreated controls. Statistically significant differences were identified using a parametric Student’s t-test. In all cases, p values below 0.05 (p < 0.05) were considered statistically significant. Results In the pre-treatment strategy in Vero cells, VOAC and VOAC-OH inhibited both viral models and OXO-VOAC inhibited only ZIKV; in U937 cells infected with CHIKV/Col, only VOAC-OH inhibited infection, but none of the compounds had activity in A549 cells; in U937 cells and A549 cells infected with ZIKV/Col, the three compounds that were effective in Vero cells also had antiviral activity. In the trans-treatment strategy, only VOAC-OH was virucidal against ZIKV/Col. In the post-treatment strategy, only rupicoline was effective in the CHIKV/Col model in Vero and A549 cells, whereas VOAC and VOAC-OH inhibited ZIKV infection in all three cell lines. In the combined strategy, VOAC, VOAC-OH and rupicoline inhibited CHIKV/Col and ZIKV/Col, but only rupicoline improved the antiviral effect of ZIKV/Col-infected cultures with respect to the individual strategies. Molecular docking showed that all the compounds had favorable binding energies with the structural proteins E2 and NSP2 (CHIKV) and E and NS5 (ZIKV). Conclusions The present study demonstrates that indole alkaloids are promising antiviral drugs in the process of ZIKV and CHIKV infection; however, the mechanisms of action evaluated in this study would indicate that the effect is different in each viral model and, in turn, dependent on the cell line.

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Section: Discussionmentioning

confidence: 99%

Indole alkaloids inhibit zika and chikungunya virus infection in different cell lines

Monsalve-Escudero

Loaiza-Cano

Pájaro-González

et al. 2021

BMC Complement Med Ther

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“…When the OAS senses dsRNA activates the production of 2′,5′-oligoadenylates that act as a second messenger on the inactive monomeric RNaseL [45]. The 2′,5-oligoadenylates binding to RNase L produces a catalytically active dimer that cleaves ssRNA [46]. This leads to the translational arrest and prevent viral replication and spreading [47].…”

Section: Ifn Signaling In Antiviral Defensementioning

confidence: 99%

Viral pathogen-induced mechanisms to antagonize mammalian interferon (IFN) signaling pathway

Rojas

Alejo

Martı́n

et al. 2020

Cell. Mol. Life Sci.

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Antiviral responses of interferons (IFNs) are crucial in the host immune response, playing a relevant role in controlling viralw infections. Three types of IFNs, type I (IFN-α, IFN-β), II (IFN-γ) and III (IFN-λ), are classified according to their receptor usage, mode of induction, biological activity and amino acid sequence. Here, we provide a comprehensive review of type I IFN responses and different mechanisms that viruses employ to circumvent this response. In the first part, we will give an overview of the different induction and signaling cascades induced in the cell by IFN-I after virus encounter. Next, highlights of some of the mechanisms used by viruses to counteract the IFN induction will be described. And finally, we will address different mechanism used by viruses to interference with the IFN signaling cascade and the blockade of IFN induced antiviral activities.

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“…dsRNA binding to OAS promotes synthesis of unique 2 0 -5 0 -linked oligoadenylate (2-5A) molecules that act as a secondary messenger to activate their only known downstream target: the latent ribonuclease (RNase L; Hovanessian & Justesen, 2007). RNase L is ubiquitously expressed and present in an inactive monomeric form in the cytoplasm; binding of 2-5A (≥3 nucleotides in length) drives RNase L dimerization and thus activation of its ribonuclease activity (Figure 1a; Dong et al, 1994;Y. Han, Whitney, Donovan, & Korennykh, 2012;Huang et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

RNA regulation of the antiviral protein 2′‐5′‐oligoadenylate synthetase

Schwartz

Conn

2019

WIREs RNA

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The innate immune system is a broad collection of critical intra‐ and extra‐cellular processes that limit the infectivity of diverse pathogens. The 2′‐5′‐oligoadenylate synthetase (OAS) family of enzymes are important sensors of cytosolic double‐stranded RNA (dsRNA) that play a critical role in limiting viral infection by activating the latent ribonuclease (RNase L) to halt viral replication and establish an antiviral state. Attesting to the importance of the OAS/RNase L pathway, diverse viruses have developed numerous distinct strategies to evade the effects of OAS activation. How OAS proteins are regulated by viral or cellular RNAs is not fully understood but several recent studies have provided important new insights into the molecular mechanisms of OAS activation by dsRNA. Other studies have revealed unanticipated features of RNA sequence and structure that strongly enhance activation of at least one OAS family member. While these discoveries represent important advances, they also underscore the fact that much remains to be learned about RNA‐mediated regulation of the OAS/RNase L pathway. In particular, defining the full complement of RNA molecular signatures that activate OAS is essential to our understanding of how these proteins maximize their protective role against pathogens while still accurately discriminating host molecules to avoid inadvertent activation by cellular RNAs. A more complete knowledge of OAS regulation may also serve as a foundation for the development of novel antiviral therapeutic strategies and lead the way to a deeper understanding of currently unappreciated cellular functions of the OAS/RNase L pathway in the absence of infection. This article is categorized under: RNA in Disease and Development > RNA in Disease RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications Translation > Translation Regulation

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Intrinsic molecular activities of the interferon-induced 2-5A-dependent RNase.

Cited by 147 publications

References 43 publications

Indole alkaloids inhibit zika and chikungunya virus infection in different cell lines

Indole alkaloids inhibit zika and chikungunya virus infection in different cell lines

Viral pathogen-induced mechanisms to antagonize mammalian interferon (IFN) signaling pathway

RNA regulation of the antiviral protein 2′‐5′‐oligoadenylate synthetase

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