Targeting the Human DEAD-Box Polypeptide 3 (DDX3) RNA Helicase as a Novel Strategy to Inhibit Viral Replication

Garbelli, Anna; Radi, Marco; Falchi, Federico; Beermann, Sandra; Zanoli, Samantha; Manetti, Fabrizio; Dietrich, Ursula; Botta, Maurizio; Maga, Giovanni

doi:10.2174/092986711796391688

Cited by 51 publications

(38 citation statements)

References 121 publications

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“…23,24), including, most recently, small molecule inhibitors that target the DDX3 RNA binding site as a potential anti-HIV therapy. 23 However, numerous studies have demonstrated that DDX3 and its yeast homolog (Ded1p) function in multiple cellular processes involved in the regulation of gene expression (reviewed in refs.…”

Section: Ddx3mentioning

confidence: 99%

DEAD box RNA helicase functions in cancer

2013

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Section: Ddx3mentioning

confidence: 99%

DEAD box RNA helicase functions in cancer

2013

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“…6C). DDX3 has recently been identified with a number of small-molecule inhibitors as a potential anti-HIV therapeutic (20,43,44,55). Therefore, the identification of DDX3 as an intracellular factor required for norovirus replication provides an additional target for small-molecule intervention against norovirus infection.…”

Section: Figmentioning

confidence: 99%

Identification of RNA-Protein Interaction Networks Involved in the Norovirus Life Cycle

Vashist

Ureña

Chaudhry

et al. 2012

J Virol

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Human noroviruses are one of the major causes of acute gastroenteritis in the developed world, yet our understanding of their molecular mechanisms of genome translation and replication lags behind that for many RNA viruses. Due to the nonculturable nature of human noroviruses, many related members of the Caliciviridae family of small RNA viruses are often used as model systems to dissect the finer details of the norovirus life cycle. Murine norovirus (MNV) has provided one such system with which to study the basic mechanisms of norovirus translation and replication in cell culture. In this report we describe the use of riboproteomics to identify host factors that interact with the extremities of the MNV genome. This network of RNA-protein interactions contains many well-characterized host factors, including PTB, La, and DDX3, which have been shown to play a role in the life cycle of other RNA viruses. By using RNA coimmunoprecipitation, we confirmed that a number of the factors identified using riboproteomics are associated with the viral RNA during virus replication in cell culture. We further demonstrated that RNA inhibition-mediated knockdown of the intracellular levels of a number of these factors inhibits or slows norovirus replication in cell culture, allowing identification of new intracellular targets for this important group of pathogens. The genomes of small positive-strand RNA viruses must not only encode the viral proteins required for viral genome replication and infectious virus production, but they must also contain cis-acting RNA sequences and structures that play critical roles in the virus life cycle (40). Host cell factors that interact with these RNA elements play important roles in all aspects of the virus life cycle (49); consequently, the manipulation of these interactions via the introduction of mutations into the viral genome is a viable approach to rational attenuation (24,26,57,78). In addition, the modification of these RNA-protein interactions by using small-molecule or peptide inhibitors has been shown to provide antiviral activity, at least in cell culture (8,19).Noroviruses, first identified in 1972 by Albert Kapikian (33), are now accepted as the major cause of viral gastroenteritis in the developed world (21). Reports indicate that in excess of 23 million cases occur each year in the United States, resulting in a significant economic impact. Now over 20 years since the first full genome sequence of a norovirus became available (77), investigators are still unable to efficiently propagate human noroviruses in cell culture (15, 37). Recent data have indicated that the viral RNA purified from the feces of individuals infected with Norwalk virus, the prototype human norovirus, can replicate when transfected into immortalized cells in culture (23). These data clearly demonstrate that one of the major blocks in the ability of human noroviruses to replicate in cell culture is the ability of the virus to enter and spread from cell to cell. It is also clear that the intracellular environ...

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“…Several inhibitors of the ATPase activity of DDX3 have been recently identified (29)(30)(31)(32)(33)(34); however, an ATP-mimetic compound may have a low degree of selectivity in vivo because of the possibility of interacting with many targets (35).…”

mentioning

confidence: 99%

Human DDX3 protein is a valuable target to develop broad spectrum antiviral agents

Brai

Fazi

Tintori

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

102

110

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Targeting a host factor essential for the replication of different viruses but not for the cells offers a higher genetic barrier to the development of resistance, may simplify therapy regimens for coinfections, and facilitates management of emerging viral diseases. DEADbox polypeptide 3 (DDX3) is a human host factor required for the replication of several DNA and RNA viruses, including some of the most challenging human pathogens currently circulating, such as HIV-1, Hepatitis C virus, Dengue virus, and West Nile virus. Herein, we showed for the first time, to our knowledge, that the inhibition of DDX3 by a small molecule could be successfully exploited for the development of a broad spectrum antiviral agent. In addition to the multiple antiviral activities, hit compound 16d retained full activity against drug-resistant HIV-1 strains in the absence of cellular toxicity. Pharmacokinetics and toxicity studies in rats confirmed a good safety profile and bioavailability of 16d. Thus, DDX3 is here validated as a valuable therapeutic target.broad spectrum antivirals | DDX3 | host factors | resistance | coinfections

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Targeting the Human DEAD-Box Polypeptide 3 (DDX3) RNA Helicase as a Novel Strategy to Inhibit Viral Replication

Cited by 51 publications

References 121 publications

DEAD box RNA helicase functions in cancer

DEAD box RNA helicase functions in cancer

Identification of RNA-Protein Interaction Networks Involved in the Norovirus Life Cycle

Human DDX3 protein is a valuable target to develop broad spectrum antiviral agents

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