Toward the Discovery of Novel Anti‐HIV Drugs. Second‐Generation Inhibitors of the Cellular ATPase DDX3 with Improved Anti‐HIV Activity: Synthesis, Structure–Activity Relationship Analysis, Cytotoxicity Studies, and Target Validation

Maga, Giovanni; Falchi, Federico; Radi, Marco; Botta, Lorenzo; Casaluce, Gianni; Bernardini, Martina; Irannejad, Hamid; Manetti, Fabrizio; Garbelli, Anna; Samuele, Alberta; Zanoli, Samantha; Esté, José A.; González, Emmanuel; Zucca, Elisa; Paolucci, Stefania; Baldanti, Fausto; Rijck, Jan De; Debyser, Zeger; Botta, Maurizio

doi:10.1002/cmdc.201100166

Cited by 96 publications

(53 citation statements)

References 32 publications

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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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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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“…Knock-down of DDX3 does not have cytotoxic effects in cell culture, but suppresses viral replication. 64 Recent studies have reported rhodanine-and triazine-based compounds, [205][206][207] and ring-expanded nucleosides 208 as DDX3 inhibitors with anti-HIV activity, as well as a small molecule that interferes with RNA binding to DDX3 and reduces the viral load of peripheral mononuclear blood cells 209 Treatment of hepatitis C. More than 170 million individuals worldwide are estimated to carry HCV. Guided by the success of anti-HIV therapies with protease inhibitors, structure-based design of therapeutic drugs against HCV have also focused on the viral protease.…”

Section: Rna Helicases As Drug Targetsmentioning

confidence: 99%

RNA helicases in infection and disease

Steimer

Klostermeier

2012

RNA Biology

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“…In fact, triazines with the general structure A represent the rigid analogues of C as shown in Figure 1. Triazines have been shown to possess antitumoral properties, 14 but their activity on breast cancer cells has not yet been fully investigated. 15 …”

Section: D (N-[n-[8-[[n-(morpholine-4-carbonyl)carbamimidoyl] Amino]mentioning

confidence: 99%

Synthesis and Biological Evaluation of Amidinourea and Triazine Congeners as Inhibitors of MDA‐MB‐231 Human Breast Cancer Cell Proliferation

et al. 2017

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Toward the Discovery of Novel Anti‐HIV Drugs. Second‐Generation Inhibitors of the Cellular ATPase DDX3 with Improved Anti‐HIV Activity: Synthesis, Structure–Activity Relationship Analysis, Cytotoxicity Studies, and Target Validation

Cited by 96 publications

References 32 publications

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

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

RNA helicases in infection and disease

Synthesis and Biological Evaluation of Amidinourea and Triazine Congeners as Inhibitors of MDA‐MB‐231 Human Breast Cancer Cell Proliferation

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