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Ko, Chunkyu,Lee, Sooyoung,Windisch, Marc P.,Ryu, Wang-Shick American Society for Microbiology 2014 Journal of virology Vol.88 No.23
<P>DDX3 is a member of the DEAD-box RNA helicase family, involved in mRNA metabolism, including transcription, splicing, and translation. We previously identified DDX3 as a hepatitis B virus (HBV) polymerase (Pol) binding protein, and by using a transient transfection, we found that DDX3 inhibits HBV replication at the posttranscriptional level, perhaps following encapsidation. To determine the exact mechanism of the inhibition, we here employed a diverse HBV experimental system. Inconsistently, we found that DDX3-mediated inhibition occurs at the level of transcription. By using tetracycline-inducible HBV-producing cells, we observed that lentivirus-mediated DDX3 expression led to a reduced level of HBV RNAs. Importantly, knockdown of DDX3 by short hairpin RNA resulted in augmentation of HBV RNAs in two distinct HBV replication systems: (i) tetracycline-inducible HBV-producing cells and (ii) constitutive HBV-producing HepG2.2.15 cells. Moreover, DDX3 knockdown in HBV-susceptible HepG2-NTCP cells, where covalently closed circular DNA (cccDNA) serves as the template for viral transcription, resulted in increased HBV RNAs, validating that transcription regulation by DDX3 occurs on a physiological template. Overall, our results demonstrate that DDX3 represents an intrinsic host antiviral factor that restricts HBV transcription.</P><P><B>IMPORTANCE</B> Upon entry into host cells, viruses encounter host factors that restrict viral infection. During evolution, viruses have acquired the ability to subvert cellular factors that adversely affect their replication. Such host factors include TRIM5α and APOBEC3G, which were discovered in retroviruses. The discovery of host restriction factors provided deeper insight into the innate immune response and viral pathogenesis, leading to better understanding of host-virus interactions. In contrast to the case with retroviruses, little is known about host factors that restrict hepatitis B virus (HBV), a virus distantly related to retroviruses. DDX3 DEAD box RNA helicase is best characterized as an RNA helicase involved in RNA metabolism, such as RNA processing and translation. Here, we show that DDX3 inhibits HBV infection at the level of viral transcription.</P>
Siddharta, Anindya,Pfaender, Stephanie,Vielle, Nathalie Jane,Dijkman, Ronald,Friesland, Martina,Becker, Britta,Yang, Jaewon,Engelmann, Michael,Todt, Daniel,Windisch, Marc P.,Brill, Florian H.,Steinman Oxford University Press 2017 The Journal of Infectious Diseases Vol.215 No.6
<P><B>Abstract</B></P><P>The World Health Organization (WHO) published 2 alcohol-based formulations to be used in healthcare settings and for outbreak-associated infections, but inactivation efficacies of these products have not been determined against (re-)emerging viruses. In this study, we evaluated the virucidal activity of these WHO products in a comparative analysis. Zika virus (ZIKV), Ebola virus (EBOV), severe acute respiratory syndrome coronavirus (SARS-CoV), and Middle East respiratory syndrome coronavirus (MERS-CoV) as (re-)emerging viral pathogens and other enveloped viruses could be efficiently inactivated by both WHO formulations, implicating their use in healthcare systems and viral outbreak situations.</P>
Kim, Hee-Young,Kong, Sunju,Oh, Sangmi,Yang, Jaewon,Jo, Eunji,Ko, Yoonae,Kim, Soo-Hyun,Hwang, Jong Yeon,Song, Rita,Windisch, Marc P. Elsevier 2016 ANTIVIRAL RESEARCH Vol.129 No.-
<P>Upon screening synthetic small molecule libraries with the infectious hepatitis C virus (HCV) cell culture system, we identified a benzothiazepinecarboxamide (BTC) scaffold that inhibits HCV. A structure-activity relationship (SAR) study with BTC5 was performed, and modifications that led to nanomolar antiviral activity and improved the selective index (CC50/EC50) by more than 1000-fold were identified. In addition, a pharmacophore modeling study determined that the tricyclic core and positive charge on the piperidine moiety were essential for antiviral activity. Furthermore, we demonstrated that BTC interferes with HCV glycoprotein E1/E2-mediated viral entry and the generation of infectious virions by using HCV pseudoparticle and cell culture supernatant transfer assays, respectively. BTC showed potent antiviral activity against HCV genotype 2 (EC50 = 0.01 +/- 0.01 mu M), but was less potent against a genotype 1/2 chimeric virus (EC50 = 2.71 +/- 0.05 mu M), which expressed the structural proteins of HCV genotype 1. In summary, we identified, optimized, and characterized novel BTC inhibitors that interfere with early and late steps of the HCV viral life cycle. (C) 2016 Elsevier B.V. All rights reserved.</P>
Automated genome-wide visual profiling of cellular proteins involved in HIV infection.
Genovesio, Auguste,Kwon, Yong-Jun,Windisch, Marc P,Kim, Nam Youl,Choi, Seo Yeon,Kim, Hi Chul,Jung, Sungyong,Mammano, Fabrizio,Perrin, Virginie,Boese, Annette S,Casartelli, Nicoletta,Schwartz, Olivier Mary Ann Liebert, Inc 2011 Journal of biomolecular screening Vol.16 No.9
<P>Recent genome-wide RNAi screens have identified >842 human genes that affect the human immunodeficiency virus (HIV) cycle. The list of genes implicated in infection differs between screens, and there is minimal overlap. A reason for this variance is the interdependence of HIV infection and host cell function, producing a multitude of indirect or pleiotropic cellular effects affecting the viral infection during RNAi screening. To overcome this, the authors devised a 15-dimensional phenotypic profile to define the viral infection block induced by CD4 silencing in HeLa cells. They demonstrate that this phenotypic profile excludes nonspecific, RNAi-based side effects and viral replication defects mediated by silencing of housekeeping genes. To achieve statistical robustness, the authors used automatically annotated RNAi arrays for seven independent genome-wide RNAi screens. This identified 56 host genes, which reliably reproduced CD4-like phenotypes upon HIV infection. The factors include 11 known HIV interactors and 45 factors previously not associated with HIV infection. As proof of concept, the authors confirmed that silencing of PAK1, Ku70, and RNAseH2A impaired HIV replication in Jurkat cells. In summary, multidimensional, visual profiling can identify genes required for HIV infection.</P>
( Suhui Yang ),( Jyothi K. R. ),( Sangbin Lim ),( Tae Gyu Choi ),( Jin-Hwan Kim ),( Salima Akter ),( Miran Jang ),( Hyun-Jong Ahn ),( Hee-Young Kim ),( Marc P. Windisch ),( Daulat B. Khadka ),( Chao Z 전남대학교 약품개발연구소 2015 약품개발연구지 Vol.24 No.-
Hepatitis C virus (HCV) is a major cause of end-stage liver disease. Direct-acting antivirals (DAAs), including inhibitors of nonstructural proteins (NS3/4A protease, NS5A, and NS5B polymerase), represent key components of anti-HCV treatment, but these are associated with increased drug resistance and toxicity. Thus, the development of host-targeted antiviral agents, such as cyclophilin A inhibitors, is an alternative approach for more effective, selective, and safer treatment. Starting with the discovery of a bis-amide derivative 5 through virtual screening, the lead compound 25 was developed using molecular modeling-based design and systematic exploration of the structure-activity relationship. The lead 25 lacked cytotoxicity, had potent anti-HCV activity, and showed selective and high binding affinity for CypA Unlike cyclosporin A, 25 lacked immunosuppressive effects, successfully inhibited the HCV replication, restored host immune responses without acute toxicity in vitro and in vivo, and exhibited a high synergistic effect in combination with other drugs. These findings suggest that the bis-amides have Significant potential to extend the arsenal of HCV therapeutics.