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JOURNAL ARTICLE
Olivia Goethals, Suzanne J F Kaptein, Bart Kesteleyn, Jean-François Bonfanti, Liesbeth Van Wesenbeeck, Dorothée Bardiot, Ernst J Verschoor, Babs E Verstrepen, Zahra Fagrouch, J Robert Putnak, Dominik Kiemel, Oliver Ackaert, Roel Straetemans, Sophie Lachau-Durand, Peggy Geluykens, Marjolein Crabbe, Kim Thys, Bart Stoops, Oliver Lenz, Lotke Tambuyzer, Sandra De Meyer, Kai Dallmeier, Michael K McCracken, Gregory D Gromowski, Wiriya Rutvisuttinunt, Richard G Jarman, Nicos Karasavvas, Franck Touret, Gilles Querat, Xavier de Lamballerie, Laurent Chatel-Chaix, Gregg N Milligan, David W C Beasley, Nigel Bourne, Alan D T Barrett, Arnaud Marchand, Tim H M Jonckers, Pierre Raboisson, Kenny Simmen, Patrick Chaltin, Ralf Bartenschlager, Willy M Bogers, Johan Neyts, Marnix Van Loock
Dengue is a major health threat and the number of symptomatic infections caused by the four dengue serotypes is estimated to be 96 million1 with annually around 10,000 deaths2 . However, no antiviral drugs are available for the treatment or prophylaxis of dengue. We recently described the interaction between non-structural proteins NS3 and NS4B as a promising target for the development of pan-serotype dengue virus (DENV) inhibitors3 . Here we present JNJ-1802-a highly potent DENV inhibitor that blocks the NS3-NS4B interaction within the viral replication complex...
March 15, 2023: Nature
#2
JOURNAL ARTICLE
Suzanne J F Kaptein, Olivia Goethals, Dominik Kiemel, Arnaud Marchand, Bart Kesteleyn, Jean-François Bonfanti, Dorothée Bardiot, Bart Stoops, Tim H M Jonckers, Kai Dallmeier, Peggy Geluykens, Kim Thys, Marjolein Crabbe, Laurent Chatel-Chaix, Max Münster, Gilles Querat, Franck Touret, Xavier de Lamballerie, Pierre Raboisson, Kenny Simmen, Patrick Chaltin, Ralf Bartenschlager, Marnix Van Loock, Johan Neyts
Dengue virus causes approximately 96 million symptomatic infections annually, manifesting as dengue fever or occasionally as severe dengue1,2 . There are no antiviral agents available to prevent or treat dengue. Here, we describe a highly potent dengue virus inhibitor (JNJ-A07) that exerts nanomolar to picomolar activity against a panel of 21 clinical isolates that represent the natural genetic diversity of known genotypes and serotypes. The molecule has a high barrier to resistance and prevents the formation of the viral replication complex by blocking the interaction between two viral proteins (NS3 and NS4B), thus revealing a previously undescribed mechanism of antiviral action...
October 2021: Nature
#3
JOURNAL ARTICLE
Rabah Nadia, Ortega Granda Oney, Quérat Gilles, Canard Bruno, Decroly Etienne, Coutard Bruno
Alphaviruses are arthropod-borne viruses of public health concern. To date no efficient vaccine nor antivirals are available for safe human use. During viral replication the nonstructural protein 1 (nsP1) catalyzes capping of genomic and subgenomic RNAs. The capping reaction is unique to the Alphavirus genus. The whole three-step process follows a particular order: (i) transfer of a methyl group from S-adenosyl methionine (SAM) onto a GTP forming m7 GTP; (ii) guanylylation of the enzyme to form a m7 GMP-nsP1adduct; (iii) transfer of m7 GMP onto 5'-diphosphate RNA to yield capped RNA...
August 1, 2020: Antiviral Research
#4
JOURNAL ARTICLE
Novel Class of Chikungunya Virus Small Molecule Inhibitors That Targets the Viral Capping Machinery.
Rana Abdelnabi, Kristina Kovacikova, Julia Moesslacher, Kim Donckers, Verena Battisti, Pieter Leyssen, Thierry Langer, Gerhard Puerstinger, Gilles Quérat, Changqing Li, Etienne Decroly, Ali Tas, Arnaud Marchand, Patrick Chaltin, Bruno Coutard, Martijn van Hemert, Johan Neyts, Leen Delang
Despite the worldwide reemergence of the chikungunya virus (CHIKV) and the high morbidity associated with CHIKV infections, there is no approved vaccine or antiviral treatment available. Here, we aimed to identify the target of a novel class of CHIKV inhibitors, i.e., the CHVB series. CHVB compounds inhibit the in vitro replication of CHIKV isolates with 50% effective concentrations in the low-micromolar range. A CHVB-resistant variant (CHVBres ) was selected that carried two mutations in the gene encoding nsP1 (responsible for viral RNA capping), one mutation in nsP2, and one mutation in nsP3...
June 23, 2020: Antimicrobial Agents and Chemotherapy
#5
JOURNAL ARTICLE
Rolando Cannalire, Delia Tarantino, Geraldine Piorkowski, Tea Carletti, Serena Massari, Tommaso Felicetti, Maria Letizia Barreca, Stefano Sabatini, Oriana Tabarrini, Alessandro Marcello, Mario Milani, Violetta Cecchetti, Eloise Mastrangelo, Giuseppe Manfroni, Gilles Querat
We report the design, synthesis, and biological evaluation of a class of 1H-pyrido[2,1-b][1,3]benzothiazol-1-ones originated from compound 1, previously identified as anti-flavivirus agent. Some of the new compounds showed activity in low μM range with reasonable selectivity against Dengue 2, Yellow fever (Bolivia strain), and West Nile viruses. One of the most interesting molecules, compound 16, showed broad antiviral activity against additional flaviviruses such as Dengue 1, 3 and 4, Zika, Japanese encephalitis, several strains of Yellow fever, and tick-borne encephalitis viruses...
July 2019: Antiviral Research
#6
JOURNAL ARTICLE
Ana S Ferreira-Ramos, Changqing Li, Cécilia Eydoux, Jean Marie Contreras, Christophe Morice, Gilles Quérat, Alba Gigante, María-Jesús Pérez Pérez, Marie-Louise Jung, Bruno Canard, Jean-Claude Guillemot, Etienne Decroly, Bruno Coutard
Alphaviruses such as the Venezuelan equine encephalitis virus (VEEV) are important human emerging pathogens transmitted by mosquitoes. They possess a unique viral mRNA capping mechanism catalyzed by the viral non-structural protein nsP1, which is essential for virus replication. The alphaviruses capping starts by the methylation of a GTP molecule by the N7-guanine methyltransferase (MTase) activity; nsP1 then forms a covalent link with m7 GMP releasing pyrophosphate (GT reaction) and the m7 GMP is next transferred onto the 5'-diphosphate end of the viral mRNA to form a cap-0 structure...
March 2019: Antiviral Research
#7
JOURNAL ARTICLE
Jessica Hernandez, Laurent Hoffer, Bruno Coutard, Gilles Querat, Philippe Roche, Xavier Morelli, Etienne Decroly, Karine Barral
No antiviral drugs to treat or prevent life-threatening flavivirus infections such as those caused by mosquito-borne Dengue (DENV) and more recently Zika (ZIKV) viruses are yet available. We aim to develop, through a structure-based drug design approach, novel inhibitors targeting the NS5 AdoMet-dependent mRNA methyltransferase (MTase), a viral protein involved in the RNA capping process essential for flaviviruses replication. Herein, we describe the optimization of a hit (5) identified using fragment-based and structure-guided linking techniques, which binds to a proximal site of the AdoMet binding pocket...
October 23, 2018: European Journal of Medicinal Chemistry
#8
JOURNAL ARTICLE
Rolando Cannalire, Delia Tarantino, Andrea Astolfi, Maria Letizia Barreca, Stefano Sabatini, Serena Massari, Oriana Tabarrini, Mario Milani, Gilles Querat, Eloise Mastrangelo, Giuseppe Manfroni, Violetta Cecchetti
Over recent years, many RNA viruses have been "re-discovered", including life-threatening flaviviruses, such as Dengue, Zika, and several encephalitis viruses. Since no specific inhibitors are currently available to treat these infections, there is a pressing need for new therapeutics. Among the flaviviral proteins, NS5 RNA-dependent RNA polymerase (RdRp) represents a validated target being essential for viral replication and it has no human analog. To date, few NS5 RdRp inhibitor chemotypes have been reported and no inhibitors are currently in clinical development...
January 1, 2018: European Journal of Medicinal Chemistry
#9
JOURNAL ARTICLE
Abdennour Amroun, Stéphane Priet, Gilles Querat
Toscana virus (TOSV) is an arthropod-borne phlebovirus within the family Phenuiviridae in the order Bunyavirales. It seems to be an important agent of human meningoencephalitis in the warm season in the Mediterranean area. Because the polymerase of Bunyavirales lacks a capping activity, it cleaves short-capped RNA leaders derived from the host cell, and uses them to initiate viral mRNA synthesis. To determine the size and nucleotide composition of the host-derived RNA leaders, and to elucidate the first steps of TOSV transcription initiation, we performed a high-throughput sequencing of the 5' end of TOSV mRNAs in infected cells at different times post-infection...
November 2017: Journal of General Virology
#10
JOURNAL ARTICLE
Toward the identification of viral cap-methyltransferase inhibitors by fluorescence screening assay.
Wahiba Aouadi, Cécilia Eydoux, Bruno Coutard, Baptiste Martin, Françoise Debart, Jean Jacques Vasseur, Jean Marie Contreras, Christophe Morice, Gilles Quérat, Marie-Louise Jung, Bruno Canard, Jean-Claude Guillemot, Etienne Decroly
Two highly pathogenic human coronaviruses associated with severe respiratory syndromes emerged since the beginning of the century. The severe acute respiratory syndrome SARS-coronavirus (CoV) spread first in southern China in 2003 with about 8000 infected cases in few months. Then in 2012, the Middle East respiratory syndrome (MERS-CoV) emerged from the Arabian Peninsula giving a still on-going epidemic associated to a high fatality rate. CoVs are thus considered a major health threat. This is especially true as no vaccine nor specific therapeutic are available against either SARS- or MERS-CoV...
August 2017: Antiviral Research
#11
JOURNAL ARTICLE
Alba Gigante, Asier Gómez-SanJuan, Leen Delang, Changqing Li, Oskía Bueno, Ana-María Gamo, Eva-María Priego, María-José Camarasa, Dirk Jochmans, Pieter Leyssen, Etienne Decroly, Bruno Coutard, Gilles Querat, Johan Neyts, María-Jesús Pérez-Pérez
Chikungunya virus (CHIKV) is a re-emerging alphavirus transmitted to humans by Aedes mosquitoes. Since 2005, CHIKV has been spreading worldwide resulting in epidemics in Africa, the Indian Ocean islands, Asia and more recently in the Americas. CHIKV is thus considered as a global health concern. There is no specific vaccine or drug available for the treatment of this incapacitating viral infection. We previously identified 3-aryl-[1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-ones as selective inhibitors of CHIKV replication and proposed the viral capping enzyme nsP1 as a target...
August 2017: Antiviral Research
#12
REVIEW
Abdennour Amroun, Stéphane Priet, Xavier de Lamballerie, Gilles Quérat
Bunyaviridae family is the largest and most diverse family of RNA viruses. It has more than 350 members divided into five genera: Orthobunyavirus, Phlebovirus, Nairovirus, Hantavirus, and Tospovirus. They are present in the five continents, causing recurrent epidemics, epizootics, and considerable agricultural loss. The genome of bunyaviruses is divided into three segments of negative single-stranded RNA according to their relative size: L (Large), M (Medium) and S (Small) segment. Bunyaviridae RNA-dependent RNA polymerase (RdRp) is encoded by the L segment, and is in charge of the replication and transcription of the viral RNA in the cytoplasm of the infected cell...
November 2017: Critical Reviews in Microbiology
#13
JOURNAL ARTICLE
L Delang, C Li, A Tas, G Quérat, I C Albulescu, T De Burghgraeve, N A Segura Guerrero, A Gigante, G Piorkowski, E Decroly, D Jochmans, B Canard, E J Snijder, M J Pérez-Pérez, M J van Hemert, B Coutard, P Leyssen, J Neyts
The chikungunya virus (CHIKV) has become a substantial global health threat due to its massive re-emergence, the considerable disease burden and the lack of vaccines or therapeutics. We discovered a novel class of small molecules ([1,2,3]triazolo[4,5-d]pyrimidin-7(6H)-ones) with potent in vitro activity against CHIKV isolates from different geographical regions. Drug-resistant variants were selected and these carried a P34S substitution in non-structural protein 1 (nsP1), the main enzyme involved in alphavirus RNA capping...
August 22, 2016: Scientific Reports
#14
JOURNAL ARTICLE
Fatiha Benmansour, Cécilia Eydoux, Gilles Querat, Xavier de Lamballerie, Bruno Canard, Karine Alvarez, Jean-Claude Guillemot, Karine Barral
Using a functional high-throughput screening (HTS) and subsequent SAR studies, we have discovered a novel series of non-nucleoside dengue viral polymerase inhibitors. We report the elaboration of SAR around hit compound 1 as well as the synthesis and antiviral evaluation of 3-phenyl-5-[(E)-2-(thiophen-2-yl)ethenyl]-1,2,4-oxadiazole and 5-phenyl-2-[2-(2-thienyl)ethenyl]-1,3,4-oxadiazole analogues derived from a rapid and easily accessible chemical pathway. A large number of compounds prepared by this method were shown to possess in vitro activity against the polymerase of dengue virus...
February 15, 2016: European Journal of Medicinal Chemistry
#15
JOURNAL ARTICLE
Fabien Aubry, Antoine Nougairède, Lauriane de Fabritus, Gilles Querat, Ernest A Gould, Xavier de Lamballerie
Reverse genetics is a key methodology for producing genetically modified RNA viruses and deciphering cellular and viral biological properties, but methods based on the preparation of plasmid-based complete viral genomes are laborious and unpredictable. Here, both wild-type and genetically modified infectious RNA viruses were generated in days using the newly described ISA (infectious-subgenomic-amplicons) method. This new versatile and simple procedure may enhance our capacity to obtain infectious RNA viruses from PCR-amplified genetic material...
November 2014: Journal of General Virology
#16
JOURNAL ARTICLE
Leen Delang, Nidya Segura Guerrero, Ali Tas, Gilles Quérat, Boris Pastorino, Mathy Froeyen, Kai Dallmeier, Dirk Jochmans, Piet Herdewijn, Felio Bello, Eric J Snijder, Xavier de Lamballerie, Byron Martina, Johan Neyts, Martijn J van Hemert, Pieter Leyssen
OBJECTIVES: T-705, also known as favipiravir, is a small-molecule inhibitor that is currently in clinical development for the treatment of influenza virus infections. This molecule also inhibits the replication of a broad spectrum of other RNA viruses. The objective of this study was to investigate the antiviral effect of favipiravir on chikungunya virus (CHIKV) replication and to contribute to unravelling the molecular mechanism of action against this virus. METHODS: The anti-CHIKV effect of favipiravir was examined in cell culture and in a mouse model of lethal infection...
October 2014: Journal of Antimicrobial Chemotherapy
#17
JOURNAL ARTICLE
S Lagarde, J-C Lagier, R Charrel, G Quérat, J Vanhomwegen, P Desprès, J Pelletier, E Kaphan
Japanese encephalitis is frequent in Asia, with a severe prognosis, but rare in travelers. Culex mosquitoes transmit Japanese encephalitis virus. Risk factors are destination, duration of stay, summer and fall seasons, outdoor activities, and type of accommodation. We report the case of a French traveler to Nepal with neutralization-based serological confirmed Japanese encephalitis. He presented classical clinical (viral syndrome before an encephalitis status with behavioral disorder, global hypotonia, mutism, movement disorders, seizure, and coma), radiological (lesions of thalami, cortico-spinal tracts, and brainstem) and biological features (lymphocytic meningitis)...
February 2014: Journal of Neurovirology
#18
JOURNAL ARTICLE
Cécile Baronti, Joséphine Sire, Xavier de Lamballerie, Gilles Quérat
Flaviviruses are single-stranded positive RNA viruses that replicate through double stranded RNA (dsRNA) intermediates. These dsRNA may be recognized as pathogen-associated molecular patterns by cellular receptors including membrane-bound Toll-like receptor 3 (TLR3) and cytosolic helicases RIG-I and MDA5. dsRNA stimulation results in signaling cascades converging to activation of interferon (IFN) regulatory factor 3 (IRF3) and to transcriptional activation of several interferon stimulated genes, including IFNss and inflammatory cytokines...
September 1, 2010: Virology
#19
REVIEW
Joséphine Sire, Gilles Quérat, Cécile Esnault, Stéphane Priet
Uracil is a natural base of RNA but may appear in DNA through two different pathways including cytosine deamination or misincorporation of deoxyuridine 5'-triphosphate nucleotide (dUTP) during DNA replication and constitutes one of the most frequent DNA lesions. In cellular organisms, such lesions are faithfully cleared out through several universal DNA repair mechanisms, thus preventing genome injury. However, several recent studies have brought some pieces of evidence that introduction of uracil bases in viral genomic DNA intermediates during genome replication might be a way of innate immune defence against some viruses...
June 5, 2008: Retrovirology
#20
REVIEW
Stéphane Priet, Joséphine Sire, Gilles Quérat
Uracil in DNA is a deleterious event that may arise either by cytosine deamination or misincorporation of dUTP. Consequently, cells from all free-living organisms have developed strategies to protect their genome against the presence of uracils, by using uracil DNA glycosylase (UNG) and deoxyuridine triphosphatase (dUTPase) enzymatic activities. In the viral kingdom, some (namely poxviruses and herpesviruses) but not all of the DNA viruses encode their own UNG and dUTPase to control uracilation of their genome...
January 2006: Current HIV Research
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