Synthesis and Biological Evaluation of 4′‐<i>C</i>,3′‐<i>O</i>‐Propylene‐Linked Bicyclic Nucleosides

Hatton, Wilfried; Hunault, Julie; Egorov, Maxim; Len, Christophe; Pipelier, Muriel; Blot, Virginie; Silvestre, Virginie; Fargeas, Valérie; Adjou, Ané; McBrayer, Tamara R.; Detorio, Mervi; Cho, Jong-Hyun; Bourgougnon, Nathalie; Dubreuil, Didier; Schinazi, Raymond F.; Lebreton, Jacques

doi:10.1002/ejoc.201100859

Cited by 7 publications

(3 citation statements)

References 52 publications

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“…Nucleoside analogs. Nucleoside derivatives (designated compounds 1 to 14) were synthesized in our laboratory according to previously reported procedures (29,(40)(41)(42)(43)(44)(45) and were at least 95% pure, as estimated by liquid chromatography-mass spectrometry (LC-MS) and nuclear magnetic resonance (NMR) analyses. Chemical structures for compounds 1 to 14 are summarized in Fig.…”

Section: Methodsmentioning

confidence: 99%

Nucleoside Analogs with Selective Antiviral Activity against Dengue Fever and Japanese Encephalitis Viruses

Zandi

Bassit

Amblard

et al. 2019

Antimicrob Agents Chemother

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Dengue virus (DENV) and Japanese encephalitis virus (JEV) are important arthropod-borne viruses from the Flaviviridae family. DENV is a global public health problem with significant social and economic impacts, especially in tropical and subtropical areas. JEV is a neurotropic arbovirus endemic to east and southeast Asia. There are no U.S. FDA-approved antiviral drugs available to treat or to prevent DENV and JEV infections, leaving nearly one-third of the world's population at risk for infection. Therefore, it is crucial to discover potent antiviral agents against these viruses. Nucleoside analogs, as a class, are widely used for the treatment of viral infections. In this study, we discovered nucleoside analogs that possess potent and selective anti-JEV and anti-DENV activities across all serotypes in cell-based assay systems. Both viruses were susceptible to sugar-substituted 2=-C-methyl analogs with either cytosine or 7-deaza-7-fluoro-adenine nucleobases. Mouse studies confirmed the anti-DENV activity of these nucleoside analogs. Molecular models were assembled for DENV serotype 2 (DENV-2) and JEV RNA-dependent RNA polymerase replication complexes bound to nucleotide inhibitors. These models show similarities between JEV and DENV-2, which recognize the same nucleotide inhibitors. Collectively, our findings provide promising compounds and a structural rationale for the development of direct-acting antiviral agents with dual activity against JEV and DENV infections.KEYWORDS Dengue virus, Japanese encephalitis virus, antiviral agents, nucleoside analogs D engue virus (DENV) and Japanese encephalitis virus (JEV) are members of the genus Flavivirus, belonging to the family Flaviviridae. Many flaviviruses are arthropod borne and cause severe infections in humans and vertebrate animals. DENV has four serotypes (DENV-1 to DENV-4), which collectively pose a health threat to 2.5 billion people worldwide, with 50 million to 100 million human infections and 500,000 cases of dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS) annually (1-3). JEV is one of the most important neurotropic flaviviruses that causes encephalitis in humans. Symptoms range from mild febrile illness to mortal illness, especially in children, with about 67,900 cases each year (4). JEV is endemic in eastern and southern Asia (including China, Indonesia, Nepal, Thailand, Saipan Island, Pakistan, and the Torres Strait) and Australia, with fatality rates of 20% to 30% and life-long neurological impairments and sequelae among one-half of the survivors (5-8). Despite a licensed vaccine to prevent JEV infection, infections occur annually due to a lack of complete coverage and access (9). A tetravalent DENV vaccine also exists but remains partially on July 10, 2020 by guest http://aac.asm.org/ Downloaded fromArg474. The triphosphate group forms electrostatic interactions with Arg474, Lys694, and two active site Mn 2ϩ ions.Nucleoside inhibitors of DENV. The same 14 nucleoside analogs were assayed against DENV using a BHK-21 cell line harboring the...

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Section: Methodsmentioning

confidence: 99%

Nucleoside Analogs with Selective Antiviral Activity against Dengue Fever and Japanese Encephalitis Viruses

Zandi

Bassit

Amblard

et al. 2019

Antimicrob Agents Chemother

Self Cite

View full text Add to dashboard Cite

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“…223 While the cytosine analog 450a was hydrogenated with hydrogen over Pd/C, the uracil derivative 450b was hydrogenated by transfer hydrogenation over Pd/C to minimize the simultaneous uracil base hydrogenation.…”

Section: Nucleoside Monophosphate Prodrugsmentioning

confidence: 99%

“…Similarly, Hatton et al reported the reduction of the 4′- C -3′- O -propylene-linked bicyclic pyrimidine nucleoside (Scheme 134 ). 223 While the cytosine analog 450a was hydrogenated with hydrogen over Pd/C, the uracil derivative 450b was hydrogenated by transfer hydrogenation over Pd/C to minimize the simultaneous uracil base hydrogenation.…”

Section: Nucleoside Monophosphate Prodrugsmentioning

confidence: 99%