Jean-François Griffon

NEW UNNATURAL L-NUCLEOSIDE ENANTIOMERS : FROM THEIR STEREOSPECIFIC SYNTHESIS TO THEIR BIOLOGICAL ACTIVITIES

Abstract Several purine and pyrimidine β-L-dideoxynucleosides were stereospecifically synthesized and their antiviral properties examined. Two of them, namely β-L-2′,3′-dideoxyadenosine (β-L-ddA) and its 2′,3′-didehydro derivative (β-L-d4A) were found to have significant anti-human immunodeficiency virus (HIV) and anti-hepatitis B virus (HBV) activities in cell culture.

Synthesis of potent and broad genotypically active NS5B HCV non-nucleoside inhibitors binding to the thumb domain allosteric site 2 of the viral polymerase.

The hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase (RdRp) plays a central role in virus replication. NS5B has no functional equivalent in mammalian cells and, as a consequence, is an attractive target for selective inhibition. This Letter describes the discovery of a new family of HCV NS5B non-nucleoside inhibitors, based on the bioisosterism between amide and phosphonamidate functions. As part of this program, SAR in this new series led to the identification of IDX17119, a potent non-nucleoside inhibitor, active on the genotypes 1b, 2a, 3a and 4a. The structure and binding domain of IDX17119 were confirmed by X-ray co-crystallization study.

Unnatural β-L-Enantiomers of Nucleoside Analogues as Potent Anti-Hepatitis B Virus Agents

Abstract Several 2′- or 3′-substituted 2′,3′-dideoxy-β-L-nucleosides bearing adenine as the base were stereospecifically synthesized and their antiviral properties examined. Two of them, namely 2′-azido- and 3′-azido-2′,3′-dideoxy-β-L-adenosine (2′-N3-−β-L-ddA and 3′-N3-−β-L-ddA) were found to have some anti-hepatitis B virus (HBV) activity in cell culture.

Study of the Enantioselectivity of Enzymes Involved in Nucleoside Analogue Metabolism: Deoxycytidine Kinase

Abstract The substrate properties of recombinant human deoxycytidine kinase (dCK) with regard to a series of D- or L-enantiomers of cytidine, 2′-deoxycytidine, and 2′,3′-dideoxycytidine analogues were studied using HPLC analysis. Our results suggest that dCK has a remarkably relaxed enantioselectivity with respect to a large number of cytidine derivatives in the β configuration.

Synthesis and Antiviral Evaluation of 4′-C-Azidomethyl-β-D-Ribofuranosyl Purine and Pyrimidine Nucleosides

In the search for inhibitors of the replication of RNA viruses, including hepatitis C virus (HCV), the hitherto unknown 4′-C-azidomethyl-β-D-ribofuranosyl nucleosides of the five naturally occurring nucleic acid bases have been synthesized and their antiviral properties examined. These 4′-C-branched nucleosides were stereospecifically prepared by glycosylation of purine and pyrimidine aglycons with a suitable peracylated 4-C-azidomethyl-D-pentofuranose sugar, followed by removal of the protecting groups. The prepared compounds were tested for their activity against several viruses, but they did not show an antiviral effect.

Discovery of benzophosphadiazine drug candidate IDX375: A novel hepatitis C allosteric NS5B RdRp inhibitor

Hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase (RdRp) plays a central role in virus replication. NS5B has no functional equivalent in mammalian cells, and as a consequence is an attractive target for selective inhibition. This paper describes the discovery of a novel family of HCV NS5B non-nucleoside inhibitors inspired by the bioisosterism between sulfonamide and phosphonamide. Systematic structural optimization in this new series led to the identification of IDX375, a potent non-nucleoside inhibitor that is selective for genotypes 1a and 1b. The structure and binding domain of IDX375 were confirmed by X-ray co-crystalisation study.