title: β-D-2'-C-Methyl-2,6-diaminopurine Ribonucleoside Phosphoramidates are Potent and Selective Inhibitors of Hepatitis C Virus (HCV) and Are Bioconverted Intracellularly to Bioactive 2,6-Diaminopurine and Guanosine 5'-Triphosphate Forms.
abstract: The conversion of selected β-D-2,6-diaminopurine nucleosides (DAPNs) to their phosphoramidate prodrug (PD) substantially blocks the conversion to the G-analog allowing for the generation of two bioactive nucleoside triphosphates (NTPs) in human hepatocytes. A variety of 2'-C-methyl DAPN-PDs were prepared and evaluated for inhibition of HCV viral replication in Huh-7 cells, cytotoxicity in various cell lines, and cellular pharmacology in both Huh-7 and primary human liver cells. The DAPN-PDs were pan-genotypic, effective against various HCV resistant mutants, and resistant variants could not be selected. 2'-C-Me-DAPN-TP and 2'-C-Me-GTP were chain terminators for genotype 1b HCV-pol, and single nucleotide incorporation assays revealed that 2'-C-Me-DAPN-TP was incorporated opposite U. No cytotoxicity was observed with our DAPN-PD when tested up to 50 μM. A novel, DAPN-PD, 15c, has been selected for further evaluation because of its good virologic and toxicologic profile and its ability to deliver two active metabolites, potentially simplifying HCV treatment.
authors: †Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia 30322, United States.
authors: Longhu
authors: L
authors: Zhou
authors: †Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia 30322, United States.
authors: Hong-wang
authors: HW
authors: Zhang
authors: †Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia 30322, United States.
authors: Sijia
authors: S
authors: Tao
authors: †Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia 30322, United States.|‡Veterans Affairs Medical Center, Decatur, Georgia 30033, United States.
authors: Leda
authors: L
authors: Bassit
authors: §CoCrystal Pharma, Inc., Tucker, Georgia 30084, United States.
authors: Tony
authors: T
authors: Whitaker
authors: ‡Veterans Affairs Medical Center, Decatur, Georgia 30033, United States.|§CoCrystal Pharma, Inc., Tucker, Georgia 30084, United States.
authors: Tamara R
authors: TR
authors: McBrayer
authors: †Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia 30322, United States.
authors: Maryam
authors: M
authors: Ehteshami
authors: †Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia 30322, United States.
authors: Sheida
authors: S
authors: Amiralaei
authors: †Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia 30322, United States.
authors: Ugo
authors: U
authors: Pradere
authors: †Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia 30322, United States.
authors: Jong Hyun
authors: JH
authors: Cho
authors: †Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia 30322, United States.|‡Veterans Affairs Medical Center, Decatur, Georgia 30033, United States.
authors: Franck
authors: F
authors: Amblard
authors: §CoCrystal Pharma, Inc., Tucker, Georgia 30084, United States.
authors: Drew
authors: D
authors: Bobeck
authors: †Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia 30322, United States.|‡Veterans Affairs Medical Center, Decatur, Georgia 30033, United States.
authors: Mervi
authors: M
authors: Detorio
authors: §CoCrystal Pharma, Inc., Tucker, Georgia 30084, United States.
authors: Steven J
authors: SJ
authors: Coats
authors: †Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia 30322, United States.|‡Veterans Affairs Medical Center, Decatur, Georgia 30033, United States.
authors: Raymond F
authors: RF
authors: Schinazi
mesh_terms: D015075:2-Aminopurine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000577:Amides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000998:Antiviral Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D002460:Cell Line; D002478:Cells, Cultured; D006160:Guanosine Triphosphate / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D016174:Hepacivirus / Q000187:drug effects* / Q000235:genetics; D006526:Hepatitis C / Q000188:drug therapy; D006801:Humans; D008745:Methylation; D010756:Phosphoric Acids / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011355:Prodrugs / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D012263:Ribonucleosides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000577:Amides; D000998:Antiviral Agents; D010756:Phosphoric Acids; D011355:Prodrugs; D012263:Ribonucleosides; D015075:2-Aminopurine; C007300:2,6-diaminopurine; D006160:Guanosine Triphosphate; C011067:phosphoramidic acid