2. Academic Validation
  3. 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

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

  • J Med Chem. 2015 Apr 23;58(8):3445-58. doi: 10.1021/jm501874e.
Longhu Zhou 1,  Hong-wang Zhang 1,  Sijia Tao 1,  Leda Bassit 1 2,  Tony Whitaker 3,  Tamara R McBrayer 2 3,  Maryam Ehteshami 1,  Sheida Amiralaei 1,  Ugo Pradere 1,  Jong Hyun Cho 1,  Franck Amblard 1 2,  Drew Bobeck 3,  Mervi Detorio 1 2,  Steven J Coats 3,  Raymond F Schinazi 1 2
Affiliations

Affiliations

  • 1 †Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia 30322, United States.
  • 2 ‡Veterans Affairs Medical Center, Decatur, Georgia 30033, United States.
  • 3 §CoCrystal Pharma, Inc., Tucker, Georgia 30084, United States.
PMID: 25849312 DOI: 10.1021/jm501874e
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.

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