Structure-activity relationship of purine ribonucleosides for inhibition of hepatitis C virus RNA-dependent RNA polymerase.
As part of a continued effort to identify inhibitors of hepatitis C viral (HCV) replication, we report here the synthesis and evaluation of a series of nucleoside analogues and their corresponding triphosphates. Nucleosides were evaluated for their ability to inhibit HCV RNA replication in a cell-based, subgenomic replicon system, while nucleoside triphosphates were evaluated for their ability to inhibit in vitro RNA synthesis mediated by the HCV RNA-dependent RNA polymerase, NS5B. 2'-C-Methyladenosine and 2'-C-methylguanosine were identified as potent inhibitors of HCV RNA replication, and the corresponding triphosphates were found to be potent inhibitors of HCV NS5B-mediated RNA synthesis. The data generated in the cell-based assay demonstrated a fairly stringent structure-activity relationship around the active nucleosides. Increase in steric bulk beyond methyl on C2, change in the stereo- or regiochemistry of the methyl substituent, or change of identity of the heterobase beyond that of the endogenous adenine or guanine was found to lead to loss of inhibitory activity. The results highlight the importance of the ribo configuration 2'- and 3'-hydroxy pharmacophores for inhibition of HCV RNA replication in the cell-based assay and demonstrate that inclusion of the 2'-C-methylribonucleoside pharmacophore leads to increased resistance to adenosine deaminase and purine nucleoside phosphorylase mediated metabolism.
Eldrup
Anne B
AB
Department of Medicinal Chemistry, Isis Pharmaceuticals, 2280 Faraday Avenue, Carlsbad, California 92008, USA. aeldrup@isisph.com
Allerson
Charles R
CR
Bennett
C Frank
CF
Bera
Sanjib
S
Bhat
Balkrishen
B
Bhat
Neelima
N
Bosserman
Michele R
MR
Brooks
Jennifer
J
Burlein
Christine
C
Carroll
Steven S
SS
Cook
P Dan
PD
Getty
Krista L
KL
MacCoss
Malcolm
M
McMasters
Daniel R
DR
Olsen
David B
DB
Prakash
Thazha P
TP
Prhavc
Marija
M
Song
Quanlai
Q
Tomassini
Joanne E
JE
Xia
Jie
J
D000243:Adenosine Deaminase / Q000737:chemistry; D016174:Hepacivirus / Q000737:chemistry*; D006860:Hydrogen Bonding; D008745:Methylation; D008968:Molecular Conformation; D011684:Purine Nucleosides / Q000138:chemical synthesis* / Q000737:chemistry; D011683:Purine-Nucleoside Phosphorylase / Q000737:chemistry; D011687:Purines / Q000737:chemistry; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D012263:Ribonucleosides / Q000138:chemical synthesis* / Q000737:chemistry; D012266:Ribose / Q000737:chemistry; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry
D011684:Purine Nucleosides; D011687:Purines; D012263:Ribonucleosides; D017361:Viral Nonstructural Proteins; D012266:Ribose; D011683:Purine-Nucleoside Phosphorylase; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase; D000243:Adenosine Deaminase