Activity and the metabolic activation pathway of the potent and selective hepatitis C virus pronucleotide inhibitor PSI-353661

被引:36
作者
Furman, Phillip A. [1 ]
Murakami, Eisuke [1 ]
Niu, Congrong [1 ]
Lam, Angela M. [1 ]
Espiritu, Christine [1 ]
Bansal, Shalini [1 ]
Bao, Haiying [1 ]
Tolstykh, Tatiana [1 ]
Steuer, Holly Micolochick [1 ]
Keilman, Meg [1 ]
Zennou, Veronique [1 ]
Bourne, Nigel [2 ]
Veselenak, Ronald L. [2 ]
Chang, Wonsuk [1 ]
Ross, Bruce S. [1 ]
Du, Jinfa [1 ]
Otto, Michael J. [1 ]
Sofia, Michael J. [1 ]
机构
[1] Pharmasset Inc, Princeton, NJ 08540 USA
[2] Univ Texas Med Branch, Galveston, TX 77555 USA
关键词
Hepatitis C virus; Antiviral; Nucleotide analog; Prodrug; Phosphoramidate; 2 '-Deoxy-2 '-fluoro-2 '-C-methylguanosine-5 '-monophosphate; PHOSPHORAMIDATE DERIVATIVES; NONNUCLEOSIDE POLYMERASE; MITOCHONDRIAL TOXICITY; ANTIVIRAL ACTIVITIES; REPLICON VARIANTS; NUCLEOSIDE; MECHANISM; REPLICATION; RESISTANCE; ANALOGS;
D O I
10.1016/j.antiviral.2011.05.003
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
PSI-353661, a phosphoramidate prodrug of 2'-deoxy-2'-fluoro-2'-C-methylguanosine-5'-monophosphate, is a highly active inhibitor of genotype 1a, 1b, and 2a HCV RNA replication in the replicon assay and of genotype la and 2a infectious virus replication. PSI-353661 is active against replicons harboring the NS5B S282T or S96T/N142T amino acid alterations that confer decreased susceptibility to nucleoside/tide analogs as well as mutations that confer resistance to non-nucleoside inhibitors of NS5B. Replicon clearance studies show that PSI-353661 was able to clear cells of HCV replicon RNA and prevent a rebound in replicon RNA. PSI-353661 showed no toxicity toward bone marrow stem cells or mitochondrial toxicity. The metabolism to the active 5'-triphosphate involves hydrolysis of the carboxyl ester by cathepsin A (Cat A) and carboxylesterase 1 (CES1) followed by a putative nucleophilic attack on the phosphorus by the carboxyl group resulting in the elimination of phenol and the alaninyl phosphate metabolite, PSI-353131. Histidine triad nucleotide-binding protein 1 (Hint 1) then removes the amino acid moiety, which is followed by hydrolysis of the methoxyl group at the O-6-position of the guanine base by adenosine deaminase-like protein 1 (ADAL1) to give 2'-deoxy-2'-fluoro-2'-C-methylguanosine-5'monophosphate. The monophosphate is phosphorylated to the diphosphate by guanylate kinase. Nucleoside diphosphate kinase is the primary enzyme involved in phosphorylation of the diphosphate to the active triphosphate, PSI-352666. PSI-352666 is equally active against wild-type NS5B and NS5B containing the S282T amino acid alteration. (C) 2011 Elsevier B.V. All rights reserved.
引用
收藏
页码:120 / 132
页数:13
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