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The Discovery of Sofosbuvir: A Liver-Targeted Nucleotide Prodrug for the Treatment and Cure of HCV

  • Michael J. SofiaEmail author
  • Phillip A. Furman
Chapter
Part of the Topics in Medicinal Chemistry book series (TMC, volume 31)

Abstract

Over the last 15 years, an increase in knowledge of the structure, function, life cycle, and pathogenesis of hepatitis C virus (HCV) led to a focused effort on the discovery and development of interferon (IFN)-free therapies that are well tolerated and have increased cure rates. This chapter describes the discovery and development of sofosbuvir, the first live-targeting prodrug of a nucleotide analog, and contains a detailed overview of the synthesis, activity, mechanism of action, toxicity, and clinical studies of sofosbuvir (PSI-7977). The identification of the cytidine nucleoside analog PSI-6130, which was shown to be a potent and nontoxic inhibitor of HCV replication, is described. A summary of the mechanism of action of PSI-6130 is presented that describes the metabolic pathway to its corresponding 5′-triphosphate and to the uridine metabolite (PSI-6206) and the uridine mono-, di-, and triphosphate. Both PSI-6130 triphosphate and PSI-6206 triphosphate were shown to be potent alternative substrate inhibitors of the HCV NS5B polymerase. Because the triphosphate of PSI-6206 was a potent inhibitor of the NS5B polymerase and because it had a long intracellular half-life, the goal was to find an approach that could be used to deliver PSI-6206 monophosphate to the liver. The thought process and approach that led to the design and synthesize of various phosphoramidate prodrugs of the uridine monophosphate metabolite is presented. Of the compounds synthesized, PSI-7851 possessed the desired characteristics. PSI-7851 was a mixture of two diastereoisomers, PSI-7976 and PSI-7977. The two isomers were separated, and PSI-7977 (sofosbuvir) which showed tenfold greater activity was moved forward into clinical development. On December 6, 2013, sofosbuvir (Sovaldi®) was approved by the US FDA for the treatment of HCV genotype (GT) 1, 2, 3, and 4 patient populations with the combination of sofosbuvir + RBV being approved for GT 2 and 3 patient populations as the first IFN-free cure for patients infected with HCV.

Keywords

2′-F-2′-C-methyl cytidine 2′-F-2′-C-methyl nucleoside 2′-F-2′-C-methyl uridine Diphosphate Epclusa® Harvoni® HCV Hepatitis C virus Liver Liver targeting Mericitabine Monophosphate NS5B polymerase Nucleoside Nucleotide Phosphoramidate Prodrug PSI-6130 PSI-6206 PSI-7851 PSI-7977 RdRp Resistance RG7128 RNA-dependent RNA polymerase S282T Sofosbuvir Sovaldi® Triphosphate Vosevi® 

Notes

Acknowledgments

The discovery and development of sofosbuvir would not have been possible if not for the dedicated staff at Pharmasset, Inc. Their commitment to finding a cure for HCV made sofosbuvir a reality. Thanks also goes to the clinical development team at Gilead Sciences, Inc. for among other things, completing the Phase III clinical studies and bringing sofosbuvir to the market so that the millions of HCV patients worldwide could realize a cure for their disease.

Compliance with Ethical Standards

Conflict of Interest Author Michael J. Sofia was an employee of Pharmasset, Inc. and Gilead Sciences Inc., and he is currently an employee and Chief Scientific Officer of Arbutus Biopharma, Inc. He is also a stockholder in Arbutus Biopharma, Inc.

Author Phillip A. Furman was an employee of Pharmasset, Inc.

Ethical Approval

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed in the studies reported in this chapter.

All procedures performed in the studies reported in this chapter involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed Consent

Informed consent was obtained from all individual participants included in the study.

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Copyright information

© Springer International Publishing AG, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Arbutus Biopharma, Inc.WarminsterUSA
  2. 2.Saint Augustine USA

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