While IFN-based hepatitis C virus (HCV) treatment regimens required long treatment duration, they only achieved a limited cure rate in HCV-infected patients and were accompanied by significant therapy-based side effects. The first curative IFN-sparing therapies revolutionized HCV treatment by utilizing a cocktail of mechanistically orthogonal direct-acting antiviral (DAA) agents to achieve much higher cure rates in a shorter period of time and with fewer side effects. One of the drug targets that these therapies usually engaged was the HCV NS5A protein. This chapter reviews the Abbott/AbbVie HCV NS5A program, which discovered inhibitors of this protein using an in vitro phenotypic screen, validated the mechanism in vivo, and ultimately discovered two FDA-approved NS5A inhibitors ombitasvir (OMB) and pibrentasvir (PIB). OMB, a first-generation NS5A inhibitor, is a component of two FDA-approved IFN-sparing DAA therapies (Viekira Pak™ and Technivie™) with approval to treat genotypes 1 and 4, respectively. PIB, a next-generation NS5A inhibitor included in AbbVie’s next-generation therapy Mavyret™ (or Maviret™), prevents replication of HCV genotypes 1–6 and exhibits an improved resistance profile relative to other FDA-approved first-generation NS5A inhibitors.
CITATION STYLE
Wagner, R., DeGoey, D. A., Randolph, J. T., Krueger, A. C., Matulenko, M. A., & Kati, W. M. (2019). HCV NS5A as an Antiviral Therapeutic Target: From Validation to the Discovery and Development of Ombitasvir and Pibrentasvir as Components of IFN-Sparing HCV Curative Treatments. In Topics in Medicinal Chemistry (Vol. 32, pp. 133–156). Springer. https://doi.org/10.1007/7355_2018_50
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