Discovery of Selective Small Molecule Type III Phosphatidylinositol 4-Kinase Alpha (PI4KIII伪) Inhibitors as Anti Hepatitis C (HCV) Agents

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• 作者：Anna L. Leivers ; Matthew Tallant ; J. Brad Shotwell ; Scott Dickerson ; Martin R. Leivers ; Octerloney B. McDonald ; Jeff Gobel ; Katrina L. Creech ; Susan L. Strum ; Amanda Mathis ; Sabrinia Rogers ; Chris B. Moore ; Janos Botyanszki
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：March 13, 2014
• 年：2014
• 卷：57
• 期：5
• 页码：2091-2106
• 全文大小：713K
• 年卷期：v.57,no.5(March 13, 2014)
• ISSN：1520-4804

文摘

Hepatitis C virus (HCV) assembles many host cellular proteins into unique membranous replication structures as a prerequisite for viral replication, and PI4KIII伪 is an essential component of these replication organelles. RNA interference of PI4KIII伪 results in a breakdown of this replication complex and cessation of HCV replication in Huh-7 cells. PI4KIII伪 is a lipid kinase that interacts with the HCV nonstructural 5A protein (NS5A) and enriches the HCV replication complex with its product, phosphoinositol 4-phosphate (PI4P). Elevated levels of PI4P at the endoplasmic reticulum have been linked to HCV infection in the liver of HCV infected patients.1 We investigated if small molecule inhibitors of PI4KIII伪 could inhibit HCV replication in vitro. The synthesis and structure鈥揳ctivity relationships associated with the biological inhibition of PI4KIII伪 and HCV replication are described. These efforts led directly to identification of quinazolinone 28 that displays high selectivity for PI4KIII伪 and potently inhibits HCV replication in vitro.