A novel class of small molecule compounds that inhibit hepatitis C virus infection by targeting the prohibitin-CRaf pathway
Autor(es): Liu Shufeng, Wang Wenyu, Brown Lauren E, Qiu Chao, Lajkiewicz Neil, Zhao Ting, Zhou Jianhua, Porco John A, Wang Tony T
Resumo: Identification of novel drug targets - affordable therapeutic agents remains a high priority in the fight against chronic hepatitis C virus (HCV) infection. Here, we report that the cellular proteins prohibitin 1 (PHB1) - 2 (PHB2) are pan-genotypic HCV entry factors functioning at a post-binding step. While predominantly found in mitochondria, PHBs localize to the plasma membrane of hepatocytes through their transmembrane domains - interact with both EGFR - CRaf. Targeting PHB by rocaglamide (Roc-A), a natural product that binds PHB1 - 2, reduced cell surface PHB1 - 2, disrupted PHB-CRaf interaction, - inhibited HCV entry at low nanomolar concentrations. A structure-activity analysis of 32 synthetic Roc-A analogs indicated that the chiral, racemic version of aglaroxin C, a natural product biosynthetically related to Roc-A, displayed improved potency - therapeutic index against HCV infection. This study reveals a new class of HCV entry inhibitors that target the PHB1/2-CRaf pathway.
Palavras-Chave: HCV; Entry factors; Entry inhibitors; Rocaglates
Imprenta: EBioMedicine, v. 2, n. 11, p. 1600-1606, 2015
Identificador do objeto digital: 10.1016/j.ebiom.2015.09.018
Descritores: Chikungunya virus - Cell ; Chikungunya virus - Molecular structure ; Chikungunya virus - Proteins ; Chikungunya virus - Infectious diseases ; Chikungunya virus - Viral infections ; Chikungunya Virus - Virus ; Chikungunya virus - Immunology ; Chikungunya virus - Public health
Data de publicação: 2015
