A Novel Class of Small Molecule Compounds that Inhibit Hepatitis C Virus Infection by Targeting the Prohibitin-CRaf Pathway
Identification of novel drug targets and 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) and 2 (PHB2) are pan-genotypic HCV entry factors functioning at a post-binding...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2015-11-01
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| Series: | EBioMedicine |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396415301377 |
| _version_ | 1818983846088015872 |
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| author | Shufeng Liu Wenyu Wang Lauren E. Brown Chao Qiu Neil Lajkiewicz Ting Zhao Jianhua Zhou John A. Porco Jr Tony T. Wang |
| author_facet | Shufeng Liu Wenyu Wang Lauren E. Brown Chao Qiu Neil Lajkiewicz Ting Zhao Jianhua Zhou John A. Porco Jr Tony T. Wang |
| author_sort | Shufeng Liu |
| collection | DOAJ |
| description | Identification of novel drug targets and 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) and 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 and interact with both EGFR and CRaf. Targeting PHB by rocaglamide (Roc-A), a natural product that binds PHB1 and 2, reduced cell surface PHB1 and 2, disrupted PHB-CRaf interaction, and 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 and therapeutic index against HCV infection. This study reveals a new class of HCV entry inhibitors that target the PHB1/2-CRaf pathway. |
| first_indexed | 2024-12-20T18:09:35Z |
| format | Article |
| id | doaj.art-3db6c94d7a9d49afbfca5ece9e4dc683 |
| institution | Directory Open Access Journal |
| issn | 2352-3964 |
| language | English |
| last_indexed | 2024-12-20T18:09:35Z |
| publishDate | 2015-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj.art-3db6c94d7a9d49afbfca5ece9e4dc6832022-12-21T19:30:30ZengElsevierEBioMedicine2352-39642015-11-012111600160610.1016/j.ebiom.2015.09.018A Novel Class of Small Molecule Compounds that Inhibit Hepatitis C Virus Infection by Targeting the Prohibitin-CRaf PathwayShufeng Liu0Wenyu Wang1Lauren E. Brown2Chao Qiu3Neil Lajkiewicz4Ting Zhao5Jianhua Zhou6John A. Porco Jr7Tony T. Wang8Center for Immunology and Infectious Diseases, Biosciences Division, SRI International, Harrisonburg, VA 22802, USADepartment of Chemistry, Center for Molecular Discovery (BU-CMD), Boston University, 590 Commonwealth Avenue, Boston, MA 02215, USADepartment of Chemistry, Center for Molecular Discovery (BU-CMD), Boston University, 590 Commonwealth Avenue, Boston, MA 02215, USAShanghai Public Health Clinical Center, Institutes of Biomedical Sciences, Key Laboratory of Medical Molecular Virology of Ministry of Education/Health, Fudan University, 2901 Caolang Road, Shanghai 201508, ChinaDepartment of Chemistry, Center for Molecular Discovery (BU-CMD), Boston University, 590 Commonwealth Avenue, Boston, MA 02215, USACollege of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USADepartment of Urology, School of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA 15232, USADepartment of Chemistry, Center for Molecular Discovery (BU-CMD), Boston University, 590 Commonwealth Avenue, Boston, MA 02215, USACenter for Immunology and Infectious Diseases, Biosciences Division, SRI International, Harrisonburg, VA 22802, USAIdentification of novel drug targets and 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) and 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 and interact with both EGFR and CRaf. Targeting PHB by rocaglamide (Roc-A), a natural product that binds PHB1 and 2, reduced cell surface PHB1 and 2, disrupted PHB-CRaf interaction, and 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 and therapeutic index against HCV infection. This study reveals a new class of HCV entry inhibitors that target the PHB1/2-CRaf pathway.http://www.sciencedirect.com/science/article/pii/S2352396415301377HCVEntry factorsEntry inhibitorsRocaglates |
| spellingShingle | Shufeng Liu Wenyu Wang Lauren E. Brown Chao Qiu Neil Lajkiewicz Ting Zhao Jianhua Zhou John A. Porco Jr Tony T. Wang A Novel Class of Small Molecule Compounds that Inhibit Hepatitis C Virus Infection by Targeting the Prohibitin-CRaf Pathway EBioMedicine HCV Entry factors Entry inhibitors Rocaglates |
| title | A Novel Class of Small Molecule Compounds that Inhibit Hepatitis C Virus Infection by Targeting the Prohibitin-CRaf Pathway |
| title_full | A Novel Class of Small Molecule Compounds that Inhibit Hepatitis C Virus Infection by Targeting the Prohibitin-CRaf Pathway |
| title_fullStr | A Novel Class of Small Molecule Compounds that Inhibit Hepatitis C Virus Infection by Targeting the Prohibitin-CRaf Pathway |
| title_full_unstemmed | A Novel Class of Small Molecule Compounds that Inhibit Hepatitis C Virus Infection by Targeting the Prohibitin-CRaf Pathway |
| title_short | A Novel Class of Small Molecule Compounds that Inhibit Hepatitis C Virus Infection by Targeting the Prohibitin-CRaf Pathway |
| title_sort | novel class of small molecule compounds that inhibit hepatitis c virus infection by targeting the prohibitin craf pathway |
| topic | HCV Entry factors Entry inhibitors Rocaglates |
| url | http://www.sciencedirect.com/science/article/pii/S2352396415301377 |
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