Inhibition of Marburg Virus RNA Synthesis by a Synthetic Anti-VP35 Antibody
- Parmeshwar AmatyaParmeshwar AmatyaDepartment of Medicine, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, Missouri 63110, United StatesDepartment of Pathology and Immunology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, Missouri 63110, United StatesMore by Parmeshwar Amatya,
- Nicole WagnerNicole WagnerDepartment of Chemistry, Washington University in St. Louis, 1 Brookings Drive, St. Louis, Missouri 63130, United StatesMore by Nicole Wagner,
- Gang ChenGang ChenDonnelly Centre for Cellular and Biomolecular Research, Banting and Best Department of Medical Research, University of Toronto, 816-160 College Street, Toronto, Ontario M5S 3E1, CanadaMore by Gang Chen,
- Priya LuthraPriya LuthraCenter for Microbial Pathogenesis, Institute for Biomedical Sciences, Georgia State University, 100 Piedmont Avenue, Atlanta, Georgia 30303, United StatesMore by Priya Luthra,
- Liuqing ShiLiuqing ShiDepartment of Chemistry, Washington University in St. Louis, 1 Brookings Drive, St. Louis, Missouri 63130, United StatesMore by Liuqing Shi,
- Dominika BorekDominika BorekDepartment of Biophysics, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, United StatesMore by Dominika Borek,
- Alevtina PavlencoAlevtina PavlencoDonnelly Centre for Cellular and Biomolecular Research, Banting and Best Department of Medical Research, University of Toronto, 816-160 College Street, Toronto, Ontario M5S 3E1, CanadaMore by Alevtina Pavlenco,
- Henry RohrsHenry RohrsDepartment of Chemistry, Washington University in St. Louis, 1 Brookings Drive, St. Louis, Missouri 63130, United StatesMore by Henry Rohrs,
- Christopher F. BaslerChristopher F. BaslerCenter for Microbial Pathogenesis, Institute for Biomedical Sciences, Georgia State University, 100 Piedmont Avenue, Atlanta, Georgia 30303, United StatesMore by Christopher F. Basler,
- Sachdev S. Sidhu*Sachdev S. Sidhu*E-mail: [email protected] (S.S.S.).Donnelly Centre for Cellular and Biomolecular Research, Banting and Best Department of Medical Research, University of Toronto, 816-160 College Street, Toronto, Ontario M5S 3E1, CanadaMore by Sachdev S. Sidhu,
- Michael L. Gross*Michael L. Gross*E-mail: [email protected] (M.L.G.).Department of Chemistry, Washington University in St. Louis, 1 Brookings Drive, St. Louis, Missouri 63130, United StatesMore by Michael L. Gross, and
- Daisy W. Leung*Daisy W. Leung*E-mail: [email protected] (D.W.L.).Department of Medicine, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, Missouri 63110, United StatesDepartment of Pathology and Immunology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, Missouri 63110, United StatesMore by Daisy W. Leung
Abstract
Marburg virus causes sporadic outbreaks of severe hemorrhagic fever with high case fatality rates. Approved, effective, and safe therapeutic or prophylactic countermeasures are lacking. To address this, we used phage display to engineer a synthetic antibody, sFab H3, which binds the Marburg virus VP35 protein (mVP35). mVP35 is a critical cofactor of the viral replication complex and a viral immune antagonist. sFab H3 displayed high specificity for mVP35 and not for the closely related Ebola virus VP35. sFab H3 inhibited viral-RNA synthesis in a minigenome assay, suggesting its potential use as an antiviral. We characterized sFab H3 by a combination of biophysical and biochemical methods, and a crystal structure of the complex solved to 1.7 Å resolution defined the molecular interface between the sFab H3 and mVP35 interferon inhibitory domain. Our study identifies mVP35 as a therapeutic target using an approach that provides a framework for generating engineered Fabs targeting other viral proteins.