J. Am. Chem. Soc.All Publications/WebsiteOR SEARCH CITATIONS Recently ViewedYou have not visited any articles yet, Please visit some articles to see contents here. RETURN TO ISSUEPREVCommunicationNEXTStructure-Guided Improvement of a Dual HPIV3/RSV Fusion InhibitorVictor K. OutlawVictor K. OutlawDepartment of Chemistry, University of Wisconsin, Madison, Wisconsin 53706, United StatesMore by Victor K. Outlawhttp://orcid.org/0000-0001-7054-4204,Jennifer T. LemkeJennifer T. LemkeDepartment of Chemistry, University of Wisconsin, Madison, Wisconsin 53706, United StatesMore by Jennifer T. Lemke,Yun ZhuYun ZhuDepartment of Pediatrics, Columbia University Medical Center, New York, New York 10032, United StatesBeijing Pediatric Research Institute, Beijing Children’s Hospital, Capital Medical University, Beijing 100045, ChinaMore by Yun Zhu,Samuel H. Gellman*Samuel H. GellmanDepartment of Chemistry, University of Wisconsin, Madison, Wisconsin 53706, United States*[email protected]More by Samuel H. Gellmanhttp://orcid.org/0000-0001-5617-0058,Matteo Porotto*Matteo PorottoDepartment of Pediatrics, Columbia University Medical Center, New York, New York 10032, United StatesCenter for Host−Pathogen Interaction, Columbia University Medical Center, New York, New York 10032, United StatesDepartment of Experimental Medicine, University of Campania \"Luigi Vanvitelli”, 81100 Caserta, Italy*[email protected]More by Matteo Porotto,andAnne Moscona*Anne MosconaDepartment of Pediatrics, Columbia University Medical Center, New York, New York 10032, United StatesCenter for Host−Pathogen Interaction, Columbia University Medical Center, New York, New York 10032, United StatesDepartment of Microbiology Immunology, Columbia University Medical Center, New York, New York 10032, United StatesDepartment of Physiology Cellular Biophysics, Columbia University Medical Center, New York, New York 10032, United States*[email protected]More by Anne MosconaCite this: J. Am. Chem. Soc. 2020, 142, 5, 2140–2144Publication Date (Web):January 17, 2020Publication History Received26 October 2019Published online17 January 2020Published inissue 5 February 2020https://doi.org/10.1021/jacs.9b11548Copyright © 2020 American Chemical SocietyRIGHTS & PERMISSIONSArticle Views1214Altmetric-Citations2LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated.Get e-AlertsAbstractHuman parainfluenza virus 3 (HPIV3) and respiratory syncytial virus (RSV) are leading causes of lower respiratory tract infections. There are currently no vaccines or antiviral therapeutics to treat HPIV3 or RSV infections. We recently reported a peptide (VIQKI), derived from the C-terminal heptad repeat (HRC) domain of the HPIV3 fusion (F) glycoprotein that inhibits infection by both HPIV3 and RSV. The dual inhibitory activity of VIQKI is due to its unique ability to bind to the N-terminal heptad repeat (HRN) domains of both HPIV3 and RSV F, thereby preventing the native HRN-HRC interactions required for viral entry. Here we describe the structure-guided design of dual inhibitors of HPIV3 and RSV fusion with improved efficacy. We show that VIQKI derivatives possessing one (I456F) or two (I454F/I456F) phenylalanine substitutions near the N-terminus exhibit more stable assemblies with the RSV-HRN domain and enhanced antiviral efficacy against both HPIV3 and RSV infection. Cocrystal structures of the new Phe-substituted inhibitors coassembled with HPIV3 or RSV-HRN domains reveal that the I456F substitution makes intimate hydrophobic contact with the core trimers of both HPIV3 and RSV F.Supporting InformationARTICLE SECTIONSJump ToThe Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacs.9b11548.Additional figures, synthetic procedures, and characterization data for all synthesized peptides, as well as protocols for thermal denaturation and plaque reduction assays (PDF)ja9b11548_si_001.pdf (11.26 MB) Most electronic Supporting Information files are available without a subscription to ACS Web Editions. Such files may be downloaded by article for research use (if there is a public use license linked to the relevant article, that license may permit other uses). Permission may be obtained from ACS for other uses through requests via the RightsLink permission system: http://pubs.acs.org/page/copyright/permissions.html. Cited ByThis article is cited by 2 publications.Victor K. Outlaw, Dale F. Kreitler, Debora Stelitano, Matteo Porotto, Anne Moscona, Samuel H. Gellman. Effects of Single α-to-β Residue Replacements on Recognition of an Extended Segment in a Viral Fusion Protein. ACS Infectious Diseases 2020, 6 , 2017-2022. https://doi.org/10.1021/acsinfecdis.0c00385Zsófia Hegedüs, Fruzsina Hóbor, Deborah K. Shoemark, Sergio Celis, Lu-Yun Lian, Chi H. Trinh, Richard B. Sessions, Thomas A. Edwards, Andrew J. Wilson. Identification of β-strand mediated protein–protein interaction inhibitors using ligand-directed fragment ligation. Chemical Science 2021, 12 , 2286-2293. https://doi.org/10.1039/D0SC05694DExport articles to MendeleyGet article recommendations from ACS based on references in your Mendeley library.Export articles to MendeleyGet article recommendations from ACS based on references in your Mendeley library. Please note: If you switch to a different device, you may be asked to login again with only your ACS ID. Please note: If you switch to a different device, you may be asked to login again with only your ACS ID. Please note: If you switch to a different device, you may be asked to login again with only your ACS ID. Please login with your ACS ID before connecting to your Mendeley account.Login with ACS ID This website uses cookies to improve your user experience. By continuing to use the site, you are accepting our use of cookies. Read the ACS privacy policy. CONTINUE