机构：[1]Department of Chemistry, University of Wisconsin, Madison, Wisconsin, 53706, United States[2]Department of Pediatrics, Columbia University Medical Center, New York, New York, 10032, United States[3]Beijing Pediatric Research Institute, Beijing Children’s Hospital, Capital Medical University, Beijing, China科研平台儿科研究所首都医科大学附属北京儿童医院[4]Center for Host–Pathogen Interaction, Columbia University Medical Center, New York, New York, 10032, United States[5]Department of Experimental Medicine, University of Campania ‘Luigi Vanvitelli’, Italy[6]Department of Microbiology & Immunology, Columbia University Medical Center, New York, New York, 10032, United States[7]Department of Physiology & Cellular Biophysics, Columbia University Medical Center, New York, New York, 10032, United States
Human 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.
基金：
NIH/NIAIDUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Allergy & Infectious Diseases (NIAID) [R01A1114736, R01A1121349]; Ruth L. Kirschstein National Research Service Award from the NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [F32GM122263]; DOE Office of ScienceUnited States Department of Energy (DOE) [DE-AC02-06CH11357]; Michigan Economic Development Corporation; Michigan Technology TriCorridor [085P1000817]; Morgan Stanley Global Alliance Morgan Stanley Children's Hospital; Beijing Children's Hospital Pediatric Initiative
第一作者机构：[1]Department of Chemistry, University of Wisconsin, Madison, Wisconsin, 53706, United States
通讯作者：
通讯机构：[1]Department of Chemistry, University of Wisconsin, Madison, Wisconsin, 53706, United States[2]Department of Pediatrics, Columbia University Medical Center, New York, New York, 10032, United States[4]Center for Host–Pathogen Interaction, Columbia University Medical Center, New York, New York, 10032, United States[5]Department of Experimental Medicine, University of Campania ‘Luigi Vanvitelli’, Italy[6]Department of Microbiology & Immunology, Columbia University Medical Center, New York, New York, 10032, United States[7]Department of Physiology & Cellular Biophysics, Columbia University Medical Center, New York, New York, 10032, United States
推荐引用方式(GB/T 7714)：
Outlaw Victor K,Lemke Jennifer T,Zhu Yun,et al.Structure-Guided Improvement of a Dual HPIV3/RSV Fusion Inhibitor.[J].JOURNAL OF THE AMERICAN CHEMICAL SOCIETY.2020,142(5):2140-2144.doi:10.1021/jacs.9b11548.
APA：
Outlaw Victor K,Lemke Jennifer T,Zhu Yun,Gellman Samuel H,Porotto Matteo&Moscona Anne.(2020).Structure-Guided Improvement of a Dual HPIV3/RSV Fusion Inhibitor..JOURNAL OF THE AMERICAN CHEMICAL SOCIETY,142,(5)
MLA：
Outlaw Victor K,et al."Structure-Guided Improvement of a Dual HPIV3/RSV Fusion Inhibitor.".JOURNAL OF THE AMERICAN CHEMICAL SOCIETY 142..5(2020):2140-2144
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