Victor K Outlaw1, Jennifer T Lemke1, Yun Zhu2,3, Samuel H Gellman1, Matteo Porotto2,4,5, Anne Moscona2,4,6,7. 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 100045 , China. 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" , 81100 Caserta , 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.
Abstract
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.
Human parainfluenza virus 3 (n class="Species">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 RSVinfections. 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 RSVinfection. 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.
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