RSV blocked by double-stapled peptide
Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infections and can produce life-threatening illness in very young and elderly patients. Despite great effort, therapeutic strategies to prevent or reduce RSV infection are limited. RSV enters host cells through the action of the fusion protein RSV F, which forms a six-helix fusogenic bundle. Small interfering peptides can prevent bundle formation and limit RSV infection in vitro; however, these peptides are highly susceptible to degradation. Gregory Bird, Sandhya Boyapalle, and colleagues at Harvard Medical School and the University of South Florida, respectively, employed a hydrocarbon stapling technique to stabilize the α-helical structure of a RSV F peptide (SAH-RSV). Administration of SAH-RSV prior to inoculation with RSV prevented infection in both cell culture and murine models. Intranasal delivery of SAH-RSV prevented viral infection within the nares of mice, while intratracheal delivery of a nanoparticle preparation of SAH-RSV prevented RSV infection in the lung. In the accompanying Commentary, Sarah Katen and Terrence Dermody of Vanderbilt University discuss the implications of this study for RSV prevention. The accompanying image shows nasal tissue (stained blue with DAPI) from 10-week old mice given nasal drops containing either vehicle (right) or SAH-RSV (left) prior to infection with GFP-expressing RSV.
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Abstract
Respiratory syncytial virus (RSV) infection accounts for approximately 64 million cases of respiratory disease and 200,000 deaths worldwide each year, yet no broadly effective prophylactic or treatment regimen is available. RSV deploys paired, self-associating, heptad repeat domains of its fusion protein, RSV-F, to form a fusogenic 6-helix bundle that enables the virus to penetrate the host cell membrane. Here, we developed hydrocarbon double-stapled RSV fusion peptides that exhibit stabilized α-helical structure and striking proteolytic resistance. Pretreatment with double-stapled RSV peptides that specifically bound to the RSV fusion bundle inhibited infection by both laboratory and clinical RSV isolates in cells and murine infection models. Intranasal delivery of a lead double-stapled RSV peptide effectively prevented viral infection of the nares. A chitosan-based nanoparticle preparation markedly enhanced pulmonary delivery, further preventing progression of RSV infection to the lung. Thus, our results provide a strategy for inhibiting RSV infection by mucosal and endotracheal delivery of double-stapled RSV fusion peptides.
Authors
Gregory H. Bird, Sandhya Boyapalle, Terianne Wong, Kwadwo Opoku-Nsiah, Raminder Bedi, W. Christian Crannell, Alisa F. Perry, Huy Nguyen, Viviana Sampayo, Ankita Devareddy, Subhra Mohapatra, Shyam S. Mohapatra, Loren D. Walensky
Abstract
Respiratory syncytial virus (RSV) is responsible for lower respiratory tract infections and annually results in 200,000 deaths worldwide. Despite the burden of RSV-associated disease, treatments and preventative measures are limited. In this issue of
Authors
Sarah P. Katen, Terence S. Dermody
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