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Infection is initiated by viral glycoprotein-mediated fusion between viral and host cell membranes. Paramyxovirus viral fusion proteins (F) insert into the target cell membrane, and form a transient intermediate that pulls the viral and cell membranes together as two heptad-repeat regions refold to form a six-helix bundle structure that can be specifically targeted by fusion-inhibitory peptides. Antiviral potency can be improved by sequence modification and lipid conjugation, and by adding linkers between the protein and lipid components. We exploit the uniquely broad spectrum antiviral activity of a parainfluenza F-derived peptide sequence that inhibits both parainfluenza and Nipah viruses, to investigate the influence of peptide orientation and intervening linker length on the peptides\u2019 interaction with transitional states of F, solubility, membrane insertion kinetics, and protease sensitivity. We assessed the impact of these features on biodistribution and antiviral efficacy <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo.<\/jats:italic> The engineering approach based on biophysical parameters resulted in a peptide that is a highly effective inhibitor of both paramyxoviruses and a set of criteria to be used for engineering broad spectrum antivirals for emerging paramyxoviruses.<\/jats:p>","DOI":"10.1038\/srep43610","type":"journal-article","created":{"date-parts":[[2018,3,13]],"date-time":"2018-03-13T09:42:58Z","timestamp":1520934178000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":46,"title":["Broad spectrum antiviral activity for paramyxoviruses is modulated by biophysical properties of fusion inhibitory peptides"],"prefix":"10.1038","volume":"7","author":[{"given":"Cyrille","family":"Mathieu","sequence":"first","affiliation":[]},{"given":"Marcelo T.","family":"Augusto","sequence":"additional","affiliation":[]},{"given":"Stefan","family":"Niewiesk","sequence":"additional","affiliation":[]},{"given":"Branka","family":"Horvat","sequence":"additional","affiliation":[]},{"given":"Laura M.","family":"Palermo","sequence":"additional","affiliation":[]},{"given":"Giuseppina","family":"Sanna","sequence":"additional","affiliation":[]},{"given":"Silvia","family":"Madeddu","sequence":"additional","affiliation":[]},{"given":"Devra","family":"Huey","sequence":"additional","affiliation":[]},{"given":"Miguel A. 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