Engineering Protease-Resistant Peptides to Inhibit Human Parainfluenza Viral Respiratory Infection

• DOI: 10.1021/jacs.1c01565
• Publication Date: 2021-04-07T11:39:02Z
• Authors: Victor K. Outlaw; Ross W. Cheloha; Eric M. Jurgens; Francesca T. Bovier; Yun Zhu; Dale F. Kreitler; Olivia Harder; Stefan Niewiesk; Matteo Porotto; Samuel H. Gellman; Anne Moscona
• Keywords: Lipopeptide; Heptad repeat

The lower respiratory tract infections affecting children worldwide are in large part caused by the parainfluenza viruses (HPIVs), particularly HPIV3, along with human metapneumovirus and syncytial virus, enveloped negative-strand RNA viruses. There no vaccines for these important pathogens, existing treatments have limited or efficacy. Infection HPIV is initiated viral glycoprotein-mediated fusion between host cell membranes. A protein (F), once activated proximity to a target cell, undergoes series of conformational changes that first extend trimer subunits allow insertion hydrophobic domains into membrane then refold stable postfusion state, driving merger Lipopeptides derived from C-terminal heptad repeat (HRC) domain HPIV3 F inhibit infection interfering structural transitions trimeric assembly. Clinical application this strategy, however, requires improving vivo stability antiviral peptides. We show HRC peptide backbone can be modified via partial replacement α-amino acid residues β-amino generate α/β-peptides retain activity but poor protease substrates. Relative conventional α-lipopeptide, our best α/β-lipopeptide exhibits improved persistence anti-HPIV3 animals.