6VJO

Human parainfluenza virus type 3 fusion glycoprotein N-terminal heptad repeat domain+alpha/beta-VI

Summary for 6VJO

• Entry DOI: 10.2210/pdb6vjo/pdb
• Descriptor: Fusion glycoprotein F0 (3 entities in total)
• Functional Keywords: fusion protein, fusion inhibitor, six-helix bundle, antiviral protein, alpha/beta-peptide
• Biological source: Human respirovirus 3; More
• Total number of polymer chains: 2
• Total formula weight: 9848.36

Authors

Outlaw, V.K.,Kreitler, D.F.,Gellman, S.H. (deposition date: 2020-01-16, release date: 2021-04-21, Last modification date: 2023-11-15)

Primary citation

Outlaw, V.K.,Cheloha, R.W.,Jurgens, E.M.,Bovier, F.T.,Zhu, Y.,Kreitler, D.F.,Harder, O.,Niewiesk, S.,Porotto, M.,Gellman, S.H.,Moscona, A.
Engineering Protease-Resistant Peptides to Inhibit Human Parainfluenza Viral Respiratory Infection.
J.Am.Chem.Soc., 143:5958-5966, 2021

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

PubMed: 33825470
DOI: 10.1021/jacs.1c01565

Experimental method

X-RAY DIFFRACTION (2 Å)