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Engineering Protease-Resistant Peptides to Inhibit Human Parainfluenza Viral Respiratory Infection
Victor K Outlaw1, Ross W Cheloha1, Eric M Jurgens2
1Department of Chemistry, University of Wisconsin, Madison, Wisconsin 53706, United States.
Insights
New alpha/beta peptides show promise in combating human parainfluenza virus type 3 (HPIV3) infections in children. These modified peptides offer improved stability and antiviral activity, addressing limitations of current treatments for respiratory infections.
Area of Science:
- Virology
- Drug Discovery
- Structural Biology
Background:
- Human parainfluenza viruses (HPIVs), particularly HPIV3, are major causes of pediatric lower respiratory tract infections.
- Current treatments for HPIVs are limited, and no vaccines are available.
- Viral fusion proteins (F) mediate entry into host cells, making them targets for antiviral therapies.
Purpose of the Study:
- To develop more stable and effective antiviral lipopeptides targeting the HPIV3 fusion protein.
- To improve the in vivo stability and efficacy of HRC-derived peptides for treating HPIV infections.
Main Methods:
- Modification of HRC peptide backbone by replacing alpha-amino acids with beta-amino acids to create alpha/beta-peptides.
- Assessment of antiviral activity and protease resistance of the generated alpha/beta-lipopeptides.
- Evaluation of in vivo stability and anti-HPIV3 activity in animal models.
Main Results:
- Generated alpha/beta-lipopeptides retained antiviral activity against HPIV3.
- Alpha/beta-peptides demonstrated increased resistance to protease degradation compared to conventional alpha-lipopeptides.
- The lead alpha/beta-lipopeptide candidate showed enhanced in vivo persistence and superior anti-HPIV3 activity in animal studies.
Conclusions:
- Alpha/beta-peptide modification is a viable strategy to enhance the stability and efficacy of HPIV3 fusion protein inhibitors.
- These findings present a promising new therapeutic approach for managing HPIV infections in children.
- Further development of alpha/beta-lipopeptides could lead to effective treatments for significant respiratory viral pathogens.
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 in vivo 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 in vivo and improved anti-HPIV3 antiviral activity in animals.
