1. In Vivo Efficacy of Measles Virus Fusion Protein-Derived Peptides Is Modulated by the Properties of Self-Assembly and Membrane Residence.
- Author
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Figueira TN, Palermo LM, Veiga AS, Huey D, Alabi CA, Santos NC, Welsch JC, Mathieu C, Horvat B, Niewiesk S, Moscona A, Castanho MARB, and Porotto M
- Subjects
- Administration, Intranasal, Amino Acid Sequence, Animals, Brain drug effects, Brain immunology, Cholesterol chemistry, Female, Half-Life, Hemagglutinins, Viral chemistry, Humans, Lung drug effects, Lung immunology, Male, Measles immunology, Measles mortality, Measles virology, Measles Vaccine chemical synthesis, Measles virus chemistry, Measles virus immunology, Nanoparticles chemistry, Peptides chemical synthesis, Sigmodontinae, Survival Analysis, Viral Fusion Proteins chemistry, Virus Internalization drug effects, Hemagglutinins, Viral immunology, Measles prevention & control, Measles Vaccine administration & dosage, Measles virus drug effects, Nanoparticles administration & dosage, Peptides immunology, Viral Fusion Proteins immunology
- Abstract
Measles virus (MV) infection is undergoing resurgence and remains one of the leading causes of death among young children worldwide despite the availability of an effective measles vaccine. MV infects its target cells by coordinated action of the MV hemagglutinin (H) and fusion (F) envelope glycoproteins; upon receptor engagement by H, the prefusion F undergoes a structural transition, extending and inserting into the target cell membrane and then refolding into a postfusion structure that fuses the viral and cell membranes. By interfering with this structural transition of F, peptides derived from the heptad repeat (HR) regions of F can inhibit MV infection at the entry stage. In previous work, we have generated potent MV fusion inhibitors by dimerizing the F-derived peptides and conjugating them to cholesterol. We have shown that prophylactic intranasal administration of our lead fusion inhibitor efficiently protects from MV infection in vivo We show here that peptides tagged with lipophilic moieties self-assemble into nanoparticles until they reach the target cells, where they are integrated into cell membranes. The self-assembly feature enhances biodistribution and the half-life of the peptides, while integration into the target cell membrane increases fusion inhibitor potency. These factors together modulate in vivo efficacy. The results suggest a new framework for developing effective fusion inhibitory peptides., Importance: Measles virus (MV) infection causes an acute illness that may be associated with infection of the central nervous system (CNS) and severe neurological disease. No specific treatment is available. We have shown that fusion-inhibitory peptides delivered intranasally provide effective prophylaxis against MV infection. We show here that specific biophysical properties regulate the in vivo efficacy of MV F-derived peptides., (Copyright © 2016 American Society for Microbiology.)
- Published
- 2016
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