title: Capturing a fusion intermediate of influenza hemagglutinin with a cholesterol-conjugated peptide, a new antiviral strategy for influenza virus.
abstract: We previously described fusion-inhibitory peptides that are targeted to the cell membrane by cholesterol conjugation and potently inhibit enveloped viruses that fuse at the cell surface, including HIV, parainfluenza, and henipaviruses. However, for viruses that fuse inside of intracellular compartments, fusion-inhibitory peptides have exhibited very low antiviral activity. We propose that for these viruses, too, membrane targeting via cholesterol conjugation may yield potent compounds. Here we compare the activity of fusion-inhibitory peptides derived from the influenza hemagglutinin (HA) and show that although the unconjugated peptides are inactive, the cholesterol-conjugated compounds are effective inhibitors of infectivity and membrane fusion. We hypothesize that the cholesterol moiety, by localizing the peptides to the target cell membrane, allows the peptides to follow the virus to the intracellular site of fusion. The cholesterol-conjugated peptides trap HA in a transient intermediate state after fusion is triggered but before completion of the refolding steps that drive the merging of the viral and cellular membranes. These results provide proof of concept for an antiviral strategy that is applicable to intracellularly fusing viruses, including known and emerging viral pathogens.
authors: Department of Medicinal Chemistry and Biomolecular Structure and Design Program, University of Washington, Seattle, Washington 98195. Electronic address: kklee@u.washington.edu.
authors: Kelly K
authors: KK
authors: Lee
authors: PeptiPharma, Via dei Castelli Romani 22, 00040 Pomezia, Rome, Italy.
authors: Antonello
authors: A
authors: Pessi
authors: Department of Medicinal Chemistry and Biomolecular Structure and Design Program, University of Washington, Seattle, Washington 98195.
authors: Long
authors: L
authors: Gui
authors: Departments of Pediatrics and of Microbiology and Immunology, Weill Medical College of Cornell University, New York, New York 10021.
authors: Alessia
authors: A
authors: Santoprete
authors: Departments of Pediatrics and of Microbiology and Immunology, Weill Medical College of Cornell University, New York, New York 10021.
authors: Aparna
authors: A
authors: Talekar
authors: Departments of Pediatrics and of Microbiology and Immunology, Weill Medical College of Cornell University, New York, New York 10021.
authors: Anne
authors: A
authors: Moscona
authors: Departments of Pediatrics and of Microbiology and Immunology, Weill Medical College of Cornell University, New York, New York 10021. Electronic address: map2028@med.cornell.edu.
authors: Matteo
authors: M
authors: Porotto
mesh_terms: D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism / Q000821:virology; D002522:Chlorocebus aethiops; D002784:Cholesterol / Q000737:chemistry* / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism; D005816:Genetic Complementation Test; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000737:chemistry*; D006388:Hemagglutinins / Q000737:chemistry; D006801:Humans; D009975:Orthomyxoviridae / Q000378:metabolism; D010455:Peptides / Q000737:chemistry; D011489:Protein Denaturation; D017510:Protein Folding; D012328:RNA Viruses / Q000378:metabolism; D014709:Vero Cells
chemical_list: D019267:Hemagglutinin Glycoproteins, Influenza Virus; D006388:Hemagglutinins; D010455:Peptides; D002784:Cholesterol