A virocidal amphipathic {alpha}-helical peptide that inhibits hepatitis C virus infection in vitro.
An amphipathic alpha-helical peptide (C5A) derived from the membrane anchor domain of the hepatitis C virus (HCV) NS5A protein is virocidal for HCV at submicromolar concentrations in vitro. C5A prevents de novo HCV infection and suppresses ongoing infection by inactivating both extra- and intracellular infectious particles, and it is nontoxic in vitro and in vivo at doses at least 100-fold higher than required for antiviral activity. Mutational analysis indicates that C5A's amphipathic alpha-helical structure is necessary but not sufficient for its virocidal activity, which depends on its amino acid composition but not its primary sequence or chirality. In addition to HCV, C5A inhibits infection by selected flaviviruses, paramyxoviruses, and HIV. These results suggest a model in which C5A destabilizes viral membranes based on their lipid composition, offering a unique therapeutic approach to HCV and other viral infections.
Cheng
Guofeng
G
Departments of Molecular and Experimental Medicine, Chemistry, and Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Montero
Ana
A
Gastaminza
Pablo
P
Whitten-Bauer
Christina
C
Wieland
Stefan F
SF
Isogawa
Masanori
M
Fredericksen
Brenda
B
Selvarajah
Suganya
S
Gallay
Philippe A
PA
Ghadiri
M Reza
MR
Chisari
Francis V
FV
D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D002942:Circular Dichroism; D003601:Cytotoxicity Tests, Immunologic; D016174:Hepacivirus / Q000235:genetics / Q000378:metabolism*; D006526:Hepatitis C / Q000235:genetics* / Q000517:prevention & control*; D006801:Humans; D066298:In Vitro Techniques; D008969:Molecular Sequence Data; D010455:Peptides / Q000235:genetics / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013329:Structure-Activity Relationship; D013778:Tetrazolium Salts; D013844:Thiazoles; D014779:Virus Replication / Q000187:drug effects*
D000998:Antiviral Agents; D010455:Peptides; D013778:Tetrazolium Salts; D013844:Thiazoles; C022616:thiazolyl blue