title: Antiviral Activity of the Human Cathelicidin, LL-37, and Derived Peptides on Seasonal and Pandemic Influenza A Viruses.
abstract: Human LL-37, a cationic antimicrobial peptide, was recently shown to have antiviral activity against influenza A virus (IAV) strains in vitro and in vivo. In this study we compared the anti-influenza activity of LL-37 with that of several fragments derived from LL-37. We first tested the peptides against a seasonal H3N2 strain and the mouse adapted H1N1 strain, PR-8. The N-terminal fragment, LL-23, had slight neutralizing activity against these strains. In LL-23V9 serine 9 is substituted by valine creating a continuous hydrophobic surface. LL-23V9 has been shown to have increased anti-bacterial activity compared to LL-23 and we now show slightly increased antiviral activity compared to LL-23 as well. The short central fragments, FK-13 and KR-12, which have anti-bacterial activity did not inhibit IAV. In contrast, a longer 20 amino acid central fragment of LL-37 (GI-20) had neutralizing activity similar to LL-37. None of the peptides inhibited viral hemagglutination or neuraminidase activity. We next tested activity of the peptides against a strain of pandemic H1N1 of 2009 (A/California/04/09/H1N1 or "Cal09"). Unexpectedly, LL-37 had markedly reduced activity against Cal09 using several cell types and assays of antiviral activity. A mutant viral strain containing just the hemagglutinin (HA) of 2009 pandemic H1N1 was inhibited by LL-37, suggested that genes other than the HA are involved in the resistance of pH1N1. In contrast, GI-20 did inhibit Cal09. In conclusion, the central helix of LL-37 incorporated in GI-20 appears to be required for optimal antiviral activity. The finding that GI-20 inhibits Cal09 suggests that it may be possible to engineer derivatives of LL-37 with improved antiviral properties.
authors.affiliation: Boston University School of Medicine, Department of Medicine, Boston, MA, United States of America.
authors.forename: Shweta
authors.initials: S
authors.lastname: Tripathi
authors.affiliation: Department of Pathology and Microbiology, University of Nebraska Medical Center, 986495 Nebraska Medical Center, Omaha, NE 68198-6495, United States of America.
authors.forename: Guangshun
authors.initials: G
authors.lastname: Wang
authors.affiliation: Boston University School of Medicine, Department of Medicine, Boston, MA, United States of America.
authors.forename: Mitchell
authors.initials: M
authors.lastname: White
authors.affiliation: National Institute of Allergy and Infectious Diseases, Bethesda, United States of America.
authors.forename: Li
authors.initials: L
authors.lastname: Qi
authors.affiliation: National Institute of Allergy and Infectious Diseases, Bethesda, United States of America.
authors.forename: Jeffery
authors.initials: J
authors.lastname: Taubenberger
authors.affiliation: Boston University School of Medicine, Department of Medicine, Boston, MA, United States of America.
authors.forename: Kevan L
authors.initials: KL
authors.lastname: Hartshorn
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D023181:Antimicrobial Cationic Peptides; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D054804:Cathelicidins / Q000235:genetics / Q000494:pharmacology*; D002478:Cells, Cultured; D024882:Drug Resistance, Viral / Q000235:genetics; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D053122:Influenza A Virus, H3N2 Subtype / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D007251:Influenza, Human / Q000188:drug therapy / Q000453:epidemiology / Q000821:virology; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D058873:Pandemics; D010446:Peptide Fragments / Q000235:genetics / Q000494:pharmacology; D011487:Protein Conformation; D012621:Seasons; D014779:Virus Replication / Q000187:drug effects
chemical_list: D023181:Antimicrobial Cationic Peptides; D000998:Antiviral Agents; D054804:Cathelicidins; D010446:Peptide Fragments