title: Hapivirins and diprovirins: novel θ-defensin analogs with potent activity against influenza A virus.
abstract: θ-Defensins are cyclic octadecapeptides found in nonhuman primates whose broad antiviral spectrum includes HIV-1, HSV-1, severe acute respiratory syndrome coronavirus, and influenza A virus (IAV). We previously reported that synthetic θ-defensins called retrocyclins can neutralize and aggregate various strains of IAV and increase IAV uptake by neutrophils. This study describes two families of peptides, hapivirins and diprovirins, whose design was inspired by retrocyclins. The goal was to develop smaller partially cyclic peptides that retain the antiviral activity of retrocyclins, while being easier to synthesize. The novel peptides also allowed for systemic substitution of key residues to evaluate the role of charge or hydrophobicity on antiviral activity. Seventy-two hapivirin or diprovirin peptides are described in this work, including several whose anti-IAV activity equals or exceeds that of normal α- or θ-defensins. Some of these also had strong antibacterial and antifungal activity. These new peptides were active against H3N2 and H1N1 strains of IAV. Structural features imparting strong antiviral activity were identified through iterative cycles of synthesis and testing. Our findings show the importance of hydrophobic residues for antiviral activity and show that pegylation, which often increases a peptide's serum t(1/2) in vivo, can increase the antiviral activity of DpVs. The new peptides acted at an early phase of viral infection, and, when combined with pulmonary surfactant protein D, their antiviral effects were additive. The peptides strongly increased neutrophil and macrophage uptake of IAV, while inhibiting monocyte cytokine generation. Development of modified θ-defensin analogs provides an approach for creating novel antiviral agents for IAV infections.
authors.affiliation: Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: Mona
authors.initials: M
authors.lastname: Doss
authors.forename: Piotr
authors.initials: P
authors.lastname: Ruchala
authors.forename: Tesfaldet
authors.initials: T
authors.lastname: Tecle
authors.forename: Donald
authors.initials: D
authors.lastname: Gantz
authors.forename: Anamika
authors.initials: A
authors.lastname: Verma
authors.forename: Alex
authors.initials: A
authors.lastname: Hartshorn
authors.forename: Erika C
authors.initials: EC
authors.lastname: Crouch
authors.forename: Hai
authors.initials: H
authors.lastname: Luong
authors.forename: Ewa D
authors.initials: ED
authors.lastname: Micewicz
authors.forename: Robert I
authors.initials: RI
authors.lastname: Lehrer
authors.forename: Kevan L
authors.initials: KL
authors.lastname: Hartshorn
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000276:immunology / Q000494:pharmacology*; D002460:Cell Line; D060326:Chemistry Techniques, Synthetic; D002851:Chromatography, High Pressure Liquid; D023082:Defensins / Q000138:chemical synthesis / Q000276:immunology* / Q000494:pharmacology*; D004285:Dogs; D006801:Humans; D009980:Influenza A virus / Q000276:immunology*; D046529:Microscopy, Electron, Transmission; D008969:Molecular Sequence Data; D009000:Monocytes / Q000821:virology; D009504:Neutrophils / Q000821:virology; D010455:Peptides; D013329:Structure-Activity Relationship; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D000998:Antiviral Agents; D023082:Defensins; D010455:Peptides; D014409:Tumor Necrosis Factor-alpha