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2012 ; 188
(6
): 2759-68
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Hapivirins and diprovirins: novel ?-defensin analogs with potent activity against
influenza A virus
#MMPMID22345650
Doss M
; Ruchala P
; Tecle T
; Gantz D
; Verma A
; Hartshorn A
; Crouch EC
; Luong H
; Micewicz ED
; Lehrer RI
; Hartshorn KL
J Immunol
2012[Mar]; 188
(6
): 2759-68
PMID22345650
show ga
?-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
?-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 ?- or ?-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 ?-defensin analogs provides an approach for
creating novel antiviral agents for IAV infections.