In Vivo Activity of Antimicrobial Peptoid Oligomers against HSV-1 in a Mouse Model of Herpes Labialis

Abstract

Herpes simplex virus type-1 (HSV-1) infections cause recurrent oral lesions and are the primary cause of infectious blindness and genital lesions in developed countries. HSV-1 can also lead to life-threatening infections in immunocompromised individuals. Currently, the primary class of antiviral therapeutics for HSV-1 treatment are nucleoside analogues such as acyclovir. However, these therapeutics are only partially effective and are subject to development of resistance. Thus, the development of new, effective antiviral agents, which can be used topically to inactivate HSV-1, is a necessity. We have recently demonstrated the potent antiviral activity of a family of biomimetic compounds. These ‘peptoid’ (N-substituted glycine) oligomers mimic the structure and activity of antimicrobial peptides like LL-37, while being highly resistant to proteases. Antiviral peptoids rapidly inactivate HSV-1 in vitro by disruption of the viral envelope, likely through interaction with the lipid phosphatidylserine on the outer membrane leaflet. To test the in vivo activity of these peptoids, we optimized a lip treatment model of HSV-1 infection. We demonstrate that delivery of a clinical isolate of HSV-1, strain 294.1, onto scarified lips of BALB/c mice led to reproducible lesions within 5 days. Treatment of these lesions on day 2 post infection with increasing concentrations of an antiviral peptoid resulted in a dose-dependent inhibition of lesion formation, comparable to acyclovir cream, and the host defense peptide LL-37. The same dose-dependence was observed when quantifying viral DNA from both the lip and the trigeminal ganglion by qPCR. The results demonstrate the ability of these peptoids to be developed as topical antiviral agents to prevent herpes labialis infections caused by HSV-1.