Engineering a Higher Efficacy Anti-Heparan Sulfate Peptide for an Entry-Based Antiviral Therapy

Primary and recurring herpes simplex virus-1 (HSV-1) infections can cause different pathologies in the eye and in severe cases it can result in permanent blindness. The current antiviral treatments for HSV-1 belong to a class of nucleoside analogs that inhibit viral DNA polymerase and block viral replication. Since they all target the same step in viral lifecycle, emergence of drug resistance is on the rise. Topical antivirals get eliminated through absorbance from ocular tissues or through the nasolacrimal duct resulting in lower bioavailability and frequent applications to reduce symptoms. These challenges need to be addressed by developing newer treatment options that target different stages in the viral lifecycle and by utilizing innovative technologies to enhance the efficacy and residence time of a drug on the cornea. Previous work from our lab discovered a unique arginine-rich peptide called G2. The peptide was specifically isolated against heparan sulfate (HS). HSV-1 used HS for attaching to cells and initiating entry. The G2 peptide binds to HS and inhibits viral entry and subsequent infection. Although peptides are fast growing as potential therapeutic molecules due to their high specificity, they are susceptible to protease degradation resulting in low activity and availability. The goal of this study is to increase the efficacy and/or stability of the G2 peptide that can either be used as a standalone preventive management or as a therapeutic in combination with existing antiviral treatments in controlling ocular herpes infection. Using peptide conjugation and peptide structure modification strategies and contact lenses as a drug delivery system, this study shows that the modified peptides are stable and significantly block viral entry and subsequent infection. The modified peptides are the first of its kind and may represent a new class of antiviral compounds. Additionally, other microorganisms such as fungi and bacteria also use HS for their pathogenesis. Thus, these efficacious forms of G2 may represent a broad-spectrum drug against these microbes.