Extended Release of an Anti-Heparan Sulfate Peptide From a Contact Lens Suppresses Corneal Herpes Simplex Virus-1 Infection.

Herpes simplex virus-1 (HSV-1) is a double-stranded DNA virus widely prevalent in humans and estimated to have infected 60% to 90% of the population.1 Primary and recurrent ocular herpetic infections cause corneal scarring, neovascularization, and epithelium and stromal keratitis; in severe cases, these result in blindness.2,3 While the current available topical treatments include the use of trifluorothymidine (TFT) or the use of ganciclovir gels, oral treatments involve the use of steroids, acyclovir and its analogues valacyclovir that are nucleoside analogues. Dual treatments with steroids are also prescribed by clinicians.4 However, some limitations to the above mentioned treatments include the following: Eye drops constitute ∼90% of ophthalmic medications and have advantages, including ease of administration, safety and efficacy, but this is limited by low residence time due to rapid drainage from the lacrimal ducts resulting in frequent applications5,6; Increasing cases of resistance to acyclovir, the first line of therapy in HSV infections7,8; Use of steroids causes ocular complications such as cataract and steroid-induced glaucoma9–11; and TFT has been shown to pose toxicity at high doses and hence cannot be prescribed for prolonged usage.12,13 While all of these treatments are effective, the limitations pose the requirement of new treatment options for ocular herpes, which may also include improved methods of administration. The envelop glycoprotein D (gD) of HSV-1 is essential for HSV-1 entry and infection.14,15 To date, the following surface receptors have been identified that bind gD and allow infection to proceed: herpesvirus entry mediator (HVEM), Nectin-1 and ‐2, and 3-O-sulfated heparan sulfate (3-OS-HS), a rare modification of the polysaccharide heparan sulfate (HS).15,16 Heparan sulfate is a highly abundant and ubiquitously expressed cell surface receptor, which is also a key molecule for infection as it is required for attachment, viral surfing, capsid penetration, and its removal is needed during egress of newly generated virions.16–18 Therefore, in our quest to target this very common entry coreceptor for antiviral effects, prior studies in our laboratory identified two 12-mer peptides, called G1 and G2, which showed strong anti–HSV-1 properties.19 The peptides G1 and G2 were specifically selected against HS and 3-OS-HS respectively. The in vivo prophylactic activity of the peptides was confirmed using a corneal infection model.19 In another study from our laboratory, the therapeutic effect of G2 along with acyclovir as a potential dual therapy was also tested.20 The aim of this study was to determine the antiviral efficacy of a relatively more stable variant of G2 peptide, G2-C, delivered via contact lenses for extended antiviral therapy. Herpes simplex virus 1 infects corneal epithelium where HS is normally prevalent during initial infection.20 The parental G2 peptide is known to inhibit the interaction19 of virus with HS, but it must be maintained for extended periods to maintain activity. As a potential alternative, many studies have successfully investigated the use of contact lenses for drug delivery to improve the bioavailability and residence time of topically applied drugs.21 Using a similar strategy, we wanted to deliver the G2-C peptide using a vehicle that would release the peptide over an extended period of time, thereby increasing the residence time of the peptide on the corneal epithelium. Our results demonstrate that a commercially available contact lens loaded with the G2-C peptide solution is able to prolong the release of the peptide and the released peptide is able to block HSV-1 infection and replication in natural target cells as well as in corneal infection models.