A topically administered stapled peptide prevents Herpes Simplex Virus-1 DNA replication for improved treatment of Herpes Ocular Keratitis.
Nearly two thirds of the world population is infected with Herpes simplex virus-1 (HSV-1). Following initial infection, recurrent activation along the ophthalmic branch of the cranial trigeminal nerve can lead to Herpes Ocular Keratitis (HK), the leading cause of corneal blindness in the US and in the world.
The gold standard for treatment of HK is acyclovir (ACV), a drug that targets viral thymidine kinase (TK). While this drug remains effective against oral and genital herpes, there is an emergence of ACV-resistant HK infections caused by mutations in the HSV-1 TK gene, and a need for therapies against alternative HSV-1 targets.
Scientists at the University of Pennsylvania have developed a stapled α-helical peptide for the treatment of HK. This stabilized peptide mimics the C-terminal α-helix of HSV-1 DNA polymerase to block interaction between the polymerase and the HSV-1 processivity factor (PF). Without PF association, the polymerase rapidly dissociates from the DNA template, preventing productive genome replication.
Successful blockade of HSV-1 DNA synthesis and HSV-1 infection by the peptide has been shown in vitro. These peptides can be prepared into a solution for topical administration and may be used alone or in addition to ACV. Systemically-delivered formulations may be further developed for additional cases of ACV-resistant HSV-1 infections.
- Specific HSV-1 DNA polymerase blockade
- Suitable for topical administration
- Stapled peptide structure increases protease resistance and functional lifetime
- Treatment of HK infections alone or in combination with ACV
- Treatment of additional ACV-resistant HSV-1 infections
- Prevention of HSV-1 propagation
The stapled α-helical peptide binds to the HSV-1 processivity factor (PF), preventing interaction with DNA polymerase (Pol) and inhibiting productive DNA synthesis.
Stage of Development:
- Designed library of peptides with variable staple locations
- Verified physical interaction between peptides and target PF protein
- Demonstrated specific blockade of HSV-1 processive DNA synthesis and HSV-1 infection in vitro