Abstract
Herpes simplex virus (HSV)-1 and HSV-2 cause painful blisters and shallow ulcers in exposed skin and mucosae during primary or recurrent infection. In addition, recurrent and potentially blinding HSV-1 infections of the eye afflict nearly half a million persons in the U.S. Current clinical therapies rely on nucleoside analog drugs such as acyclovir (ACV) or ganciclovir to ameliorate primary infections and reduce the frequency and duration of reactivations. However, these treatments do not fully suppress viral shedding and drug-resistant mutants develop in the eye and in vulnerable, immunosuppressed patients. Herpesvirus DNA replication requires several enzymes in the nucleotidyl transferase superfamily (NTS) that have recombinase and nuclease activities. We previously found that compounds which block NTS enzymes efficiently inhibit replication of HSV-1 and HSV-2 by up to 1 million-fold in Vero and human foreskin fibroblasts. Among the compounds with potent suppressive effects in culture is the anti-fungal drug ciclopirox. Here we report that topical application of ciclopirox olamine to the eyes of mice infected with HSV-1 reduced virus shed from the corneal epithelium compared with saline control, and reduced development of blepharitis to the level of mice treated with ACV. Results were dose-dependent. In addition, treatment with ciclopirox olamine significantly reduced acute and latent HSV-1 infection of the peripheral nervous system. These results support further development of ciclopirox olamine as a repurposed topical agent for HSV infections.