Design of prodrugs of acyclovir for ocular, oral and genital herpes virus infections: Targeting the oligopeptide and amino acid transporter on the cornea and intestine for improved bioavailability, safety and therapeutic activity

Infection with herpes simplex virus is the single most frequent cause of corneal opacities in developed countries. Currently available therapy for HSV keratitis involves the use of trifluorothymidine, idoxuridine and vidarabine. However, one of the major problems associated with these drugs is their poor ocular absorption and cytotoxicity restricting their use in long-term treatment. L-Valyl ester prodrug of Acyclovir (ACV), valacyclovir (VACV) has been indicated in the treatment of genital herpes, the incidence of which has increased significantly in the last 20 years. Although genital herpes is self-limiting in healthy adults, the disease is painful and distressing, with severe psychosocial impact. Thus, the development of a safe, long-acting, effective, non-toxic, and stable topical antiviral drops and oral formulations that require less frequent dosing for fewer days or lower concentrations would represent a significant improvement over the currently available antivirals used against ocular, oral and genital HSV infections.;Recently significant amount of work has been reported on substrate specificities of membrane transporters and receptors leading to successful design of prodrugs targeted to them for improved efficacy and absorption. VACV is such a prodrug that is recognized by the peptide transporter, hPEPT1 resulting in enhancement of oral bioavailability of acyclovir by three to five fold in humans. Utilizing transporters present on the corneal epithelium may enhance corneal permeability of polar compounds. The presence of an oligopeptide and amino acid transport system on the corneal epithelium has been established. A series of novel water-soluble dipeptide and amino acid ester prodrugs of acyclovir were thus synthesized in order to target the transporters on the cornea for improved ocular bioavailability of acyclovir. These prodrugs once transported across or influxed into the target cells undergo chemical as well as enzymatic hydrolysis to release the active parent drug, ACV.;In conclusion more permeable, less cytotoxic ACV dipeptide prodrugs exhibited excellent chemical stability and antiviral activity against herpes simplex viruses. These prodrugs also demonstrated higher bioavailability upon topical as well as oral administration, thereby rendering these compounds promising drug candidates against ocular, oral and genital herpes infections.