Design of amino acid prodrugs of acyclovir for improved bioavailability and therapeutic activity: Utility in treating ocular, oral and genital herpes infections

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 major problems associated with these drugs is their poor ocular absorption and cytotoxicity restricting their use in long-term treatment. Acyclovir and L-Valyl ester prodrug of acyclovir (ACV), valacyclovir (VACV) have been indicated in the treatment of genital herpes, the incidence of which has increased significantly in the last 20 years. Acyclovir with its selective mechanism of action can cause less cytotoxicity but its poor permeability across cellular barrier limits its utility. 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 of 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, PEPT1 and amino acid transporter, B0,+ 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. Recently the presence of oligopeptide and amino acid transport system on the corneal epithelium has been established in our laboratory. A series of novel water soluble amino acid ester prodrugs of acyclovir were thus synthesized in order to target the transporters present on the cornea and intestine 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 SACV exhibited excellent chemical/enzymatic 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.