Developing novel combination therapies for HSV genital infection.

Herpes simplex virusesandHSVHSVcause a wide range of serious diseasesincluding oral genital lesionscorneal blindness and eczema herpeticumHSVand HSVare both transmitted sexually and can infect babies during birthTherapy for HSV relies primarily on nucleoside analogs such as acyclovirACVwhich are insufficiently effectiveand resistant viruses are becoming common among immunosuppressed personsThereforethere is an urgent need for better anti herpesvirus drugsThe nucleotidyl transferase superfamilyNTSof enzymes comprises a range of nucleases and recombinases that are essential for DNA replicationrecombinationand nucleic acid turnoverOur screening program to identify inhibitors of HSV replication demonstrated profound activity in vitro by two NTS enzyme inhibitorsciclopirox and piroctonewhich are approved drugs for other indicationsThese two drugs also suppress replication of ACV resistant HSV strainsIn this STTR projectwe will execute a program to translate the observed anti HSV in vitro of these two select drug candidates into topical application in an animal model of HSVdiseaseAdditionallythe potent action of these drug candidates in vitro will be examined in combination with ACV to evaluate synergyAimExecute a proof of concept in vivo demonstration of the anti HSV activity of formulated drug candidates for topical application in a mouse model of HSVinfectionWe anticipate topical treatment with formulated ciclopirox and piroctone will suppress HSVreplication in the genital tract and the nervous systemand reduce genital disease and weight loss without inducing unacceptable toxicityThe experiments will yield critical preliminary data about the effectiveness of topical treatment with these drugs for suppression of HSVreplication and diseaseand a guide for the effective doseDemonstration that either or both of these formulated drug candidates reduces HSVreplication and spread in vivo would strongly support development of these NTS enzyme inhibitors as drugs for herpesvirus infectionsAimEvaluate the potential for synergy and toxicity between ciclopirox and or piroctone and acyclovir in vitroWe have strong data indicating ACV and ciclopirox and piroctone have different mechanisms of actionand preliminary data showing in vitro synergy between ciclopirox and ACVThereforewe anticipate synergism will be confirmed in vitro for either or both of the select drug candidates and ACVSignificant ImpactNew therapies are urgently needed for patients who suffer from recurrent outbreaks of HSVand especially immunocompromised individuals infected with nucleoside analog resistant strainsThis project will translate in vitro results into an animal model of disease and explore synergy of drug combination sThe goal is to guide development of new therapeutic drug candidate sfor treatment of herpes virus infectionsincluding HSVas monotherapies or in synergistic combination with existing drugs Herpes simplex virusesHSVHSVcause a wide range of serious human diseases but current treatment with nucleoside analog drugs such as acyclovirACVis insufficiently effectiveand resistant viruses are prevalentWe recently identified two known drugs which profoundly suppress HSV replication in cell cultureIn this proposal we plan to translate these in vitro findings by using formulated drug candidates to suppress HSV infection in a mouse model of HSVinfection and diseaseand to explore synergism in vitro between these drug candidates and ACV