Hit to Lead optimization of small molecule inhibitors of herpes simplex viruses

Herpes simplex viruses and HSV HSV cause a wide range of significant diseases including oral genital lesions corneal blindness and encephalitis HSV and HSV are both transmitted sexually and can infect babies during birth Therapy for HSV relies primarily on nucleoside analogs such as acyclovir ACV which are insufficiently effective and resistant viruses are becoming common among immunosuppressed persons Therefore there is an urgent need for better anti herpesvirus drugs The nucleotidyl transferase superfamily NTS of enzymes comprises a range of nucleases and recombinases that are essential for DNA replication recombination and nucleic acid turnover Our screening program to identify inhibitors of HSV replication demonstrated that a set of NTS enzyme inhibitors have profound anti HSV activity in vitro without significant cytotoxicity They also suppress replication of ACV resistant mutant strains In this STTR project we will execute a Hit to Lead program based on an initial set of highly active small molecule confirmed hits against HSV An established preliminary SAR will be the starting platform from which the project will begin the process of optimizing already potent inhibitors through in vitro evaluation and prioritization and ultimately generate a lead series for Lead Optimization LO Aim Iteratively produce enhanced Hit To Lead HT inhibitors of HSV replication Compounds sets will be iteratively synthesized and tested for HSV replication inhibition specificity human RNaseH counter screen and cytotoxicity Chemical design for LO to increase drug like characteristics will be performed Top hits will be tested for synergy with ACV Aim Profile in vitro ADME and toxicity parameters ADME will be evaluated in mouse and human liver microsomes and expanded toxicity assessments will be conducted in mouse and human cell types Aim Identify select Lead Compounds through further pre clinical profiling and Lead Optimization Biological profiling Aims and in conjunction with evaluation of physico chemical properties of promising derivatives will guide selection of Lead Compound s with high activity and low toxicity profiles These will be advanced to further in vitro profiling in protein binding and Caco permeability assays Significant Impact New therapies are urgently needed for patients who suffer from recurrent outbreaks of HSV infections and especially immunocompromised individuals infected with nucleoside analog resistant strains This project will result in the generation of a lead series of highly active compounds suitable for LO efforts The ultimate goal is directed at generating new therapeutic drug candidate s for the treatment of herpesvirus infections including HSV as monotherapies or combination therapies with existing drugs Herpes simplex viruses HSV HSV cause a wide range of serious human diseases but current treatment with nucleoside analog drugs such as acyclovir ACV is insufficiently effective and resistant viruses are prevalent in immunosuppressed patients In this proposal we plan to use existing hits and a preliminary structure activity relationship to develop a Lead series of small molecule inhibitors of HSV replication for advancement into drug development This Lead series will be subjected to in vitro biological and physicochemical analyses to select promising Lead candidates for optimization as drug candidates