The goal of this continuing application is to develop species selectivity in compounds that inhibit a single, essential function, so to develop a new paradigm that will leverage drug development across many species. The essential enzyme function is the well recognized anti-cancer target, human thymidylate synthase (TS), the rate-limiting enzyme that provides the sole de novo pathway for synthesis of the DNA-base dTMP from the RNA base dUMP. The structures of TSs from human and from four, often lethal human pathogenic organisms are being determined as the basis of antiproliferative drug development: these include Pneumocystis carinii, Cryptococcus neoformans, Cryptosporidoum parvum, and Toxoplasma gondii. These are each the source of major opportunistic infections that cause early death, especially in patients with AIDS. Five additional species may be included in assays for selectivity of inhibition, as the program progresses. These include TS's from protozoa that are responsible for major worldwide diseases: Plasmodium falciparum, malaria; Trypanosoma cruz,i Trypanosoma burcei (Chagas' disease); Mycobacterisum tuberculosis (Tuberculosis) and Leishmania major. Inhibitors of TS are to be developed based on 1. Derivatives of leads based on phenolpthalein, originally discovered at UCSF; so far these have lead to 100 fold specificity for Cryptococus versus human TS, and 1000 fold inhibition of bacterial versus human TS. 2. Structures of known anti-cancer lead compounds bound to TS. New leads indicate new chemical entities that can encode high selectivity. 3. Fragment assembly, in which small molecules that have inhibitory activity are linked together, thus enhancing the potency. Here Dr. Stroud seeks to develop a new paradigm in drug development that relies on screening for (weak) inhibitors first, followed by combination, versus and normal reverse of synthesis followed by screening. 4. De novo drug discovery deriving from phage-discovered peptidic lead inhibitors of TS. Crystal structures of compounds bound to TS will direct how well they can be conjugated to enhance potency for human TS, or for pathogen versus human TS. New drug leads are to be developed using iterative cycles of structure-based development, followed by assays for affinity and selectivity. Public domain access to the structures of therapeutic targets and technology will encourage their use by major pharmaceutical companies for the better design of therapeutics.
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