Schistosome parasites infect 200 million people, resulting in significant morbidity and more than 200, 000 deaths annually. Schistosomiasis control strategies rely almost exclusively on chemotherapy, and tens of millions of people are treated with the only available drug, praziquantel (PZQ). There are no new drugs in the clinical pipeline. With projected levels of PZQ use, it is inevitable that PZQ-resistant parasites will evolve. Therefore, it is imperative to find new drug targets and drugs for schistosomiasis treatment, our long-term objective. We identified a highly promising drug target: the worm selenocysteine-containing enzyme thioredoxin glutathione reductase (TGR). We established that TGR is a central and essential mediator of antioxidant defenses in the worm. The antioxidant defenses of vertebrates are diversified to three enzymes, glutathione reductase, thioredoxin reductase, and glutaredoxin, whereas schistosomes rely solely on TGR. TGR is a chokepoint and its inhibition leads to rapid worm death in all developmental stages. In contrast, PZQ has poor activity against juvenile worms, often resulting in partial cures. TGR is a defined molecular target, active as a recombinant protein, and we have established biochemical assays amenable to rapid compound screening, SAR, and optimization. We initiated several HTS of large compound libraries, which identified TGR inhibitors that have been used to obtain both liganded and ligand-free crystal structures of TGR, allowing a structure-based approach to hit optimization. These studies have elucidated an inhibitory mechanism that is completely novel for this family of proteins, allowing the development of non-covalent inhibitors. Although very successful, this initial study was focused largely on aspects other than optimization of oral bioavailability of TGR inhibitors, impeding their further development. We hypothesize that it will be possible to optimize our novel TGR inhibitors for oral administration while maintaining efficacy comparable to that for compound 2 administered IP, an objective for this feasibility study. To achieve this objective, we propose: to optimize novel TGR inhibitors using cutting-edge structure- and ligand-based computer-aided design, medicinal chemistry, and pharmacokinetics approaches for oral availability while also improving potency, selectivity, solubility, and safety. Select compounds will be assessed for efficacy against schistosome infections in mice. To accomplish these aims, we assembled a team of experts in schistosome biochemistry and drug discovery, medicinal chemistry, computer-aided molecular design, chemical and structural biology of TGR. The varied and synergistic expertise of the team will facilitate overcoming critical barriers to development of schistosomicidal therapeutics. While additional preclinical studies would be needed, discovery of novel orally bioavailable TGR inhibitors with demonstrated activity in animal models is the first step in the development of novel therapeutic approaches for the treatment of schistosomiasis.
Public Health Relevance Statement: NARRATIVE The proposed studies focus on schistosomiasis, a significant, unmet medical need in 78 endemic countries, with more than 200 million people infected, 20 million with significant morbidity, and more than 200, 000 deaths annually. Current schistosomiasis control strategies rely almost exclusively on chemotherapy; there is only one available drug and it is inevitable that drug-resistant parasites will evolve. The proposed research will exploit differences in redox defenses between schistosome worms and humans to discover and optimize small molecule orally bioavailable inhibitors to selectively disrupt worm redox for new treatments for schistosomiasis. Terms: <21+ years old; 3-Selenylalanine; 3-selenyl-L-alanine; Active Follow-up; Adolescent; Adolescent Youth; Adsorption; Adult; Adult Human; Animal Model; Animal Models and Related Studies; Antioxidants; Assay; Bilharzia; Bilharziasis; Binding; Bioassay; Bioavailability; Biochemical; Biochemistry; Biological Assay; Biological Availability; Biological Chemistry; Blood Plasma; Cessation of life; Chemicals; Chronic Disease; Chronic Illness; Chronic disability; Clinical; Computer Assisted; Computer-Aided Design; Computer-Assisted Design; Country; Cryo-electron Microscopy; Cryoelectron Microscopy; Death; Development; Disease; Disorder; Drug Design; Drug Kinetics; Drug Targeting; Drug resistance; Drugs; Electron Cryomicroscopy; Enzyme Gene; Enzymes; Evolution; Excretory function; Feasibility Studies; Follow-Up Studies; Followup Studies; Future; Glutathione Reductase; Goals; High Throughput Assay; Human; In Vitro; Infection; Intermediary Metabolism; LD-50; LD50; Lead; Lethal Dose 50; Libraries; Ligands; Mammalian Cell; Mediator; Medical; Medication; Medicinal Chemistry; Metabolic Processes; Metabolism; Mice; Mice Mammals; Modern Man; Molecular; Molecular Interaction; Molecular Target; Molecular Weight; Morbidity; Morbidity - disease rate; Murine; Mus; Oral; Oral Administration; Oral Drug Administration; Oxidation-Reduction; PZQ resistance; PZQ resistant; Parasite resistance; Parasites; Pb element; Persistent disability; Persons; Pharmaceutic Chemistry; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacokinetics; Physiologic Availability; Plasma; Plasma Serum; Post-Transcriptional Gene Silencing; Posttranscriptional Gene Silencing; Prasiquantel; Praziquantel; Praziquantel resistance; Praziquantel resistant; Property; Protein Family; Proteins; Publishing; RNA Interference; RNA Silencing; RNAi; Recombinant Proteins; Redox; Research; Research Design; Resistance to Praziquantel; Reticuloendothelial System, Serum, Plasma; Roentgen Rays; S mansoni; S. mansoni; Safety; Schistosoma; Schistosoma mansoni; Schistosome; Schistosome Parasite; Schistosomiasis; Schistosomicides; Selenocysteine; Sequence-Specific Posttranscriptional Gene Silencing; Solubility; Structure; Study Type; TRX gene; TRX protein; TRX1; TXN gene; Therapeutic; Thioredoxin; Toxic effect; Toxicities; Vertebrate Animals; Vertebrates; X-Radiation; X-Ray Radiation; X-ray; Xray; active followup; adulthood; chemotherapy; chronic disorder; comparable efficacy; comparative efficacy; compare efficacy; computer aided; cryo-EM; cryoEM; cryogenic electron microscopy; design; designing; determine efficacy; developmental; drug discovery; drug metabolism; drug resistant; drug/agent; efficacy analysis; efficacy assessment; efficacy determination; efficacy evaluation; efficacy examination; enzyme activity; evaluate efficacy; examine efficacy; excretion; follow up; follow-up; followed up; followup; glutaredoxin; heavy metal Pb; heavy metal lead; high throughput screening; improved; in silico; in vivo; inhibitor; intraoral drug delivery; intraperitoneal; juvenile; juvenile human; meeting; meetings; member; model of animal; neglect; new drug target; new drug treatments; new druggable target; new drugs; new pharmacological therapeutic; new pharmacotherapy target; new therapeutic approach; new therapeutic intervention; new therapeutic strategies; new therapeutic target; new therapeutics; new therapy; new therapy approaches; new therapy target; new treatment approach; new treatment strategy; next generation therapeutics; novel; novel drug target; novel drug treatments; novel druggable target; novel drugs; novel pharmaco-therapeutic; novel pharmacological therapeutic; novel pharmacotherapy target; novel therapeutic approach; novel therapeutic intervention; novel therapeutic strategies; novel therapeutic target; novel therapeutics; novel therapy; novel therapy approach; novel therapy target; oxidation reduction reaction; parasite resistant; phase 2 study; phase II study; pre-clinical study; preclinical study; resistance to Drug; resistance to Parasite; resistant parasite; resistant to Drug; resistant to Parasite; scaffold; scaffolding; screening; screenings; small molecule; standard of care; structural biology; study design; thioredoxin reductase; vertebrata
