Toxoplasma (T.) gondii, the causative agent of toxoplasmosis, is a ubiquitous opportunistic pathogen that infects both immune-competent and immune-compromised individuals worldwide, and is the leading cause of severe congenital neurological and ocular disease in humans. Toxoplasmosis is also a major opportunistic infection that causes illness, disability and death in HIV/AIDS patients. T. gondii remains a serious medical problem in this post-HAART age which justifies the commercial development of new medicines for large segments of the U.S. and world population. Infection in immune- compromised persons who are at risk for toxoplasmosis include those infected with the parasite who also have cancer, undergo organ transplantation, autoimmune disease or those who receive immunosuppressive medicine for treatment of these and other diseases. T. gondii is the leading cause of uveitis (ocular disease) in the world, causing visual impairment and blindness. Congenital toxoplasmosis is a devastating infection that occurs when a pregnant woman acquires T. gondii infection for the first time and transmits the infection to the fetus. Incidence in the U.S. is 1 per 5000 live births. Congenital toxoplasmosis can cause severe vision loss, brain damage, and even death. Primary, acute and chronic infection occurs in immune-competent people as T. gondii infection is most commonly acquired through the ingestion of contaminated food or water. Acute acquired infection is often undiagnosed or misdiagnosed because infected persons either experience lymphadenopathy or flu-like symptoms. Chronic infection occurs in approximately 1/3 to 1/2 of the world population (i.e., 2-3 billion persons).T. gondii is designated as a Category B biodefense pathogen by the NIAID due to its environmental persistence and its potential for rapid dissemination through contaminated food and water supplies. No vaccine is available, and existing small-molecule drugs for toxoplasmosis are inadequate or poorly tolerated for many patients. Therefore, an urgent need exists for the discovery of safer and more effective medicines for toxoplasmosis therapy. In response to this need, Snowdon is developing small-molecule inhibitors of an essential biological pathway exclusive to T. gondii and other Apicomplexan parasites that controls their invasive machinery necessary for survival. Specifically, these inhibitors are designed to disrupt a key protein-protein interaction between the unusual Myosin A (MyoA) and the Myosin A_Tail Interacting Protein (MTIP). Guided by computational approaches, we have already discovered a novel early-stage Drug Lead, SN_T18, that exhibits sub-micromolar inhibitory activity (IC50 < 600 nM) against T. gondii in parasitic assays. SN_T18 is a simple organic molecule that is easy to synthesize, possesses good chemical stability, is non-toxic and exhibits good intestinal permeability when administered orally to mice. Starting with SN_T18, we now propose to generate and explore a focused series of SN_T18 analogs to identify the most promising compound(s) as potential drug candidates. The primary objective of this proposed study is to discover safe and effective treatments for T. gondii infection. In this project, Snowdon will employ an integrated approach that combines rational (computer-aided) design, chemical synthesis, and both in vitro and in vivo biological evaluation to attack this novel drug target. To our best knowledge, these inhibitors will be the first of their kind that target the vulnerable invasive machinery of these parasites.
Public Health Relevance: Brief description This SBIR Phase I study aims to implement a novel strategy for the development of molecules targeting a key protein-protein interaction between the unusual Myosin A (MyoA) and the Myosin A Tail Interacting Protein (MTIP) in Toxoplasma (T.) gondii, as treatments for toxoplasmosis which affects HIV/AIDS patients.
Public Health Relevance Statement: Brief description This SBIR Phase I study aims to implement a novel strategy for the development of molecules targeting a key protein-protein interaction between the unusual Myosin A (MyoA) and the Myosin A Tail Interacting Protein (MTIP) in Toxoplasma (T.) gondii, as treatments for toxoplasmosis which affects HIV/AIDS patients.
NIH Spending Category: Biodefense; Biotechnology; Emerging Infectious Diseases; Eye Disease and Disorders of Vision; Food Safety; Infectious Diseases; Neurosciences
Project Terms: 2,4-Pyrimidinediamine, 5-(4-chlorophenyl)-6-ethyl-; 7-Chloro-7-deoxylincomycin; AIDS; AIDS Virus; AIDS/HIV; AIDS/HIV problem; Absorption; Acquired Immune Deficiency; Acquired Immune Deficiency Syndrome; Acquired Immune Deficiency Syndrome Virus; Acquired Immuno-Deficiency Syndrome; Acquired Immunodeficiency Syndrome; Acquired Immunodeficiency Syndrome Virus; Acquired brain injury; Acute; Affect; Affinity; Age; Allergy; Animals; Antiparasitic Agents; Antiparasitic Drugs; Antiparasitics; Antiretroviral Therapy, Highly Active; Assay; Attention; Autoimmune Diseases; Binding; Binding (Molecular Function); Binding Sites; Bioassay; Biologic Assays; Biological; Biological Assay; Blindness; Brain Injuries; Budgets; C. difficile; C.difficile; CD4 Positive T Lymphocytes; CD4 T cells; CD4 lymphocyte; CD4+ T cell; CD4+ T-Lymphocyte; CD4-Positive Lymphocytes; Cancers; Categories; Cell Count; Cell Number; Cells, CD4; Cessation of life; Chlolincocin; Chlorlincocin; Chronic; Clindamycin; Clinical Trials, Phase I; Clinical, Transplantation, Organ; Clostridium difficile; Combining Site; Computer-Aided Design; Computer-Assisted Design; Congenital Toxoplasma gondii Infection; Congenital Toxoplasmosis; Control, Parasite; Daraprim; Death; Development; Diarrhea; Disease; Disorder; Docking; Drug Delivery; Drug Delivery Systems; Drug Targeting; Drug Targetings; Drugs; Early-Stage Clinical Trials; Encephalitis; Europe; Evaluation; Excretory function; Exhibits; Family; Fetus; Food; Generations; Goals; Grafting Procedure; Guidelines; HAART; HIV; HIV Infections; HIV-1; HIV-I; HIV/AIDS; HIV/AIDS problem; HIV1; HTLV-III; HTLV-III Infections; HTLV-III-LAV Infections; Highly Active Antiretroviral Therapy; Housing; Human; Human Immunodeficiency Viruses; Human T-Cell Leukemia Virus Type III; Human T-Cell Lymphotropic Virus Type III; Human T-Lymphotropic Virus Type III; Human immunodeficiency virus 1; Human, General; Hydrogen Oxide; Hypersensitivity; IC50; Immune; Immunodeficiency Virus Type 1, Human; Immunologic Deficiency Syndrome, Acquired; Immunosuppressants; Immunosuppressive Agents; In Vitro; Incidence; Individual; Infection; Inflammation, Brain; Ingestion; Inhibitory Concentration 50; Intermediary Metabolism; Intestinal; Intestines; Invaded; Knowledge; L-threo-alpha-D-galacto-Octopyranoside, methyl 7-chloro-6,7,8-trideoxy-6-(((1-methyl-4-propyl-2-pyrrolidinyl)carbonyl)amino)-1-thio-, (2S-trans)-; LAV-HTLV-III; Lead; Libraries; Live Birth; Lymphadenopathy-Associated Virus; Lymphatic Diseases; Lytotoxicity; METBL; Malignant Neoplasms; Malignant Tumor; Mammals, Mice; Man (Taxonomy); Man, Modern; Medical; Medication; Medicine; Metabolic; Metabolic Processes; Metabolism; Mice; Molecular Interaction; Morbidity; Morbidity - disease rate; Mortality; Mortality Vital Statistics; Murine; Mus; Myosin A; Myosin IIA; Myosin Light Chains; Myosin Type IIA, Non-Muscle; NIAID; National Institute of Allergy and Infectious Disease; Nature; Neurologic; Neurological; Neutropenia; Nonmuscle Myosin Type IIA; Normal Cell; Opportunistic Infections; Organ Transplantation; Organ Transplants; Organ Transplants, Including Bone Marrow for DCT; Parasite Control; Parasite resistance; Parasites; Parasiticides; Partial Sight; Pathway interactions; Patients; Pb element; Permeability; Persons; Pharmaceutic Preparations; Pharmaceutical Preparations; Phase; Phase 1 Clinical Trials; Phase I Clinical Trials; Phase I Study; Population; Pregnant Women; Process of absorption; Protein Binding; Proteins; Pyrimethamine; Reactive Site; Relapse; Risk; SBIR; SBIRS (R43/44); Science of Medicine; Secondary to; Series; Small Business Innovation Research; Small Business Innovation Research Grant; Specific qualifier value; Specified; Staging; Sulfonamides; Symptoms; T-Lymphotropic Virus Type III Infections, Human; T. gondii; T. gondii infection; T4 Cells; T4 Lymphocytes; Tail; Technology; Time; Toxic effect; Toxicities; Toxoplasma; Toxoplasma Infections, Congenital; Toxoplasma gondii; Toxoplasma gondii Infection; Toxoplasmosis; Toxoplasmosis, Congenital; Transplantation Surgery; Uveitis; Vaccines; Virtual Library; Virus-HIV; Vision, Diminished; Vision, Low; Vision, Reduced; Vision, Subnormal; Visual impairment; Water; Water Supply; absorption; adenopathy; analog; anti-retroviral therapy, highly active; autoimmune disorder; biodefense; bowel; brain damage; brain lesion (from injury); chemical stability; chemical synthesis; cost; cytotoxicity; design; designing; disability; disease/disorder; drug candidate; drug/agent; effective therapy; excretion; experience; flu; gene product; heavy metal Pb; heavy metal lead; helper T cell; human T cell leukemia virus III; human T lymphotropic virus III; immunosuppressive; improved; in vitro Assay; in vivo; inhibitor; inhibitor/antagonist; lymphadenopathy; lymphatic disorder; malignancy; milligram; mouse model; neoplasm/cancer; new approaches; novel; novel approaches; novel strategies; novel strategy; organ allograft; organ graft; organ xenograft; parasite resistant; pathogen; pathway; phase 1 study; phase 1 trial; phase I trial; preclinical study; protein protein interaction; protocol, phase I; public health relevance; resistance to Parasite; resistant to Parasite; response; small molecule; visually impaired
