Development of an Inhibitor of Toxoplasma gondii

弓形虫抑制剂的研制

• 批准号: 7611189
• 负责人: RICHARD D WOOD
• 金额: $ 31.17万
• 依托单位: SNOWDON PHARMACEUTICALS, INC.
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-04 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7611189
• 关键词: AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Acute; Affect; Affinity; Age; Animals; Antiparasitic Agents; Attention; Autoimmune Diseases; Binding; Binding Sites; Biological; Biological Assay; Blindness; Brain Injuries; Budgets; CD4 Positive T Lymphocytes; Categories; Cell Count; Cessation of life; Chronic; Clindamycin; Clostridium difficile; Computer-Aided Design; Congenital Toxoplasmosis; Development; Diarrhea; Disease; Docking; Drug Delivery Systems; Encephalitis; Europe; Evaluation; Excretory function; Exhibits; Family; Fetus; Food; Generations; Goals; Guidelines; HIV; HIV Infections; HIV-1; Highly Active Antiretroviral Therapy; Housing; Human; Hypersensitivity; Immune; Immunosuppressive Agents; In Vitro; Incidence; Individual; Infection; Ingestion; Inhibitory Concentration 50; Intestines; Invaded; Knowledge; Lead; Libraries; Live Birth; Lymphatic Diseases; Malignant Neoplasms; Medical; Medicine; Metabolic; Metabolism; Morbidity - disease rate; Mus; Myosin Light Chains; National Institute of Allergy and Infectious Disease; Nature; Neurologic; Neutropenia; Nonmuscle Myosin Type IIA; Normal Cell; Opportunistic Infections; Organ Transplantation; Parasite Control; Parasite resistance; Parasites; Pathway interactions; Patients; Permeability; Persons; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Population; Pregnant Women; Protein Binding; Proteins; Pyrimethamine; Relapse; Risk; Secondary to; Series; Small Business Innovation Research Grant; Specific qualifier value; Staging; Sulfonamides; Symptoms; Tail; Technology; Time; Toxic effect; Toxoplasma; Toxoplasma gondii; Toxoplasmosis; Uveitis; Vaccines; Virtual Library; Visual impairment; Water; Water Supply; absorption; analog; biodefense; chemical stability; chemical synthesis; cost; cytotoxicity; design; disability; drug candidate; effective therapy; experience; flu; improved; in vitro Assay; in vivo; inhibitor/antagonist; milligram; mortality; mouse model; novel; novel strategies; pathogen; preclinical study; protein protein interaction; public health relevance; response; small molecule

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：弓形虫病的致病药物弓形虫（T.）是一种无处不在的机会性病原体，它在全球范围内感染了免疫能力和免疫促进性个体，并且是严重的人类神经和眼疾病的主要原因。弓形虫病也是一种主要的机会感染，会导致艾滋病毒/艾滋病患者疾病，残疾和死亡。在这个临时时代，贡迪（T. Gondii）仍然是一个严重的医疗问题，这证明了美国和世界人口的新药物的商业开发是合理的。受到弓形虫病风险的免疫受损的人的感染包括那些感染了也患有癌症的寄生虫，进行器官移植，自身免疫性疾病或接受免疫抑制药物治疗这些疾病和其他疾病的人。 T. gondii是世界上葡萄膜炎（眼部疾病）的主要原因，导致视觉障碍和失明。先天性弓形虫病是一种毁灭性的感染，当孕妇首次感染T. gondii感染并将感染传播到胎儿时发生。美国的发病率为每5000例活生生1。先天性弓形虫病可能会导致严重的视力丧失，脑损伤甚至死亡。免疫能力的人会发生原发性，急性和慢性感染，因为弓形虫感染最常见于摄入受污染的食物或水。急性获得的感染通常无法诊断或误诊，因为受感染的人会经历淋巴结肿大或类似流感的症状。慢性感染发生在大约1/3至1/2的世界人口（即2-3亿人）中。 Gondii由于环境持久性及其通过受污染的食品和供水而被指定为B级生物卵形病原体。没有疫苗可用，现有的小分子药物用于许多患者的毒性毒素不足或耐受性不佳。因此，迫切需要发现弓形虫病治疗更安全，更有效的药物。为了应对这种需求，Snowdon正在开发小分子抑制剂，该抑制剂是T. gondii和其他Apicomplexan寄生虫所独有的必需生物途径，该寄生虫控制着其生存所需的侵入性机制。具体而言，这些抑制剂旨在破坏不寻常的肌球蛋白A（MyOA）和肌球蛋白A_Tail相互作用蛋白（MTIP）之间的关键蛋白质蛋白质相互作用。在计算方法的指导下，我们已经发现了一种新型的早期药物铅SN_T18，该药物在寄生分析中针对T. gondii表现出亚微摩尔抑制活性（IC50 <600 nm）。 SN_T18是一种简单的有机分子，易于合成，具有良好的化学稳定性，无毒，并且在口服口服时表现出良好的肠渗透性。从SN_T18开始，我们现在建议生成和探索一系列集中的SN_T18类似物，以将最有希望的化合物识别为潜在的候选药物。这项拟议的研究的主要目的是发现针对T. gondii感染的安全有效治疗。在这个项目中，斯诺登将采用一种综合方法，结合了理性（计算机辅助）设计，化学合成以及体外和体内生物学评估，以攻击这一新型药物靶标。据我们所知，这些抑制剂将是针对这些寄生虫脆弱的侵入性机制的第一个抑制剂。公共卫生相关性：简要说明这一SBIR I阶段研究旨在实施一种新的策略，以开发针对不寻常的肌球蛋白A（MyOA）和肌球蛋白A尾巴相互作用蛋白（MTIP）在毒素（T.）Gondii中的尾巴相互作用（MTIP），作为对Toxoplasmis的治疗，这会影响HIV的治疗。