Development of an Inhibitor of Toxoplasma gondii

描述（由申请人提供）：弓形虫（T.）弓形虫病的病原体--刚地弓形虫是一种普遍存在的机会病原体，它感染全世界免疫能力强和免疫功能低下的个体，并且是人类严重先天性神经和眼部疾病的主要原因。弓形虫病也是一种主要的机会性感染，可导致艾滋病毒/艾滋病患者患病、残疾和死亡。T.在HAART后时代，弓形虫仍然是一个严重的医学问题，这证明了为美国和世界人口的大部分进行新药的商业开发是合理的。处于弓形体病风险中的免疫受损的人的感染包括感染寄生虫的那些人，其也患有癌症、经历器官移植、自身免疫疾病或接受免疫抑制药物以治疗这些和其它疾病的那些人。T.弓形虫是世界上葡萄膜炎（眼病）的主要病因，可导致视力受损和失明。先天性弓形虫病是一种毁灭性的感染，当孕妇获得T。首次感染弓形虫并将感染传播给胎儿。美国的发病率为每5000例活产1例。先天性弓形虫病可导致严重的视力丧失、脑损伤，甚至死亡。原发性、急性和慢性感染发生在免疫功能正常的人群中，如T。弓形虫感染最常见的途径是进食受污染的食物或水。急性获得性感染往往未被诊断或误诊，因为感染者要么经历淋巴结病或流感样症状。慢性感染发生在大约1/3至1/2的世界人口中（即，2-3 10亿人）。由于弓形虫在环境中的持久性及其通过受污染的食物和水源快速传播的潜力，NIAID将其指定为B类生物防御病原体。没有疫苗可用，现有的弓形虫病小分子药物不足或耐受性差，许多患者。因此，迫切需要发现用于弓形虫病治疗的更安全和更有效的药物。为了满足这一需求，斯诺登正在开发一种小分子抑制剂，抑制T。弓形虫和其他顶复门寄生虫控制其生存所必需的入侵机制。具体而言，这些抑制剂被设计为破坏不寻常的肌球蛋白A（MyoA）和肌球蛋白A_尾相互作用蛋白（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的早期药物先导物SN_T18，它对T.寄生虫试验中的弓形虫。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，并且当口服给药于小鼠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，以确定最有前途的化合物作为潜在的候选药物。这项研究的主要目的是发现安全有效的治疗T。弓形虫感染在这个项目中，Snowdon将采用一种综合方法，结合合理的（计算机辅助）设计，化学合成，以及体外和体内生物学评价来攻击这种新的药物靶点。据我们所知，这些抑制剂将是第一个针对这些寄生虫脆弱的入侵机制的抑制剂。公共卫生相关性：本SBIR I期研究旨在实施一种新的策略，用于开发靶向弓形虫（T.）中不寻常的肌球蛋白A（MyoA）和肌球蛋白A尾相互作用蛋白（MTIP）之间关键蛋白质-蛋白质相互作用的分子。弓形虫，用于治疗影响艾滋病毒/艾滋病患者的弓形虫病。

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.