Development of an Inhibitor of Toxoplasma gondii

描述(申请人提供)：弓形虫(T.)弓形虫是弓形虫病的病原体，是一种普遍存在的机会性病原体，在世界范围内感染免疫功能正常和免疫功能低下的人，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，会导致艾滋病毒/艾滋病患者的疾病、残疾和死亡。在这个后HAART时代，弓形虫仍然是一个严重的医疗问题，这证明了为美国和世界大部分人口进行新药商业开发的合理性。存在弓形虫病风险的免疫受损人群的感染包括感染寄生虫的人，这些人也患有癌症、接受器官移植、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。弓形虫是世界上葡萄膜炎(眼病)的主要原因，导致视力障碍和失明。先天性弓形虫病是一种毁灭性的感染，当孕妇第一次感染弓形虫并将感染传播给胎儿时，就会发生这种感染。美国的发病率是每5000名活产儿中就有一名。先天性弓形虫病会导致严重的视力丧失、脑损伤，甚至死亡。原发、急性和慢性感染发生在具有免疫能力的人身上，因为弓形虫感染最常见的是通过摄入受污染的食物或水。急性获得性感染经常被漏诊或误诊，因为感染者要么出现淋巴结病，要么出现流感样症状。慢性感染发生在大约1/3到1/2的世界人口中(即20-30亿人)。由于弓形虫在环境中的持久性以及它可能通过受污染的食物和水迅速传播，因此被NIAID指定为B类生物防御病原体。没有疫苗可用，现有的治疗弓形虫病的小分子药物对许多患者来说不足或耐受性差。因此，迫切需要发现更安全、更有效的治疗弓形虫病的药物。为了回应这一需求，斯诺登正在开发一种基本生物途径的小分子抑制剂，这种途径是弓形虫和其他Apicomplexan寄生虫所独有的，它控制着它们生存所需的入侵机制。具体地说，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的早期药物先导，SN_T18，在寄生虫试验中对弓形虫具有亚微摩尔抑制活性(IC50&lt；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，小鼠灌胃给药具有良好的肠道通透性。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，以确定最有希望的化合物(S)作为潜在的候选药物。这项拟议研究的主要目标是寻找安全有效的治疗弓形虫感染的方法。在这个项目中，斯诺登将采用一种综合的方法，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评估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种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：简介：这项SBIR第一阶段研究旨在实施一种新的策略，以开发针对弓形虫(T.)中不寻常的肌球蛋白A(MyoA)和肌球蛋白A尾部相互作用蛋白(MTIP)之间的关键蛋白质-蛋白质相互作用的分子。作为影响艾滋病毒/艾滋病患者的弓形虫病的治疗方法。

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.