MICA: Development of new agents for the treatment of cryptosporidiosis

最近在非洲和南亚进行的一项临床研究发现，隐孢子虫病是发展中国家儿童因腹泻疾病死亡和患病的最重要原因之一。隐孢子虫病是由单细胞原生动物寄生虫引起的；感染人类的主要种类是人隐孢子虫和小隐孢子虫。这种寄生虫主要生活在肠壁的细胞中，具有复杂的生命周期。感染是由于食用了被寄生虫污染的水或食物。寄生虫通过受感染者的粪便传播。在健康和营养良好的人群中，这种疾病在几周内自然消失。然而，对于营养不良的人（特别是幼儿）和免疫系统功能不正常的人（例如艾滋病毒/艾滋病患者），这种疾病的影响要大得多。痢疾是幼儿致命腹泻的主要原因，在撒哈拉以南非洲和印度次大陆，24个月以下儿童中有290万至470万例痢疾，每年导致20多万人死亡。隐孢子虫病还与儿童营养不良和发育迟缓有关，并可能引起持续数周或数月的慢性感染。唯一注册用于治疗这种疾病的药物是nitazoxanide，它不是很有效，特别是对那些由于免疫系统薄弱和/或营养不良而受到最严重影响的患者。因此，迫切需要开发新的药物来治疗：(1)<24个月的儿童，特别是营养不良和慢性腹泻的儿童；(2)患有晚期艾滋病和慢性腹泻的免疫功能低下儿童和成人。隐孢子虫可能是该患者队列中多达75%的慢性腹泻的原因。我们已经发现了一些可以用于药物发现计划的化学起点。我们有一系列的化合物可以杀死寄生虫，也可以非常有效地清除啮齿动物隐孢子虫病模型中的寄生虫。这些化合物被认为是通过阻止寄生虫制造蛋白质来起作用的。这个项目的目的是利用这些起点，并对它们进行优化，以制造出有潜力成为药物的分子。这将需要我们优化分子的多个特征：它杀死寄生虫的能力，它到达寄生虫居住的身体部位而不被分解的能力，以及它的安全性。在这个项目结束时，我们希望有一个“临床前候选人”。我们认为这是一种适合进入人体临床试验的化合物。这个项目之后，在人体临床试验之前的步骤将是在适当规定的条件下更大规模地制造这种化合物，并进行正式的安全测试。

A recent clinical study in Africa and South Asia has found that cryptosporidiosis is one of the most significant causes of death and illness from diarrheal diseases amongst children in the developing world. Cryptosporidiosis is caused by a single-celled protozoan parasite; the predominant species infecting humans are called Cryptosporidium hominis and Cryptosporidium parvum. This parasite mainly lives in the cells in the gut wall and has a complex life-cycle. Infection occurs due to consumption of water or food contaminated with the parasites. Parasites are spread from an infected individual through their faeces. In people who are healthy and well nourished, the disease clears naturally within a couple of weeks. However, in people who are malnourished (particularly in young children) and people with an immune system that is not functioning properly (for example HIV/AIDS victims), the disease can have a much more significant impact. It is the major contributor to life-threatening diarrhea in young children, with 2.9-4.7 million cases in children under 24 months in sub-Saharan Africa and the Indian sub-continent, leading to more than 200,000 deaths per year. Cryptosporidiosis is also associated with malnutrition and stunted growth in children and probably causes chronic infections, which last for weeks or months. The only drug registered for the treatment of this disease is nitazoxanide, which is not very effective, especially in those patients who are most severely affected due to a weak immune system and/ or malnutrition. Therefore there is an urgent need for the development of new drugs to treat: (1) children <24 months, especially those that are malnourished and with chronic diarrhea; and (2) immunocompromised children and adults with advanced AIDS and chronic diarrhea. Cryptosporidium may be the cause of as much as 75% of chronic diarrhea in this patient cohort. We have discovered some chemical starting points that can be used for a drug discovery programme. We have a series of compounds that kill the parasites and also are very effective in clearing the parasites from rodent models of cryptosporidiosis. The compounds are thought to work through preventing the parasite making proteins. The aim of this project is to take these starting points and optimise them to make a molecule which has the potential to be a drug. This will require us to optimise multiple features of the molecule: its ability to kill the parasite, its ability to reach the sites in the body where the parasite resides without being broken down, and its safety. At the end of this project we hope to have a "preclinical candidate". This is a compound that we think should be suitable to enter human clinical trials. The steps after this project, prior to human clinical trials will be to make the compound on a larger scale under properly defined conditions and to carry out formal safety testing.