Converting natural product leads into structure- and ligand-based drug discovery campaigns against leishmaniasis and Chagas' disease

被忽视的寄生虫病，内脏利什曼病(VL)和恰加斯病(CD)，估计每年在世界范围内造成50,000人死亡。大多数受这些可怕疾病影响的人属于最贫穷的社会成员，往往生活在偏远的农村地区。尽管死亡人数如此之多，但由于许多原因，目前可用的治疗方法并不充分。这些问题包括副作用、化合物作用不是很有效、对当前药物的抗药性以及要求静脉给药或重复注射，这些要求不适合这些疾病通常发现的农村环境。因此，开发新的、有效和安全的口服药物提供了一个机会，通过减少这些疾病的发病率、死亡率和经济后果，挽救许多人的生命，提高整个发展中世界区域的生活质量。不幸的是，为VL和CD开发的化合物很少。在这项提议中，我们的目标是为药物发现计划确定潜在的新靶点。这些是典型的酶，对导致疾病的寄生虫的生命至关重要。我们的目标是通过测试天然产品对抗寄生虫的能力来确定这些起点。对于那些杀死寄生虫的天然产品，我们将找出这些化合物是如何杀死寄生虫的。天然产物是从植物和细菌等自然来源中发现的化合物。它们通常具有独特的化学结构，这些结构以前从未由人类制造过，很难合成。因此，它们提供了很好的工具来确定通常无法通过其他手段找到的潜在药物靶点。一旦我们确定了分子靶标(酶)，我们就可以进行药物发现计划，要么以这些天然产物为起点，要么使用传统的药物发现方法来寻找酶的抑制剂，然后将它们优化为潜在的药物。S·卡洛斯由邓迪大学和S圣保罗大学组成的一个成熟的、全面整合的团队汇集了发现这些急需的药物所需的广泛专业知识。该团队结合了天然产品专业知识、世界知名的寄生虫学、在确定这些寄生虫中化合物的作用模式方面的专业知识、开发可以杀死寄生虫的分子的丰富经验，以及开发适合临床试验进展的候选药物所需的大量专业知识和基础设施。

The neglected parasitic diseases, visceral leishmaniasis (VL), and Chagas' disease (CD), together cause an estimated 50,000 deaths annually world-wide. Most of the people affected by these terrible diseases are amongst the poorest members of society and often live in remote rural areas. Despite this death toll, the current treatments available are inadequate for many reasons. These problems include side effects, compounds not working very effectively, resistance to current drugs and the requirement for intravenous administration or repeated injections which are not suitable for the rural environments where these diseases are typically found. Consequently, the development of new, effective and safe oral drugs provides an opportunity to save many lives and improve the quality of life for whole regions of the developing world, through the reduction of the morbidity, mortality and the economic consequences of these diseases. Unfortunately there are very few compounds being developed for VL and CD.In this proposal we aim to identify potential new targets for drug discovery programmes. These are typically enzymes, which are vital to the life of the parasites that cause the diseases. We aim to identify these start points by testing natural products against the parasites. For those natural products that kill the parasites, we will then find out how the compounds are killing the parasites. Natural products are chemical compounds that are found from natural sources, such as plants and bacteria. They often have unique chemical structures, that have not been made before by humans and are difficult to make synthetically. Therefore they provide good tools to identify potential drug targets that often would not be found by other means. Once we have identified the molecular target (enzymes) we can then carry out a drug discovery programme, either by using these natural products as starting points or using conventional drug discovery approaches to find inhibitors of the enzyme and then optimise them into potential drugs.An established, fully integrated team comprised of the University of Dundee and University of São Paulo, São Carlos brings together the broad range of expertise required to discover these much needed drugs. The team combines natural product expertise, world renowned parasitology, expertise in identifying the modes of action of compounds in these parasites, extensive experience developing molecules that can kill the parasites, and the substantial expertise and infrastructure required to develop drug candidates suitable for progress toward clinical trials.