Multi-target approach to rational design of novel therapeutics for human African trypanosomiasis

多目标方法合理设计非洲人类锥虫病新疗法

• 批准号: 10466942
• 负责人: EMMANUEL OLUWADARE BALOGUN
• 金额: $ 11.53万
• 依托单位: AHMADU BELLO UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-11 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10466942
• 关键词: Adopted; Africa; Africa South of the Sahara; African; African Trypanosomiasis; Animals; Biological Assay; Blood; California; Camels; Categories; Cattle; Cells; Cessation of life; Chemicals; Communicable Diseases; Data; Development; Disease; Doctor of Philosophy; Drug Design; Drug Interactions; Economic Development; Endemic Diseases; Enzymes; Failure; Future; Generations; Glucose; Glycerol Kinase; Glycolysis; Grant; Human; Human Activities; Infection; Journals; Lead; Libraries; Luciferases; Macronutrients Nutrition; Mentors; Metabolism; Methods; Microscopy; Molecular Target; Nigeria; Organism; Outcome; Parasites; Pathway interactions; Persons; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacotherapy; Pharmacy Schools; Phase; Prevention; Production; Proteins; Publishing; Records; Reporting; Ruminants; Science; Starvation; Stream; Structure; Structure-Activity Relationship; System; Therapeutic; Toxic effect; Trypanosoma; Trypanosoma brucei brucei; Trypanosomiasis; Tsetse Flies; Universities; Vaccination; Work; X-Ray Crystallography; alternative oxidase; base; chemical genetics; design; disability-adjusted life years; drug candidate; drug development; drug discovery; global health; glucose metabolism; health economics; infection risk; inhibitor; innovation; kinase inhibitor; multidisciplinary; nanomolar; new therapeutic target; novel; novel therapeutics; pathogen; professor; rational design; repository; screening; side effect; small molecule libraries; success; three dimensional structure

Project Summary This proposal aims to develop safer and effective drug for the treatment of human African trypanosomiasis (HAT), an infectious disease that are endemic to sub-Saharan Africa. HAT is of global health concerns due to the lack of hope for prevention by vaccination and the unsatisfactory treatment options. There is need for the development of new drugs with novel mechanism of action. To rationally develop a good drug, it is important to identify molecular targets in the parasites. These target molecules should fulfill the following criteria: (i) important for the parasites’ survival, (ii) absent in humans or not important in humans, and (iii) if present in humans, it should be structurally different from the human molecule. After which we can then search for chemical compounds that can specifically interact with the target molecules to stop them from functioning, and eventually killing the parasites. The energy (ATP) metabolism pathway of blood stream forms of the trypanosomes (BSFs) presents such a novel target for drug discovery because it differs from that of animals. We have identified two interesting target proteins in the parasites that are important for their energy generation and survival in the human host; these are the trypanosomal alternative oxidase (TAO) and glycerol kinase (TGK). However, both enzymes must be simultaneously blocked in order to effectively kill the parasites and cure the infection. TAO is absent in humans; although TGK is present, the structure revealed that some functional regions are very different from GK of other organisms, providing encouraging preliminary data towards successful development of TGK-specific inhibitor(s). The co-administration of TGK and TAO inhibitors will selectively kill the parasite and likely avoiding toxicity issues. One of the innovations in our proposal is that we aim to design single inhibitors that co-target TAO and TGK. This will avoid the chances of drug-drug interaction versus undesirable side effect that readily accompanies administration of multiple drugs to treat a disease. This will be achieved by experimental screening of the 100,000 compounds in the Libraries of Small Molecule Repository of Skaggs School of Pharmacy and Pharmaceutical Sciences (SSPPS), University of California San Diego (UCSD), USA against the enzymatic activities of TGK and TAO and then selecting those displaying inhibitory capability against both enzymes. In parallel, the compounds will also be screened against the parasite for identifying those with trypanosomes killing effects. Both category of compounds will then be optimized for killing the trypanosomes in culture, for inhibition of TAO and TGK, and for lack of effects on human glycerol kinase and cultured human cells. Overall, the present proposal will lead to the design single non-toxic and effective trypanocidal compound(s). The PI, Emmanuel O. Balogun, PhD, will collaborate on this project with a team of multidisciplinary experts in USA and Nigeria: at SSPPS UCSD Professors James H. McKerrow (USA Lead Mentor), Larissa Podust and Jair Siqueira-Neto (USA Co-Mentors); Professors Mamman Mohammed (Nigeria Lead Mentor), Christian Happi, Maryam Aminu, and Mohammed N Shuaibu (Nigeria Co-Mentors).

项目摘要 这项提议旨在开发治疗人类非洲锥虫病(HAT)的更安全有效的药物， 撒哈拉以南非洲的一种地方性传染病。这是全球关注的健康问题，因为缺乏 通过接种疫苗预防的希望和不令人满意的治疗选择。发展是有必要的。 具有新作用机制的新药。要合理开发一种好的药物，重要的是要识别 寄生虫中的分子靶标。这些目标分子应满足以下标准：(I)对 寄生虫的生存，(Ii)在人类中不存在或在人类中不重要，以及(Iii)如果在人类中存在，它应该是 在结构上与人类分子不同。之后，我们就可以搜索可以 特别是与目标分子相互作用，阻止它们发挥作用，最终杀死寄生虫。 锥虫(Trypanosome，BSFs)血流形态的能量(ATP)代谢途径呈现这样一种 药物发现的新靶点，因为它不同于动物。我们已经确定了两个有趣的目标 寄生虫中对它们的能量产生和在人类宿主中的生存至关重要的蛋白质；这些是 锥体交替氧化酶(TAO)和甘油激酶(TGK)。然而，这两种酶必须是 同时堵塞，以有效杀灭寄生虫，治愈感染。道在人类中是缺失的； 虽然TGK存在，但结构显示某些功能区与其他GK区有很大不同 为成功开发TGK特异性抑制剂提供了令人鼓舞的初步数据(S)。 TGK和TAO抑制剂的联合应用将选择性地杀死寄生虫，并可能避免毒性问题。 我们提案中的创新之一是，我们的目标是设计共同靶向TAO和TGK的单一抑制剂。 这将避免药物-药物相互作用的机会与容易伴随的不良副作用 使用多种药物来治疗一种疾病。这将通过对100,000人进行实验性筛选来实现 斯卡格斯药学院小分子资料库中的化合物 美国加州大学圣地亚哥分校(UCSD)的SSPPS对TGK和TGK的酶活性的影响 然后选择那些对这两种酶都有抑制能力的。同时，这些化合物 还将对这种寄生虫进行筛查，以识别那些具有锥虫杀死作用的人。两个类别 然后将优化化合物的种类，以杀灭培养中的锥虫，抑制TAO和TGK，以及 对人甘油蛋白激酶和培养的人细胞缺乏影响。总体而言，目前的提议将导致 本设计单一无毒有效的杀锥虫化合物(S)。私家侦探伊曼纽尔·O·巴洛根博士将 与美国和尼日利亚的多学科专家团队在这个项目上合作：在SSPPS加州大学圣地亚哥分校 James H.McKerrow教授(美国首席导师)、Larissa Podust教授和Jair Siqueira-Neto教授(美国联合导师)； Mamman Mohammed教授(尼日利亚首席导师)、Christian Happi、Maryam Aminu和Mohammed N 帅布(尼日利亚联合导师)。