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: 10296873
• 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/10296873
• 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; 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/antagonist; innovation; kinase inhibitor; multidisciplinary; nanomolar; new therapeutic target; novel; novel therapeutics; pathogen; professor; 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 该提案旨在开发更安全有效的治疗非洲人类锥虫病（HAT）的药物， 一种在撒哈拉以南非洲地区流行的传染病。HAT是全球健康问题，因为缺乏 接种疫苗预防的希望和不令人满意的治疗方案。有必要发展 具有新作用机制的新药。要合理开发好药，重要的是鉴别 寄生虫的分子靶点这些靶分子应满足以下标准：（i）对靶分子的生物学特性重要。 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）如果存在于人类中， 与人类分子结构不同。之后我们就可以寻找化合物 特异性地与靶分子相互作用，阻止它们发挥作用，最终杀死寄生虫。 血流形式的锥虫（BSF）的能量（ATP）代谢途径呈现出这样的特点： 这是药物发现的新靶点，因为它不同于动物。我们发现了两个有趣的目标 寄生虫中的蛋白质，对它们在人类宿主中的能量产生和生存很重要;这些是 锥虫交替氧化酶（TAO）和甘油激酶（TGK）。然而，这两种酶必须 同时阻断，以便有效地杀死寄生虫并治愈感染。TAO在人类中不存在; 虽然存在TGK，但结构显示某些功能区域与其他GK非常不同， 生物，为成功开发TGK特异性抑制剂提供了令人鼓舞的初步数据。 TGK和TAO抑制剂的共同施用将选择性地杀死寄生虫，并且可能避免毒性问题。 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。 这将避免药物相互作用的机会，而不是容易伴随的不良副作用 给药多种药物以治疗疾病。这将通过对100，000名 Skaggs药学院小分子库中的化合物 Sciences（SSPPS），University of加州圣地亚哥大学（UCSD），USA针对TGK和TPK的酶活性， TAO，然后选择对两种酶都显示抑制能力的那些。同时，化合物 也将对寄生虫进行筛选，以确定具有杀死锥虫效果的那些。两类 然后将优化化合物的浓度以杀死培养物中的锥虫，抑制TAO和TGK， 因为对人甘油激酶和培养的人细胞没有影响。总的来说，目前的建议将导致 所设计的单一无毒且有效的杀锥虫化合物。PI，Emmanuel O。Balogun博士，将 与美国和尼日利亚的多学科专家团队合作开展该项目：在SSPPS UCSD James H. McKerrow（美国首席导师）、Larissa Podust和Jair Siqueira-Neto（美国联合导师）; 教授马曼穆罕默德（尼日利亚首席导师），基督教Happi，玛丽亚姆阿米努，和穆罕默德N Shuaibu（尼日利亚共同导师）。