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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

基本信息

批准号：
10706306
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
项目类别：
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/10706306
关键词：
Ablation Adopted Africa Africa South of the Sahara African African Trypanosomiasis Animals Biological Assay Blood California Camels Categories Cattle Cells Cessation of life Chemicals Collaborations Communicable Diseases Data Development Disease Doctor of Philosophy Drug Design Drug Interactions Economic Development Endemic Diseases Enzymes Failure Future Generations Genetic Glucose Glycerol Kinase Glycolysis Grant Health 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 Populations at Risk Prevention Production Proteins Publishing Records Reporting Ruminants Science Starvation Stream Structure Structure-Activity Relationship System Therapeutic Toxic effect Trypanocidal Agents Trypanosoma Trypanosoma brucei brucei Trypanosomiasis Tsetse Flies Universities Vaccination Work X-Ray Crystallography alternative oxidase design disability-adjusted life years drug candidate drug development drug discovery global health glucose metabolism 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 transmission process

项目摘要

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).

项目总结

项目成果

期刊论文数量（11）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Identification of megacerotonic acid and a quinazoline derivative from Universal Natural Product Database as potential inhibitors of Trypanosoma brucei brucei alternative oxidase: molecular docking, molecular dynamic simulation and MM/PBSA analysis.

从通用天然产物数据库中鉴定大丙酮酸和喹唑啉衍生物作为布氏锥虫替代氧化酶的潜在抑制剂：分子对接、分子动力学模拟和 MM/PBSA 分析。

DOI：
10.1080/07391102.2021.2003862
发表时间：
2023
期刊：
Journal of biomolecular structure & dynamics
影响因子：
4.4
作者：
Adamu,RahmaMuhammad;Ibrahim,Bashiru;Ibrahim,MohammedAuwal;Balogun,EmmanuelOluwadare
通讯作者：
Balogun,EmmanuelOluwadare

Prevalence and Associated Risk Factors of Urinary Schistosomiasis among Primary School Pupils in the Jidawa and Zobiya Communities of Jigawa State, Nigeria.

DOI：
10.5334/aogh.3704
发表时间：
2022
期刊：
ANNALS OF GLOBAL HEALTH
影响因子：
2.9
作者：
Balogun, J. B.;Adewale, B.;Balogun, S. U.;Lawan, A.;Haladu, I. S.;Dogara, M. M.;Aminu, A. U.;Caffrey, C. R.;De Koning, H. P.;Watanabe, Y.;Balogun, E. O.
通讯作者：
Balogun, E. O.

Glycerol biosynthetic pathway plays an essential role in proliferation and antioxidative defense in the human enteric protozoan parasite Entamoeba histolytica.

DOI：
10.1038/s41598-023-40670-z
发表时间：
2023-09-05
期刊：
Scientific reports
影响因子：
4.6
作者：
通讯作者：

Molecular detection of Sodalis glossinidius, Spiroplasma and Wolbachia endosymbionts in wild population of tsetse flies collected in Cameroon, Chad and Nigeria.

在喀麦隆、乍得和尼日利亚采集的采采蝇野生种群中对 Sodalis glsinidius、螺原体和沃尔巴克氏体内共生体进行分子检测。

DOI：
10.21203/rs.3.rs-2902767/v1
发表时间：
2023
期刊：
Research square
影响因子：
0
作者：
Mfopit,YoussoufMouliom;Weber,JudithSophie;Chechet,GloriaDada;Ibrahim,MahamatAlhadjMoussa;Signaboubo,Djoukzoumka;Achukwi,DanielMbunkah;Mamman,Mohammed;Balogun,EmmanuelOluwadare;Shuaibu,MohammedNasir;Kabir,Junaidu;Kelm,Soerge
通讯作者：
Kelm,Soerge

Upregulation of sialyltransferases ST3Gal1 and ST6Gal1 promotes stabilization of erythrocyte mass and recovery of anemia in Trypanosoma brucei brucei-infected pigs.

DOI：
10.1016/j.rvsc.2022.02.012
发表时间：
2022-07
期刊：
RESEARCH IN VETERINARY SCIENCE
影响因子：
2.4
作者：
Atata, J. A.;Enam, S. J.;Ogbuagu, N. E.;Balogun, E. O.;Adamu, S.;Esievo, K. A. N.
通讯作者：
Esievo, K. A. N.