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New tools for antimalarial target identification

抗疟靶点识别的新工具

基本信息

批准号：
10581574
负责人：
Kathryn Jean Wicht
金额：
$ 14.06万
依托单位：
UNIVERSITY OF CAPE TOWN
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-03-22 至 2025-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10581574
关键词：
Academic Medical Centers Amodiaquine Antimalarials Artemisinins Binding Biological Assay Cambodian Cells Characteristics Chemicals Clinical Collection Computing Methodologies Data Databases Development Docking Drug Metabolic Detoxication Endocytosis Erythrocytes Exhibits Falciparum Malaria Genes Grant Hematin Heme Hemoglobin Investigation Laboratories Libraries Literature Malaria Maps Measurement Measures Mefloquine Methods Modeling Molecular Multi-Drug Resistance National Center for Advancing Translational Sciences New York Parasites Pathway interactions Pharmaceutical Preparations Pharmacologic Substance Pharmacology Phenotype Plasmodium falciparum Predisposition Prevalence Process Proteins Proteolysis Publications Publishing Refractory Reporting Research Resistance Role Series Site Solvents South Africa Testing Training United States National Institutes of Health Universities Validation Volatilization Work analytical method benflumetol design detection method drug discovery experience experimental study hemozoin high throughput screening improved in silico inhibitor insight kinetic model liquid chromatography mass spectrometry mathematical model mutant novel overexpression pathogen plasmepsin predictive modeling pyridine pyronaridine resistant Plasmodium falciparum screening small molecule libraries success tool virtual laboratory virtual screening

项目摘要

Target identification is a vital step in the drug discovery process and represents a substantial hurdle to further development when large numbers of hit compounds are identified by high throughput phenotypic screening. This problem is especially challenging in the case of antimalarial drug discovery because of the prevalence of unconventional targets such as hemozoin, the formation of which is thought to be inhibited by nearly half the clinical antimalarials and many experimental compounds. A key feature of the success of these drugs is that hemozoin is derived from host hemoglobin and is therefore not mutable, thereby reducing the ability of P. falciparum to acquire resistance. Prior studies have shown that target identification is complicated by the fact that the ability to inhibit abiotic synthetic hemozoin (-hematin) formation is a necessary, but not sufficient predictor of hemozoin inhibition in Plasmodium falciparum malaria parasites and conversely, decreased hemozoin formation in the parasite is not itself confirmation of direct inhibition of hemozoin formation. We hypothesize that direct measurement of increased unsequestered heme together with decreased hemozoin in the intra-erythrocytic parasite is the most consistent method of identifying hemozoin inhibitors and that the latter cause characteristic perturbations of the heme detoxification pathway that can be exploited in target deconvolution. We further hypothesize that these inhibitors occupy a distinct region of chemical space that can be mapped in silico. To achieve our objectives, the following specific aims are proposed: 1) Develop generalizable methods to measure and detect hemozoin inhibition in Plasmodium falciparum; 2) Use in silico methods to map hemozoin inhibition in chemical space; and 3) Develop a model of the full heme detoxification pathway. To realize these aims, the research will be conducted as a collaborative and synergistic project between Timothy Egan at the University of Cape Town (UCT), Katherine de Villiers at Stellenbosch University (SU), South Africa and David Fidock at the Columbia University Medical Center (CUMC), New York, NY. Generalizable analytical methods for measuring unsequestered heme will be developed at UCT and transferred to CUMC for investigation of compound collections available at that site. A laboratory strain expected to exhibit universally reduced susceptibility to hemozoin inhibitors will be generated at CUMC. In silico methods for mapping -hematin inhibitors will be developed at SU and screening via molecular docking performed at UCT. Validation of these methods will take place at UCT and SU. The input data for modeling the heme detoxification pathway will be collected at UCT, while the mathematical model of this pathway will be developed at SU. Validation of the model will be conducted at UCT and CUMC. We expect that this work will transform our ability to discern the role of hemoglobin degradation and hemozoin synthesis in the mode of action of antimalarials, and provide vital tools to identify novel inhibitors that are refractory to a rapid gain of resistance and can treat multidrug-resistant P. falciparum malaria.

目标识别是药物发现过程中至关重要的一步，也是进一步研究的一个重大障碍

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Identifying inhibitors of β-haematin formation with activity against chloroquine-resistant Plasmodium falciparum malaria parasites via virtual screening approaches.

DOI：
10.1038/s41598-023-29273-w
发表时间：
2023-02-14
期刊：
Scientific reports
影响因子：
4.6
作者：
通讯作者：

Identification of 2,4-Disubstituted Imidazopyridines as Hemozoin Formation Inhibitors with Fast-Killing Kinetics and In Vivo Efficacy in the Plasmodium falciparum NSG Mouse Model.

DOI：
10.1021/acs.jmedchem.0c01411
发表时间：
2020-11-12
期刊：
Journal of medicinal chemistry
影响因子：
7.3
作者：
Horatscheck A;Andrijevic A;Nchinda AT;Le Manach C;Paquet T;Khonde LP;Dam J;Pawar K;Taylor D;Lawrence N;Brunschwig C;Gibhard L;Njoroge M;Reader J;van der Watt M;Wicht K;de Sousa ACC;Okombo J;Maepa K;Egan TJ;Birkholtz LM;Basarab GS;Wittlin S;Fish PV;Street LJ;Duffy J;Chibale K
通讯作者：
Chibale K

Naphthylisoquinoline alkaloids, validated as hit multistage antiplasmodial natural products.

萘基异喹啉生物碱，被验证为热门的多级抗疟原虫天然产物。

DOI：
10.1016/j.ijpddr.2020.05.003
发表时间：
2020
期刊：
International journal for parasitology. Drugs and drug resistance
影响因子：
0
作者：
Moyo,Phanankosi;Shamburger,William;vanderWatt,MariëtteE;Reader,Janette;deSousa,AnaCarolinaC;Egan,TimothyJ;Maharaj,VineshJ;Bringmann,Gerhard;Birkholtz,Lyn-Marie
通讯作者：
Birkholtz,Lyn-Marie

Intrinsic fluorescence properties of antimalarial pyrido[1,2-a]benzimidazoles facilitate subcellular accumulation and mechanistic studies in the human malaria parasite Plasmodium falciparum.

抗疟疾吡啶多[1,2-A]苯咪多唑的固有荧光特性促进了人类疟原虫恶性疟原虫的亚细胞积累和机械研究。