Evolutionary medicine in the development of antimalaria drugs

抗疟疾药物开发中的进化医学

• 批准号: 9198129
• 负责人: Daniel L HARTL
• 金额: $ 2.28万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-03-15 至 2018-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9198129
• 关键词: Alleles; Amino Acids; Antimalarials; Artemisinins; Bacteria; Basic Science; Biological Models; Biology; Cell division; Chemical Structure; Clinical; Code; Collaborations; Communicable Diseases; Development; Dihydrofolate Reductase; Disease; Drug Design; Drug Targeting; Drug resistance; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Evaluation; Evolution; Experimental Models; Folic Acid Antagonists; Future; Generations; Genes; Genetic Polymorphism; Goals; Growth; Head; Health; Immune; Intervention; Knowledge; Laboratories; Lead; Learning; Life; Malaria; Medical Research; Medicine; Mutagenesis; Mutation; Parasites; Pharmaceutical Preparations; Pharmacologic Substance; Plasmodium falciparum; Plasmodium vivax; Prevention; Production; Proteins; Public Health; Pyrimethamine; Research; Research Personnel; Resistance; Resources; Structure; System; Testing; Therapeutic; Thinking; Time; Toxoplasmosis; Transcriptional Regulation; Transgenic Organisms; Translating; Translational Regulation; Translational Research; Triazines; Virulence; Work; Yeasts; artemisinine; cell growth; combinatorial; cost; dissemination research; drug development; genetic manipulation; mutant; novel; novel therapeutics; research study; resistance allele; response

DESCRIPTION (provided by applicant): Evolutionary Medicine is the application of evolutionary thinking to problems in medicine and medical research. This approach has exceptional merit in infectious diseases, in which evolution is critically important in understanding virulence, immune evasion, drug resistance, and other features critical in public health and clinical intervention. This proposal takes an evolutionary approach to the evaluation of lead compounds for the development of third-generation triazine inhibitors of the enzyme dihydrofolate reductase (DHFR). DHFR is one of the most effective drug targets used for the prevention and treatment of malaria. The goal of this project is twofold: (1) To apply evolutionary thinking to make informed choices of the best lead compounds to select for further development into clinically effective drugs with a long therapeutic lifetime; and (2) To perform the studies in such a way as to explore how adaptive landscapes of drug resistance change as a function of drug concentration and in response to differing perturbagens. In Specific Aim 1 we will examine the wildtype allele and all known naturally occurring polymorphisms in DHFR of P. falciparum and P. vivax for their resistance to five potential lead compounds for third-generation antifolates These tests will use both the yeast and bacterial transgenic DHFR expression systems. The use of experimental models is essential, as P. vivax cannot be cultured in the laboratory, and the production of the isogenic strains needed for the tests in P. falciparum is not feasible in regard to time or cost. In Specific Aim 2, we will augment the studies in Specific Aim 1 by creating the "missing intermediate" alleles to allow a complete combinatorial analysis of the adaptive landscape with respect to each of the novel triazine antifolates as perturbagens. In Specific Aim 3 we will carry out mutagenesis and selection experiments in the P. falciparum and P. vivax transgenic systems to determine whether the wildtype allele or any of the polymorphisms are easily converted via new mutations to resistance against any of the novel antifolates. This is a critical issue in evaluating the potential therapeutic lifetime of new drugs. The lead compounds to be tested are the five triazine antifolates WR99210, JPC-2067, JPC-2122, JPC-1058, and JPC-1054. The research will be carried out in collaboration with the Jacobus Pharmaceutical Company, a small company that is nevertheless a world leader in developing and producing antifolates against malaria and toxoplasmosis. Our collaborator, David P. Jacobus, MD has a distinguished track record of collaboration with academic researchers and open dissemination of research resources and information. The research is a unique combination of drug development and evolutionary biology with the potential to contribute to the development of new life-saving drugs while at the same time revealing new principles of protein evolution.

描述（由申请人提供）：进化医学是进化思维在医学和医学研究中的问题。这种方法在传染病中具有出色的优点，其中进化对于理解毒力，免疫逃避，耐药性和其他在公共卫生和临床干预中至关重要的特征至关重要。该提案采用进化方法来评估铅化合物，以开发二氢叶酸酸酯还原酶（DHFR）的第三代三嗪抑制剂。 DHFR是用于预防和治疗疟疾的最有效的药物靶标之一。该项目的目标是双重的：（1）应用进化 想到对最佳铅化合物做出明智的选择，以选择长期治疗寿命的临床有效药物的进一步开发； （2）进行研究 探索耐药性的自适应景观如何随着药物浓度的函数以及对不同的脑外形响应的函数的方式。在特定的目标1中，我们将检查野生型等位基因和所有已知的天然发生的多态性，在恶性疟原虫和Vivax的DHFR中，它们对第三代抗细胞的五种潜在铅化合物的抗性这些测试将同时使用酵母和细菌性转基因DHFR DHFR表达系统。实验模型的使用是必不可少的，因为在实验室中不能培养体育假单胞菌，并且在时间或成本方面，恶性疟原虫测试所需的同基因菌株不可行。在特定的目标2中，我们将通过创建“缺失的中间”等位基因来增强特定目标1的研究，以允许相对于每种新型三嗪抗脱落的抗脑外形，对自适应景观进行完整的组合分析。在特定的目标3中，我们将在恶性疟原虫和维瓦克斯疟原虫转基因系统中进行诱变和选择实验，以确定野生型等位基因或任何多态性是否可以通过新的突变很容易转化以抵抗任何新型抗染料。这是评估新药潜在的治疗寿命的关键问题。要测试的铅化合物是五种三嗪抗毒酸WR99210，JPC-2067，JPC-2122，JPC-1058和JPC-1054。这项研究将与雅各布斯制药公司合作进行，该公司仍然是一家世界领导者，在开发和生产反对疟疾和弓形虫病的抗臭虫方面是世界领导者。我们的合作者David P. Jacobus，医学博士与学术研究人员合作并开放研究资源和信息的杰出记录。这项研究是药物开发和进化生物学的独特结合，有可能为新的挽救生命的药物的发展做出贡献，同时揭示了蛋白质进化的新原理。