Evolutionary medicine in the development of antimalaria drugs

抗疟疾药物开发中的进化医学

• 批准号: 8820233
• 负责人: Daniel L HARTL
• 金额: $ 33.8万
• 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/8820233
• 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; 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; 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）：进化医学是将进化思想应用于医学和医学研究中的问题。这种方法在传染病研究中具有特殊的价值，在传染病研究中，进化对于理解毒力、免疫逃避、耐药性以及其他对公共卫生和临床干预至关重要的特征至关重要。本研究采用进化方法对开发第三代三嗪类二氢叶酸还原酶（DHFR）抑制剂的先导化合物进行评价。DHFR是用于预防和治疗疟疾的最有效药物靶点之一。这个项目的目标是双重的：(1)应用进化