Antitoxoplasmosis Drug Design and Optimization

抗弓形虫病药物设计与优化

• 批准号: 7860289
• 负责人: Lorraine V. Jones Brando
• 金额: $ 36.92万
• 依托单位: PORTLAND STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-15 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7860289
• 关键词: Active Sites; Affinity; Antiparasitic Agents; Binding; Biochemical; Biological Assay; Bioterrorism; Blindness; Blood; Cells; Cessation of life; Chemical Structure; Chemicals; Child; Chronic; Clinical; Communicable Diseases; Computer Simulation; Congenital Abnormality; Consumption; Crystallization; Cyst; Development; Disease; Docking; Drug Delivery Systems; Drug Design; Drug Kinetics; Encephalitis; Evaluation; Exhibits; Eye; Genes; Genome; Genomics; Growth; Guidelines; Health; Health protection; Heart; Homology Modeling; Human; Immune system; In Vitro; Individual; Infection; Infectious Agent; Inhibitory Concentration 50; Lead; Life; Liver; Lung; Mammalian Cell; Measurement; Membrane Potentials; Mental Retardation; Metabolic; Methodology; Methods; Mission; Molecular Weight; Monitor; Mus; National Institute of Allergy and Infectious Disease; Nervous System Trauma; Organ; Organelles; Organism; Parasites; Patients; Persons; Pharmaceutical Preparations; Pharmacodynamics; Pregnant Women; Preparation; Prevention; Process; Proteins; Public Health; Quinolones; Reading; Research; Research Support; Resistance; Schools; Screening procedure; Solubility; Spleen; Staging; Structure; Surface Antigens; Symptoms; Techniques; Therapeutic; Time; Tissues; Toxic effect; Toxoplasma; Toxoplasma gondii; Toxoplasmosis; Ursidae Family; Vaccines; Virtual Library; Work; analog; aqueous; base; biodefense; cytotoxic; design; drug development; drug discovery; expectation; genome sequencing; high throughput screening; improved; in vitro activity; in vivo; inhibitor/antagonist; meetings; mitochondrial membrane; mutant; non-drug; novel; parasite genome; pharmacophore; prevent; public health relevance; small molecule; success; therapeutic target; therapy development; unborn child

DESCRIPTION (provided by applicant): Toxoplasma gondii is the causative agent of toxoplasmosis. For most of the estimated 60 million US citizens that have been exposed to the Toxoplasma parasite, most will have very few symptoms because a healthy person's immune system usually keeps the parasite from causing illness. However, pregnant women and individuals who have compromised immune systems are vulnerable to the full spectrum of serious health problems caused by the disease including blindness, encephalitis, mental retardation, and death. Treatment of toxoplasmosis with available therapeutics is not ideal and does not eradicate the parasite from the patient and therefore re-infections may occur. Work Accomplished: We have discovered and seek to improve an entirely new type of drug for prevention and treatment of toxoplasmosis. With IC50 values in the low nanomolar and picomolar range our most active compounds, so-called, "ELQs", are far more potent (in vitro) than any drug in clinical use today for treating toxoplasmosis. If these drugs prove to be safe and effective enough to go into actual use, the potential benefit is nothing less than saving lives and sparing many individuals from long-term neurological damage, as well as damage to other organs such as the eyes, liver and spleen, heart and lung. Work Proposed: Specific objectives to be pursued as part of the project plan include: (1) to optimize the chemical structure of the ELQ pharmacophore by continued synthesis and design of analogs, (2) to screen new derivatives for selective potency against T. gondii in vitro and in vivo and in rational combination with standard therapeutics, (3) to monitor the metabolic stability of lead candidate ELQs in vitro in microsomal preparations and to determine pharmacokinetics and pharmacodynamic parameters in vivo in mice, and (4) to investigate the mechanism underlying the selective and potent antitoxoplasmial effects of ELQs. Taken together, we're excited by the possibilities and the potential for new drug development for treatment of toxoplasmosis in humans. Relevance to NIAID's mission: A primary mission of the NIAID is to conduct and support research that helps to provide protection against emerging and chronic infectious diseases that represent a threat to public health. Bioterrorism represents a new threat to public health and to meet the challenges posed by biodefense, NIAID supports research on countermeasures to infectious agents (including Toxoplasma gondii) that may be weaponized for bioterrorism. The development of therapies to prevent or treat infectious diseases, including diseases that are caused by potential agents of bioterror, is fundamental to the ever-expanding mission served by NIAID. Thus, for a multiplicity of reasons including public health, protection of the unborn child from birth defects, as well as biodefense, the proposed project is entirely relevant to NIAID's mission. PUBLIC HEALTH RELEVANCE: We have discovered and seek to improve an entirely new type of drug for prevention and treatment of toxoplasmosis. If these drugs prove to be safe and effective enough to go into actual use, the potential benefit is nothing less than saving lives and sparing many individuals from long-term neurological damage, as well as damage to other organs such as the eyes, liver and spleen, heart and lung.

描述（由申请人提供）：弓形虫Gondii是弓形虫病的病因。对于大多数暴露于弓形虫寄生虫的美国公民中，大多数美国公民的症状很少，因为健康的人的免疫系统通常会使寄生虫无法引起疾病。但是，受到损害免疫系统的孕妇和个人容易受到由疾病，包括失明，脑炎，智力低下和死亡的全部严重健康问题的影响。用可用的治疗剂治疗弓形虫病是不理想的，也不会消除患者的寄生虫，因此可能会重新感染。完成的工作：我们发现并寻求改善一种全新的药物，以预防和治疗弓形虫病。在低纳摩尔和皮摩尔范围内的IC50值的情况下，我们最活跃的化合物（所谓的“ ELQ”）比如今的任何临床用途中的任何药物都更有效（体外）。如果这些药物被证明是安全有效的，可以实际使用，那么潜在的好处无非是挽救生命，并使许多人免于长期神经损害，以及对其他器官，例如眼睛，肝脏和脾脏，心脏和肺部的损害。提出的工作：作为项目计划的一部分，要实现的特定目标包括：（1）通过持续合成和设计类似物的持续合成和设计来优化ELQ药片的化学结构，（2）筛选新的衍生物，以选择性效力，以在体外，体外和体外和体内以及与标准治疗中的有效性相结合（3）的稳定性，（3）并确定小鼠体内的药代动力学和药效学参数，以及（4）研究ELQ的选择性和有效抗毒性作用的基础机制。综上所述，我们对治疗人类弓形虫病的新药物开发的可能性和潜力感到兴奋。与NIAID的使命相关：NIAID的主要任务是进行和支持研究，有助于保护对构成对公共卫生威胁的新兴和长期传染病的保护。生物恐怖主义代表了对公共卫生的新威胁，并应满足生物探空素的挑战，NIAID支持对可能被武器生物恐怖主义武器的传染性药物（包括弓形虫gondii）进行对策的研究。预防或治疗传染病的疗法的发展，包括由Bioterror潜在药物引起的疾病，是Niaid不断扩大的任务的基础。因此，出于多种原因，包括公共卫生，保护未出生的儿童免受先天缺陷以及生物形式，该建议的项目与Niaid的使命完全相关。公共卫生相关性：我们发现并寻求改善一种全新类型的药物，以预防和治疗弓形虫病。如果这些药物被证明是安全有效的，可以实际使用，那么潜在的好处无非是挽救生命，并使许多人免于长期神经损害，以及对其他器官，例如眼睛，肝脏和脾脏，心脏和肺部的损害。