Exploration of Chitinase Inhibitors for Human Health

几丁质酶抑制剂对人类健康的探索

• 批准号: 8441996
• 负责人: Kim Janda
• 金额: $ 28.43万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8441996
• 关键词: Address; Adopted; Adult; Affect; Africa; Animal Model; Anthelmintics; Bacterial Infections; Biochemical; Biological; Blindness; Caenorhabditis elegans; Central America; Chemicals; Chitinase; Clinical; Development; Developmental Process; Disease; Drug Industry; Drug Targeting; Enzymes; Evolution; Force of Gravity; Goals; Health; Human; In Vitro; Infection; Inhibitory Concentration 50; Intestinal Volvulus; Ionophores; Ivermectin; Laboratories; Libraries; Mediating; Mitochondria; Modeling; Modification; Molting; Morbidity - disease rate; Nematoda; Ocular Onchocerciasis; Onchocerca volvulus; Onchocerciasis; Parasites; Parasitic Diseases; Parasitic infection; Parasitic nematode; Penetration; Permeability; Pharmaceutical Preparations; Plague; Play; Poverty; Protons; RNA Interference; Reporting; Resistance; Role; Simuliidae; South America; Specificity; Structure-Activity Relationship; Therapeutic; Tropical Disease; Veins; Yemen; base; chemical synthesis; chemotherapy; effective therapy; inhibitor/antagonist; insight; neglect; new therapeutic target; public health relevance; research study; salicylanilide; scaffold; screening; small molecule; therapeutic target

DESCRIPTION (provided by applicant): Neglected tropical diseases (NTD) include 13 poverty-promoting parasitic and bacterial infections that affect over 1 billion people worldwide, primarily in impoverished regions. One NTD for which there is a great need for a therapeutic evolution is onchocerciasis, or river blindness, a leading cause of blindness in the developing world. The infection is caused by the parasitic nematode Onchocerca volvulus, which is transmitted to humans by the blackfly. Despite several eradication efforts, the disease affects more than 37 million people in Africa, Central and South America and Yemen. Currently, the only drug available for mass treatment is ivermectin (Mectizan(R), Merck). Although this drug has proved successful in reducing morbidity, resistance to ivermectin is emerging. Despite the gravity of such diseases on human health, the pharmaceutical industry has largely neglected the development of chemotherapies for NTDs and no new anthelmintic classes for humans have been described within the past 15 years. Thus, there is a crucial need to identify chemical probes toward the goal of validating new therapeutic targets for the development of effective treatments for onchocerciasis. Recently, our laboratory has investigated the O. volvulus chitinase, OvCHT1, as an antilarval drug target. As a starting point, we screening The Johns Hopkins Clinical Compound Library and uncovered the known veterinary anthelmintic drug, closantel, as a chitinase inhibitor. Using function-specific chemical probes based upon closantel's general scaffolding, we have explored both small molecule OvCHT1 inhibitors and proton ionophores as anti-molting agents, as closantel possesses both of these biochemical activities. Interestingly, initial studies indicate that both activities are required for potent inibition of molting; however, further studies are required to unravel how each mechanism of action impacts larval development. To gain a deeper understanding, we will adopt both chemical- and biological-mediated modulation tactics by using small molecule chemical probes and RNAi. From these studies we hope to not only be able to address the druggability of filarial chitinases but also provide useful insights toward the goal of validating chitinases as a new therapeutic target for the development of effective treatments for onchocerciasis.

描述（由申请人提供）：被忽视的热带疾病（NTD）包括13个促进贫困的寄生虫和细菌感染，这些寄生和细菌感染影响了全球超过10亿人，主要在贫困地区。一个NTD非常需要治疗进化的NTD是OnChocercerisis或River Blindness，这是发展中国家失明的主要原因。感染是由寄生线虫OnChocerca Volvulus引起的，该chocerca volvulus由黑蝇传递给人类。尽管消除了几项努力，但这种疾病仍影响了非洲，中美洲和也门的3700万人。目前，唯一可用于大规模治疗的药物是伊维菌素（Mectizan（R），默克）。尽管该药物已被证明在降低发病率方面成功，但对伊维菌素的抗性正在出现。尽管这种关于人类健康的疾病具有严重性，但制药行业在很大程度上忽略了NTD的化学疗法的发展，并且在过去15年内没有描述过人类的新驱虫类。因此，至关重要的是要确定化学探针以验证新的治疗靶标，以开发有效的脑凝集治疗。最近，我们的实验室研究了O. volvulus几丁质酶OVCHT1，作为抗高清药物靶标。作为起点，我们筛选了约翰·霍普金斯临床化合物文库，并发现了已知的兽医驱虫药Closantel，作为几丁质酶抑制剂。使用基于Closantel的一般脚手架的功能特异性化学探针，我们已经探索了小分子OVCHT1抑制剂和质子离子载体作为抗摩尔剂，因为Closantel都具有这两种生物化学活性。有趣的是，初步研究表明，这两种活动都是有效滴分解所必需的。但是，需要进一步的研究来阐明每种作用机理如何影响幼体发展。为了获得更深入的了解，我们将通过使用小分子化学探针和RNAi采用化学和生物介导的调节策略。从这些研究中，我们希望不仅能够解决丝状几丁质酶的可药用性，而且还提供了有用的见解，以验证几丁质酶，作为开发有效治疗脑尾cer虫的新治疗靶标。