Novel Macrofilaricidal Compounds: Target Identification and Chemical Optimizatio

新型杀丝虫化合物：目标识别和化学优化

• 批准号: 7405218
• 负责人: MICHAEL J CRAWFORD
• 金额: $ 10万
• 依托单位: DIVERGENCE, INC.
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-03-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7405218
• 关键词: Adolescent; Adult; Affect; Albendazole; Animals; Anthelmintics; Area; Biochemical; Biological Assay; Brugia malayi; Caenorhabditis elegans; Cell Line; Cell Respiration; Cell-Mediated Cytolysis; Characteristics; Chemical Actions; Chemicals; Clinical; Clinical Trials; Cloning; Collaborations; Collection; Communicable Diseases; Country; Databases; Development; Diethylcarbamazine; Disease; Disease Clusterings; Dose; Drug Design; Drug Kinetics; Drug resistance; Economic Burden; Electrons; Elephantiasis; Evaluation; Face; Female; Filarial Elephantiases; Formazans; Foundations; Generations; Genetic; Genetic Complementation Test; Genetic Screening; Genomics; Ghana; Goals; Guanosine Monophosphate; Health; Human; Hydrogen; In Vitro; Individual; Infection; International; Ivermectin; Jird; Larva; Lead; Life; Mammalian Cell; Maps; Measures; Microfilaria; Modeling; Molecular; Molecular Target; Molecular Weight; Monitor; Morbidity - disease rate; Mutation; Nematoda; Numbers; Ocular Onchocerciasis; Onchocerciasis; Orthologous Gene; Outcome; Parasites; Parasitic nematode; Patients; Pharmaceutical Preparations; Phase; Phase II Clinical Trials; Plants; Population; Process; Production; Property; Range; Rate; Research; Resistance; Risk; Rodent Model; S Phase; Screening procedure; Series; Small Business Funding Mechanisms; Small Business Innovation Research Grant; Staging; Structure; Structure-Activity Relationship; Surface Properties; Technology; Testing; Toxicology; Work; World Health Organization; analog; base; blind; cell motility; chemical synthesis; cheminformatics; clinically significant; cost; cytotoxicity; design; desire; disability; drug development; filaria; gene cloning; genome sequencing; health economics; improved; in vitro Assay; in vivo; killings; male; molecular modeling; mutant; next generation; novel; pre-clinical; pressure; programs; scaffold; scale up; small molecule

DESCRIPTION (provided by applicant): Parasitic infect over 140 million people, with up to one billion at risk in 80 countries. Lymphatic filariasis creates an enormous health and economic burden within affected areas and is the second leading cause of long-term disability. In 2000, international groups including the World Health Organization (WHO) launched an initiative to eliminate lymphatic filariasis by annual mass drug administration. Although the compounds available for this ambitious program (ivermectin, albendazole, diethylcarbamazine) are effective at killing larvae (microfilariae), the adult reservoir of parasites (macrofilariae) survive and can remain in the human host for a decade. In addition, the extreme selective pressure caused by mass treatment has been accompanied by recent evidence of parasite drug resistance. Similar challenges face the campaigns to reduce onchocerciasis with ivermectin. The long- term objective of this SBIR proposal is to develop desperately needed macrofilaricidal compounds that can eliminate the adult parasite reservoir and protect current drugs from the development of broad resistance. Divergence has recently implemented a proprietary technology that represents a fundamental advance in molecular modeling and allows the identification of structurally unrelated compounds that have a shared mode of action. Divergence has already succeeded with this approach in creating a valuable chemical collection with a high rate (~17%) of potent hits against animal and plant parasitic nematodes. A number of compounds in the collection also have very promising macrofilaricidal activity against female and male Brugia malayi filarial worms in vitro. Two objectives will be accomplished during Phase I. First, as our compounds represent a broad and novel nematicidal mode of action, Divergence will initiate genetic studies in C. elegans to identify the compounds' molecular target. Second, structure-activity and optimization strategies will be pursued through the acquisition and synthesis of analogs. The resultant molecules will be evaluated against adult B. malayi in vitro and subsequently assayed for cytotoxicity in a mammalian cell line and microsomal stability. During Phase II studies, promising molecules will progress to evaluation of filarial control in a rodent model along with toxicology and pharmacokinetic evaluation. Molecular targets identified in the Phase I genetic screen will be cloned and characterized for use in development of next generation leads and eventual resistance monitoring in a project compound reaching clinical use. The expected outcome of this work is the identification of potent lead molecules that demonstrate in vivo macrofilaricidal activity with a novel mode of action. In collaboration with agencies that have demonstrated a commitment to global health equity (such as the Gates Foundation and WHO), Phase III efforts will focus on the initiation of clinical trials in humans with the ultimate goal of greatly reducing the human health burden of filarial diseases. Project Narrative: Parasitic nematodes (roundworms) currently infect over one billion people globally, causing severe morbidity and economic burden. The goal of this project to identify and develop desperately needed drugs to combat filarial nematodes, which cause some of the most pernicious infectious diseases in humans - elephantiasis and river blindness.

描述（由申请人提供）：寄生虫感染超过1.4亿人，在80个国家中有高达10亿人处于危险之中。淋巴丝虫病在受影响地区造成巨大的健康和经济负担，是造成长期残疾的第二大原因。2000年，包括世界卫生组织（世卫组织）在内的国际组织发起了一项倡议，通过每年大规模给药来消除淋巴丝虫病。尽管这一雄心勃勃的计划中可用的化合物（伊维菌素、阿苯达唑、二乙基卡马嗪）对杀死幼虫（微丝虫）有效，但寄生虫（大丝虫）的成虫库存活下来，并可在人类宿主体内停留10年。此外，大规模治疗造成的极端选择压力伴随着最近寄生虫耐药性的证据。用伊维菌素减少盘尾丝虫病的运动也面临着类似的挑战。这项SBIR提案的长期目标是开发迫切需要的巨丝杀虫化合物，这些化合物可以消除成体寄生虫库并保护现有药物免受广泛耐药性的发展。