Novel Therapeutics to Target Parasite Cytochrome bc1

针对寄生虫细胞色素 bc1 的新疗法

• 批准号: 10665031
• 负责人: Michael Kevin RISCOE
• 金额: $ 62.01万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-15 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10665031
• 关键词: Address; Adherence; Animal Model; Anopheles Genus; Antimalarials; Area; Biological Availability; Blood; Blood Circulation; Case Management; Chemoprevention; Chemoprotection; Chloroguanide; Clinical; Combination Drug Therapy; Complex; Culicidae; Cytochrome bc1 Complex; Cytochromes b; Data; Development; Digit structure; Disease model; Drug Combinations; Drug Kinetics; Drug Targeting; Dust; Elements; Enzymes; Exhibits; Exposure to; Formulation; Genes; Genetic; Goals; Human; In Vitro; Infection; Infection prevention; Intestines; Journals; Knowledge; Lead; Life Cycle Stages; Liquid substance; Liver; Malaria; Malaria prevention; Mammalian Cell; Medicine; Metabolic; Midgut; Mitochondria; Modeling; Multi-Drug Resistance; Multienzyme Complexes; Mus; Mutation; Oral; Parasites; Parasitology; Parents; Patients; Performance; Pharmaceutical Preparations; Phenotype; Plasmodium; Plasmodium falciparum; Population; Positioning Attribute; Predisposition; Prodrugs; Property; Prophylactic treatment; Publishing; Qi; Quinolones; Regimen; Resistance; Resistance development; Risk; Rodent Model; Seasons; Series; Side; Site; Solubility; Structure; Testing; United States National Institutes of Health; Update; Work; absorption; atovaquone; compliance behavior; crystallinity; cytotoxicity; design; dimer; improved; in vitro activity; in vivo; in vivo evaluation; inhibitor; malaria infection; monomer; nanomolar; novel; novel therapeutics; pharmacologic; pill; pre-clinical; prevent outbreaks; prophylactic; protein structure; resistance frequency; resistant Plasmodium falciparum; resistant strain; scaffold; small molecule libraries; toxicant; transmission blocking; transmission process; vector mosquito; water solubility

Project Summary / Abstract The Medicines for Malaria Venture (MMV) recently published a “roadmap” for the types of medicines that are needed to support the long-term goal of malaria elimination and eradication. The roadmap consists of a wish list of target candidate profiles (TCP) and medicines (target product profiles, i.e., TPP). With the most recent revision to the anti-malarial target candidates and product profiles the MMV highlighted the need for identifying new rapid acting medicines for active case management while other drugs are needed for chemo-protection and chemo- prevention with long-acting molecules, and/or parenteral formulations (i.e., TCP-2) (Burrows, JN et al., 2017, Malaria Journal, 16:26). According to their updated roadmap new drugs are needed to protect populations entering areas of high endemicity during the final stages of malaria elimination. And drugs with causal liver- stage activity are needed for chemoprevention to prevent infection or outbreak of resistance during malarial seasons. This TCP has been modeled on the combination drug atovaquone + proguanil. As a potent and selective inhibitor of the parasite’s cytochrome bc1 complex ELQ-300 selectively targets Plasmodium falciparum in the blood and liver stages and even kills parasites developing in the midgut of the mosquito vector. Unlike atovaquone, ELQ-300 is a selective inhibitor of the Qi site of the target enzyme complex. With support from the NIH and US DOD we have been successful in developing an oral formulation of prodrug ELQ-331 for use in humans for weekly prophylaxis against malaria. In the present application we seek NIH support for work to develop ELQ derivatives that more effectively and comprehensively inhibit the parasite cytochrome bc1 complex. Advanced designs for improved ELQ constructs are supported by preliminary data provided with the application as well as our extensive knowledge of Endochin-Like Quinolone derivatives as inhibitors of the Plasmodium falciparum cytochrome bc1 Qo or Qi sites. Superior molecules will advance through a down-selection test cascade for assessment of selective potency and lack of mammalian cytotoxicity, metabolic stability, solubility in simulated intestinal fluids, resistance propensity and mode of action as well as efficacy against blood and liver stage malaria in mice. Prodrugs of superior molecules will be explored to assess for enhancement of oral bioavailability and antimalarial performance over parent molecules.

项目概要/摘要 疟疾药物风险投资公司 (MMV) 最近发布了一份针对疟疾药物类型的“路线图” 需要支持消除和根除疟疾的长期目标。路线图由愿望清单组成 目标候选概况 (TCP) 和药品（目标产品概况，即 TPP）。随着最新的修订 对于抗疟疾候选目标和产品概况，MMV 强调需要确定新的快速 积极的病例管理需要药物，而化疗保护和化疗则需要其他药物 使用长效分子和/或肠胃外制剂（即 TCP-2）进行预防（Burrows, JN 等人，2017 年， 疟疾杂志，16:26）。根据他们更新的路线图，需要新药来保护人群 在消除疟疾的最后阶段进入高流行地区。以及与肝脏相关的药物- 化学预防需要阶段性活动，以防止疟疾期间的感染或耐药性的爆发 季节。该 TCP 以阿托伐醌 + 氯胍组合药物为模型。 作为寄生虫细胞色素 bc1 复合物的有效选择性抑制剂，ELQ-300 选择性靶向 恶性疟原虫在血液和肝脏阶段甚至杀死在中肠中发育的寄生虫 蚊子载体。与阿托伐醌不同，ELQ-300 是目标酶复合物 Qi 位点的选择性抑制剂。 在 NIH 和美国国防部的支持下，我们成功开发了前药的口服制剂 ELQ-331 用于人类每周预防疟疾。在本申请中，我们寻求 NIH 支持开发更有效、更全面抑制寄生虫的ELQ衍生物的工作 细胞色素 bc1 复合物。初步数据支持改进 ELQ 结构的先进设计 提供了该应用程序以及我们对类内啡肽喹诺酮衍生物的广泛知识，例如 恶性疟原虫细胞色素 bc1 Qo 或 Qi 位点的抑制剂。优秀的分子将通过 用于评估选择性效力和缺乏哺乳动物细胞毒性的下调选择测试级联， 代谢稳定性、模拟肠液中的溶解度、耐药倾向和作用方式以及 对小鼠血液期和肝期疟疾的功效。将探索优质分子的前药来评估 与母体分子相比，可增强口服生物利用度和抗疟性能。

项目成果

Endochin-like quinolone-300 and ELQ-316 inhibit Babesia bovis, B. bigemina, B. caballi and Theileria equi.

• DOI: 10.1186/s13071-020-04487-3
• 发表时间: 2020-12-03
• 期刊: Parasites & vectors
• 影响因子: 3.2
• 作者: Silva MG;Bastos RG;Stone Doggett J;Riscoe MK;Pou S;Winter R;Dodean RA;Nilsen A;Suarez CE
• 通讯作者: Suarez CE

Radical cure of experimental babesiosis in immunodeficient mice using a combination of an endochin-like quinolone and atovaquone.

• DOI: 10.1084/jem.20151519
• 发表时间: 2016-06-27
• 期刊: The Journal of experimental medicine
• 作者: Lawres LA;Garg A;Kumar V;Bruzual I;Forquer IP;Renard I;Virji AZ;Boulard P;Rodriguez EX;Allen AJ;Pou S;Wegmann KW;Winter RW;Nilsen A;Mao J;Preston DA;Belperron AA;Bockenstedt LK;Hinrichs DJ;Riscoe MK;Doggett JS;Ben Mamoun C
• 通讯作者: Ben Mamoun C

A New Scalable Synthesis of ELQ-300, ELQ-316, and other Antiparasitic Quinolones.

• DOI: 10.1021/acs.oprd.1c00099
• 发表时间: 2021-08-20
• 期刊: Organic process research & development
• 影响因子: 3.4
• 作者: Pou S;Dodean RA;Frueh L;Liebman KM;Gallagher RT;Jin H;Jacobs RT;Nilsen A;Stuart DR;Doggett JS;Riscoe MK;Winter RW
• 通讯作者: Winter RW

Improving solubility and oral bioavailability of a novel antimalarial prodrug: comparing spray-dried dispersions with self-emulsifying drug delivery systems.

• DOI: 10.1080/10837450.2020.1725893
• 发表时间: 2020-06
• 期刊: Pharmaceutical development and technology
• 影响因子: 3.4
• 作者: Potharaju S;Mutyam SK;Liu M;Green C;Frueh L;Nilsen A;Pou S;Winter R;Riscoe MK;Shankar G
• 通讯作者: Shankar G

2-hydroxy-1,4-naphthoquinones with 3-alkyldiarylether groups: synthesis and Plasmodium falciparum inhibitory activity.

具有 3-烷基二芳基醚基团的 2-羟基-1,4-萘醌：合成和恶性疟原虫抑制活性。

• DOI: 10.4155/fmc-2022-0127
• 发表时间: 2022
• 期刊: Future medicinal chemistry
• 影响因子: 4.2
• 作者: Berg,Amanda;Swartchick,ChelseaB;Forrest,Noah;Chavarria,Matthew;Deem,MadeleineC;Sillin,AlysonN;Li,Yuexin;Riscoe,TeresaM;Nilsen,Aaron;Riscoe,MichaelK;Wood,WarrenJl
• 通讯作者: Wood,WarrenJl