Mechanisms of varied sensitivity of P. falciparum field isolates to the antimalarial drug pipeline

恶性疟原虫现场分离株对抗疟药物管道的不同敏感性机制

• 批准号: 10734407
• 负责人: Philip Jon Rosenthal
• 金额: $ 73.02万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-22 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10734407
• 关键词: Africa; African; Antimalarials; Area; Artemisinins; Burkina Faso; Coculture Techniques; Collaborations; Combined Modality Therapy; Communicable Diseases; Complex; Data; Development; Drug Combinations; Drug Targeting; Drug resistance; Falciparum Malaria; Funding; Genes; Genetic Polymorphism; Genotype; Goals; Growth; Individual; Infection; Laboratories; Laboratory Study; Lead; Link; Malaria; Mediator; Medicine; Molecular; Mutation; New Agents; Parasites; Pattern; Pharmaceutical Preparations; Phenotype; Plasmodium falciparum; Predisposition; Property; Proteins; Resistance; Role; Seasons; Site; Southeastern Asia; Technology; Testing; Time; Toxic effect; Treatment Efficacy; Uganda; antagonist; drug action; drug discovery; drug sensitivity; fitness; genome sequencing; improved; interest; malaria transmission; next generation; novel; resistance mechanism; synergism; transmission process; whole genome

Project Summary With widespread resistance of malaria parasites to older agents, artemisinin-based combination therapies are the mainstay for antimalarial treatment, but efficacy is threatened by resistance to artemisinins and partner drugs. New antimalarial drugs are needed. Spearheaded by the Medicines for Malaria Venture (MMV), a robust pipeline of new lead antimalarial compounds is under development. However, resistance to new agents can be anticipated. In a number of cases drug targets and resistance mechanisms have been identified, but studies have focused on small numbers of P. falciparum laboratory strains. It is critical also to consider sensitivity to lead antimalarials of fresh P. falciparum field isolates, especially isolates from Africa. With these data, genotypic and additional phenotypic analysis can allow identification of mechanisms underlying varied susceptibility, as we have described for multiple compounds to date, informing optimal development of next- generation combination antimalarials. This application seeks continued funding for a project characterizing susceptibilities of malaria parasites isolated in Uganda and Burkina Faso to lead antimalarials under development. We offer state-of-the-art assessment of ex vivo P. falciparum susceptibilities linked to high throughput genotypic characterization to improve our understanding of mechanisms of drug action and resistance. As supported by data generated to date, we hypothesize that African P. falciparum isolates will demonstrate varied sensitivity to lead antimalarial compounds, and that characterization of genotypes and phenotypes of field isolates will identify shared resistance mechanisms and guide selection of optimal combination therapies. These results will be of great value as we develop next-generation combination antimalarials and continue efforts toward discovery of additional novel compounds. Our specific aims will be: (1) to characterize ex vivo susceptibilities to lead antimalarial compounds of P. falciparum field isolates, (2) to characterize genotypes to identify mediators of decreased susceptibility in field isolates to lead antimalarial compounds, and (3) to characterize phenotypes of drug sensitivity outliers to elucidate mechanisms of resistance of lead antimalarial compounds. Our studies will define resistance mechanisms for the most important new compounds under development as antimalarials and inform choices of optimal antimalarial drug combinations and the direction of continued drug discovery efforts.

项目摘要 由于疟疾寄生虫对较老的药剂普遍具有抗药性， 青蒿素是抗疟治疗的主要药物，但疗效受到青蒿素耐药性的威胁， 毒品需要新的抗疟疾药物。由疟疾新药研发公司（MMV）牵头， 目前正在开发新的抗疟先导化合物。然而，对新药剂的抵抗 可以预期。在许多情况下，已经确定了药物靶点和耐药机制，但 研究集中在少量的恶性疟原虫实验室菌株上。同样重要的是， 新鲜的恶性疟原虫野外分离株，特别是来自非洲的分离株对铅抗疟药的敏感性。与这些 数据、基因型和额外的表型分析可以允许鉴定各种 敏感性，因为我们已经描述了多种化合物的日期，通知下一个最佳的发展- 代组合抗疟药。该申请寻求继续资助一个项目， 在乌干达和布基纳法索分离的疟疾寄生虫对抗疟药物的敏感性 发展我们提供了最先进的评估离体恶性疟原虫易感性与高 通量基因型表征，以提高我们对药物作用机制的理解， 阻力根据迄今为止产生的数据，我们假设非洲恶性疟原虫分离株将 显示出对主要抗疟化合物的不同敏感性，以及基因型和 田间分离物的表型将确定共同的抗性机制，并指导选择最佳的 联合治疗这些结果将是非常有价值的，因为我们开发下一代的组合 抗疟药，并继续努力发现其他新的化合物。我们的具体目标是： (1)为了表征恶性疟原虫野外分离株对先导抗疟化合物的离体亲和性，（2） 描述基因型以确定田间分离株对铅抗疟药敏感性降低的介质 化合物，和（3）表征药物敏感性异常值的表型，以阐明药物敏感性异常的机制。 抗疟化合物的耐药性。我们的研究将为大多数人定义耐药机制。 正在开发重要新化合物作为抗疟药，并为最佳抗疟药的选择提供信息 联合用药和继续药物发现努力的方向。

项目成果

The antimalarial MMV688533 provides potential for single-dose cures with a high barrier to Plasmodium falciparum parasite resistance.

• DOI: 10.1126/scitranslmed.abg6013
• 发表时间: 2021-07-21
• 期刊: Science translational medicine
• 影响因子: 17.1
• 作者: Murithi JM;Pascal C;Bath J;Boulenc X;Gnädig NF;Pasaje CFA;Rubiano K;Yeo T;Mok S;Klieber S;Desert P;Jiménez-Díaz MB;Marfurt J;Rouillier M;Cherkaoui-Rbati MH;Gobeau N;Wittlin S;Uhlemann AC;Price RN;Wirjanata G;Noviyanti R;Tumwebaze P;Cooper RA;Rosenthal PJ;Sanz LM;Gamo FJ;Joseph J;Singh S;Bashyam S;Augereau JM;Giraud E;Bozec T;Vermat T;Tuffal G;Guillon JM;Menegotto J;Sallé L;Louit G;Cabanis MJ;Nicolas MF;Doubovetzky M;Merino R;Bessila N;Angulo-Barturen I;Baud D;Bebrevska L;Escudié F;Niles JC;Blasco B;Campbell S;Courtemanche G;Fraisse L;Pellet A;Fidock DA;Leroy D
• 通讯作者: Leroy D

Discovery and Preclinical Pharmacology of INE963, a Potent and Fast-Acting Blood-Stage Antimalarial with a High Barrier to Resistance and Potential for Single-Dose Cures in Uncomplicated Malaria.

• DOI: 10.1021/acs.jmedchem.1c01995
• 发表时间: 2022-03-10
• 期刊: JOURNAL OF MEDICINAL CHEMISTRY
• 影响因子: 7.3
• 作者: Taft, Benjamin R.;Yokokawa, Fumiaki;Kirrane, Tom;Mata, Anne-Catherine;Huang, Richard;Blaquiere, Nicole;Waldron, Grace;Zou, Bin;Simon, Oliver;Vankadara, Subramanyam;Chan, Wai Ling;Ding, Mei;Sim, Sandra;Straimer, Judith;Guiguemde, Armand;Lakshminarayana, Suresh B.;Jain, Jay Prakash;Bodenreider, Christophe;Thompson, Christopher;Lanshoeft, Christian;Shu, Wei;Fang, Eric;Qumber, Jafri;Chan, Katherine;Pei, Luying;Chen, Yen-Liang;Schulz, Hanna;Lim, Jessie;Abas, Siti Nurdiana;Ang, Xiaoman;Liu, Yugang;Angulo-Barturen, Inigo;Belen Jimenez-Diaz, Maria;Javier Gamo, Francisco;Crespo-Fernandez, Benigno;Rosenthal, Philip J.;Cooper, Roland A.;Tumwebaze, Patrick;Campos Aguiar, Anna Caroline;Campo, Brice;Campbell, Simon;Wagner, Jurgen;Diagana, Thierry T.;Sarko, Christopher
• 通讯作者: Sarko, Christopher

Development of a Highly Selective Plasmodium falciparum Proteasome Inhibitor with Anti-malaria Activity in Humanized Mice.

• DOI: 10.1002/anie.202015845
• 发表时间: 2021-04-19
• 期刊: Angewandte Chemie (International ed. in English)
• 作者: Zhan W;Zhang H;Ginn J;Leung A;Liu YJ;Michino M;Toita A;Okamoto R;Wong TT;Imaeda T;Hara R;Yukawa T;Chelebieva S;Tumwebaze PK;Lafuente-Monasterio MJ;Martinez-Martinez MS;Vendome J;Beuming T;Sato K;Aso K;Rosenthal PJ;Cooper RA;Meinke PT;Nathan CF;Kirkman LA;Lin G
• 通讯作者: Lin G

Structure-Activity Relationship Studies of Antimalarial Plasmodium Proteasome Inhibitors─Part II.

抗疟疟原虫蛋白酶体抑制剂的构效关系研究——第二部分。

• DOI: 10.1021/acs.jmedchem.2c01651
• 发表时间: 2023
• 期刊: Journal of medicinal chemistry
• 影响因子: 7.3
• 作者: Zhang,Hao;Ginn,John;Zhan,Wenhu;Leung,Annie;Liu,YiJ;Toita,Akinori;Okamoto,Rei;Wong,Tzu-Tshin;Imaeda,Toshihiro;Hara,Ryoma;Michino,Mayako;Yukawa,Takafumi;Chelebieva,Sevil;Tumwebaze,PatrickK;Vendome,Jeremie;Beuming,Thijs;Sato
• 通讯作者: Sato

Proteasome inhibitors: The next generation of antimalarial drugs?

蛋白酶体抑制剂：下一代抗疟药？

• DOI: 10.1016/j.chembiol.2023.04.013
• 发表时间: 2023
• 期刊: Cell chemical biology
• 影响因子: 8.6
• 作者: Rosenthal,PhilipJ