Optimizing Inhibitors of T. gondii ENR

优化弓形虫 ENR 抑制剂

• 批准号: 8445246
• 负责人: Rima L McLeod
• 金额: $ 80.56万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8445246
• 关键词: Achievement; Affect; Anthrax disease; Bacillus (bacterium); Binding; Binding Sites; Biological Assay; Biological Availability; Bioterrorism; Categories; Cells; Complex; Computer Simulation; Coupled; Crystallization; Data; Development; Enzymes; Growth; Hand; Hybrids; Immune; In Vitro; Infection; Instruction; Knowledge; Lead; Libraries; Medicine; Modification; Molecular; Mus; Nature; Organism; Parasites; Pathway interactions; Permeability; Pharmaceutical Chemistry; Plasmodium; Principal Investigator; Reagent; Recombinants; Resistance; Safety; Solubility; Structure; Testing; Toxic effect; Toxoplasma; Toxoplasma gondii; Toxoplasmosis; Triclosan; Work; absorption; antimicrobial; base; catalyst; design; enoyl reductase; enzyme pathway; fatty acid biosynthesis; improved; in vivo; inhibitor/antagonist; mortality; novel; pathogen; pharmacophore; programs; scaffold; screening; success; tissue culture; working group

DESCRIPTION (provided by applicant): Toxoplasma gondii infections cause suffering and mortality in those congenitally infected or immune compromised. Easily genetically manipulated and disseminated in nature, this parasite is considered a category B bioterrorism pathogen. Improved, new antimicrobials are greatly needed to treat this infection. Type 2 fatty acid biosynthesis (fas), structurally different from mammalian type 2 fas, is a validated target essential for Toxoplasma gondii growth in vitro and survival of the parasite in mice. Enoyl reductase (ENR) is an enzyme in the type 2 fas biosynthetic pathway. Triclosan and two newly synthesized lead compounds, in nanomolar amounts, inhibit T. gondii ENR activity and in low micromolar amounts inhibit T. gondii growth in vitro. Triclosan also inhibits T. gondii growth in mice. Structures of T. gondii ENR complexed with inhibitors have been solved. Unique features of T. gondii ENR will be used to develop novel tight binding inhibitors. With these data in hand, and to be acquired during the work proposed, using a structure based design approach, it will be possible to modify and thereby optimize and create a novel tight binding inhibitor of T. gondii ENR. We will create a new compound based on theoretical information derived from analyses of lead inhibitory compounds' and ENR structures and their interactions coupled with enzyme and parasite inhibitory data. Information we have in hand from our preliminary analyses of triclosan and other novel compounds we have synthesized and tested in enzyme, in vitro parasite and co-crystallization and structure analyses will inform this structure-based ENR inhibitor design program. If new leads are needed, as an additional alternative approach, a Catalyst-based pharmacophore approach will be used. Inhibitors will undergo rounds of modification and testing to find more druggable ENR inhibitors with better ADMET profiles. As new inhibitory compounds are identified, their fit to the enzyme binding site will be compared, and hybrid structures that incorporate desirable features from different molecular scaffolds will be created to optimize activity. ClogP, or PSA, and Caco2 cell permeability will be optimized. It is likely that either a completely new molecule will be created or that the phenyl rings of triclosan will be converted to heterocycles having improved solubility, activity, and safety. RELEVANCE (See instructions): Development of inhibitors useful as medicines will be progressed by modification of lead compounds to obviate potential problems with resistance and toxicity and optimize solubility, pharmokinetics, and bioavailability. This work will create a greatly needed novel class of compound to treat toxoplasmosis.

描述（由申请人提供）：弓形虫感染会导致先天性感染或免疫受损的人遭受痛苦和死亡。这种寄生虫很容易在自然界中进行基因操纵和传播，被认为是 B 类生物恐怖主义病原体。治疗这种感染非常需要改进的新型抗菌药物。 2 型脂肪酸生物合成 (fas) 在结构上与哺乳动物 2 型 fas 不同，是弓形虫体外生长和小鼠体内寄生虫生存所必需的经过验证的靶标。烯酰还原酶 (ENR) 是 2 型 fas 生物合成途径中的一种酶。三氯生和两种新合成的先导化合物，在纳摩尔量下，可抑制弓形虫 ENR 活性，在低微摩尔量下，可在体外抑制弓形虫生长。三氯生还可以抑制小鼠体内弓形虫的生长。弓形虫 ENR 与抑制剂复合的结构已被解析。弓形虫 ENR 的独特特征将用于开发新型紧密结合抑制剂。有了这些数据，并且在拟议的工作期间获得这些数据，使用基于结构的设计方法，将有可能修改并从而优化和创建弓形虫 ENR 的新型紧密结合抑制剂。我们将根据对先导抑制化合物和 ENR 结构及其相互作用以及酶和寄生虫抑制数据的分析得出的理论信息来创建一种新化合物。我们从对三氯生和其他新化合物的初步分析中获得的信息，以及我们在酶、体外寄生虫、共结晶和结构分析中合成和测试的信息，将为基于结构的 ENR 抑制剂设计程序提供信息。如果需要新的先导化合物，作为额外的替代方法，将使用基于催化剂的药效基团方法。抑制剂将经过多轮修改和测试，以找到更多具有更好 ADMET 特征的可药物化 ENR 抑制剂。当新的抑制化合物被识别时，将比较它们与酶结合位点的适合度，并且将创建结合不同分子支架的所需特征的混合结构以优化活性。 ClogP（或 PSA）和 Caco2 细胞通透性将得到优化。很可能会产生一种全新的分子，或者三氯生的苯环将转化为具有改善的溶解度、活性和安全性的杂环。相关性（参见说明）：可用作药物的抑制剂的开发将通过修饰先导化合物来进行，以避免潜在的耐药性和毒性问题，并优化溶解度、药代动力学和生物利用度。这项工作将创造出一种急需的新型化合物来治疗弓形虫病。

项目成果

Spiroindolone that inhibits PfATPase4 is a potent, cidal inhibitor of Toxoplasma gondii tachyzoites in vitro and in vivo.

抑制 PfATPase4 的螺吲哚酮是体外和体内弓形虫速殖子的有效杀灭抑制剂。

• 发表时间: 2014
• 影响因子: 4.9
• 作者: Zhou, Ying;Fomovska, Alina;Muench, Stephen;Lai, Bo;Mui, Ernest;McLeod, Rima
• 通讯作者: McLeod, Rima

Novel type II fatty acid biosynthesis (FAS II) inhibitors as multistage antimalarial agents.

新型 II 型脂肪酸生物合成 (FAS II) 抑制剂作为多级抗疟药。

• 发表时间: 2013-03
• 影响因子: 3.4
• 作者: Schrader, Florian C;Glinca, Serghei;Sattler, Julia M;Dahse, Hans;Afanador, Gustavo A;Prigge, Sean T;Lanzer, Michael;Mueller, Ann;Klebe, Gerhard;Schlitzer, Martin
• 通讯作者: Schlitzer, Martin

Synthesis, biological evaluation, and structure-activity relationships of N-benzoyl-2-hydroxybenzamides as agents active against P. falciparum (K1 strain), Trypanosomes, and Leishmania.

N-苯甲酰基-2-羟基苯甲酰胺作为抗恶性疟原虫（K1 株）、锥虫和利什曼原虫活性剂的合成、生物学评价和结构活性关系。

• 发表时间: 2012-04-12
• 影响因子: 7.3
• 作者: Stec, Jozef;Huang, Qingqing;Pieroni, Marco;Kaiser, Marcel;Fomovska, Alina;Mui, Ernest;Witola, William H.;Bettis, Samuel;McLeod, Rima;Brun, Reto;Kozikowski, Alan P.
• 通讯作者: Kozikowski, Alan P.

Modification of triclosan scaffold in search of improved inhibitors for enoyl-acyl carrier protein (ACP) reductase in Toxoplasma gondii.

修饰三氯生支架以寻找改进的弓形虫烯酰基载体蛋白（ACP）还原酶抑制剂。

• 发表时间: 2013-07
• 影响因子: 3.4
• 作者: Stec, Jozef;Fomovska, Alina;Afanador, Gustavo A;Muench, Stephen P;Zhou, Ying;Lai, Bo;El Bissati, Kamal;Hickman, Mark R;Lee, Patty J;Leed, Susan E;Auschwitz, Jennifer M;Sommervile, Caroline;Woods, Stuart;Roberts, Craig W;Rice, David;Pr
• 通讯作者: Pr

The benzimidazole based drugs show good activity against T. gondii but poor activity against its proposed enoyl reductase enzyme target.

基于苯并咪唑的药物对弓形虫表现出良好的活性，但对其提议的烯酰还原酶靶点活性较差。

• 发表时间: 2014-02-01
• 影响因子: 2.7
• 作者: Wilkinson, Craig;McPhillie, Martin J;Zhou, Ying;Woods, Stuart;Afanador, Gustavo A;Rawson, Shaun;Khaliq, Farzana;Prigge, Sean T;Roberts, Craig W;Rice, David W;McLeod, Rima;Fishwick, Colin W;Muench, Stephen P
• 通讯作者: Muench, Stephen P