Inhibitors of Human Factor XIIIa as New Anticoagulants

人类因子 XIIIa 抑制剂作为新型抗凝剂

基本信息

批准号：
10629057
负责人：
Rami A Al-Horani
金额：
$ 14.9万
依托单位：
XAVIER UNIVERSITY OF LOUISIANA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-17 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10629057
关键词：
Active Sites Affect African American population Alkanesulfonates Allosteric Site Animal Model Anions Anticoagulants Antiplasmin Area Binding Binding Sites Biochemical Biological Biological Assay Blood Blood Coagulation Factor Blood coagulation Body Weight decreased Cardiovascular Diseases Cell Line Cessation of life Clinical Coagulation Process Contracts Data Reporting Deposition Disease Economics Erythrocytes Evaluation Exhibits Factor XIIIa Factor Xa Fibrin Fibrinogen Fibrinolysis Future Genetic Polymorphism Glutaminase Glycosaminoglycans Goals Hemorrhage Hemostatic function Heterozygote Human In Vitro Investigation Lead Libraries Mediating Meta-Analysis Minority Morbidity - disease rate Mus Mutation NOR Mouse Naphthalene Nature Normal Range Pathologic Pathology Patients Peptide Hydrolases Persons Pharmacologic Substance Phenocopy Physiology Plasmin Polymers Prevalence Prevention Property Public Health Recurrence Recurrent disease Regulation Research Risk Role Route Serine Protease Specificity Structure Therapeutic Thrombin Thrombus Transglutaminases Venous Wild Type Mouse chemical synthesis clinically relevant crosslink design economic impact effective therapy experimental study improved inhibitor innovation interdisciplinary approach mimetics molecular modeling mouse model new technology new therapeutic target novel strategies pharmacologic polymerization prevent therapeutic target tool venous thromboembolism

项目摘要

SUMMARY The long-term goal of our research is to develop effective anticoagulants that do not cause bleeding complications to be safely used for a wider range of patients suffering from venous thromboembolism (VTE). This project aims at developing effective and safer anticoagulants by targeting human factor XIIIa (FXIIIa). All available anticoagulants are associated with a significant risk of bleeding. Current anticoagulants inhibit directly or indirectly thrombin and/or factor Xa. This is the reason why they are clinically effective, but it is also the reason why they cause bleeding. The central hypothesis is that inhibiting FXIIIa will result in effective protection against VTE without causing significant bleeding. In contrast to all other clotting factors which are serine proteases, FXIIIa is a transglutaminase that catalyzes the last step in the coagulation process. This unique biochemical aspect of FXIIIa has been under investigation in the context of VTE. In vitro experiments showed that treating normal human blood with an experimental transglutaminase inhibitor increases RBC extrusion from contracting clots and reduces clot size. Various studies also suggested that a certain FXIIIa polymorphism provides significant protection against VTE and that heterozygous FXIII-deficient mice do not show signs of excessive bleeding. Thus, FXIIIa may serve as a potential therapeutic target to develop a new effective treatment for VTE that does not significantly increase the bleeding risk. Despite this promise, very few FXIIIa inhibitors have been developed, all of which lack substantial selectivity as they can also inhibit other transglutaminases by blocking their active sites. Thus, I have proposed sulfonated non-saccharide glycos- aminoglycan mimetics as a platform to develop FXIIIa inhibitors. The sulfonated molecules are to inhibit FXIIIa potently and selectively through allosteric modulation. In preliminary studies, I discovered two sulfonated molecules that inhibit FXIIIa with low micromolar potencies. The two molecules inhibited FXIIIa-mediated polymerization of fibrin. The two molecules did not affect other clotting factors and did not affect the viability of three cell lines. Molecular modeling projected a plausible binding site for these molecules on FXIIIa. In this proposal, I specifically aim at using a multidisciplinary approach to establish the principles of effective and selective inhibition of FXIIIa by sulfonated molecules. I will synthesize advanced libraries of two “lead” molecules and evaluate their biochemical and biological potential as anticoagulants. The proposal is innovative because i) it puts forward a novel approach to overcome the limitations of current VTE treatment; ii) it exploits a multidisciplinary approach to investigate the specific aims; and iii) it introduces new technologies with proprietary structural and mechanistic aspects. The project is also significant because it will: i) identify 2-3 potent, specific, and allosteric FXIIIa inhibitors for future evaluation in animal models of VTE and bleeding; ii) offer new tools to better understand FXIIIa role in the coagulation physiology and pathology; iii) investigate an alternative approach to modulate FXIIIa via allostery to pave the way to transforming anticoagulants.

概括我们研究的长期目标是开发不会引起出血的有效抗凝剂并发症可安全用于更广泛的静脉血栓栓塞（VTE）患者。该项目旨在通过针对人类因子 XIIIa (FXIIIa) 开发有效且更安全的抗凝剂。现有的抗凝剂与出血的显着风险相关。或间接凝血酶和/或Xa因子，这就是它们在临床上有效的原因，但这也是它们的原因。它们导致出血的原因主要是抑制 FXIIIa 会产生有效的效果。与所有其他凝血因子相比，可预防 VTE，且不会引起严重出血。 FXIIIa 是一种丝氨酸蛋白酶，是一种转谷氨酰胺酶，可催化凝血过程的最后一步。 FXIIIa 独特的生化特性已在体外 VTE 实验中得到研究。表明用实验性转谷氨酰胺酶抑制剂处理正常人血液会增加红细胞各种研究还表明，某些 FXIIIa 可以从收缩的血块中挤出并减小血块尺寸。多态性对 VTE 具有显着的保护作用，而杂合 FXIII 缺陷型小鼠则不能显示出过度出血的迹象，因此，FXIIIa 可能作为开发新药物的潜在治疗靶点。尽管有这样的承诺，但治疗 VTE 的方法却很少，不会显着增加出血风险。 FXIIIa 抑制剂已被开发出来，但所有这些抑制剂都缺乏实质性选择性，因为它们还可以抑制其他药物通过阻断转谷氨酰胺酶的活性位点，我提出了磺化非糖糖。氨基聚糖模拟物作为开发 FXIIIa 抑制剂的平台磺化分子旨在抑制 FXIIIa。在初步研究中，我发现了两种磺化物质。以低微摩尔效力抑制 FXIIIa 的分子这两种分子抑制 FXIIIa 介导的。纤维蛋白的聚合不会影响其他凝血因子，也不会影响细胞的活力。分子模型在 FXIIIa 上预测了这些分子的合理结合位点。提案中，我的具体目标是使用多学科方法来建立有效性和有效性的原则通过磺化分子选择性抑制 FXIIIa 我将合成两个“先导”的高级文库。分子并评估其作为抗凝剂的生化和生物潜力。创新是因为 i) 它提出了一种克服当前 VTE 治疗局限性的新方法；它利用多学科方法来研究具体目标；并且 iii) 引入了新技术；该项目还具有专有的结构和机械方面的意义，因为它将： i) 确定 2-3 种强效、特异性和变构 FXIIIa 抑制剂，用于未来在 VTE 和出血动物模型中进行评估； ii) 提供新工具以更好地了解 FXIIIa 在凝血生理学和病理学中的作用 iii) 研究；另一种通过变构调节 FXIIIa 的方法，为转变抗凝剂铺平道路。