Potent and Safe Inhibitors of B. anthracis Lethal Factor

炭疽芽孢杆菌致死因子的有效且安全的抑制剂

• 批准号: 7565963
• 负责人: Maurizio Pellecchia
• 金额: $ 68.04万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-01 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7565963
• 关键词: Active Sites; Adverse effects; Aerobic; Affect; Alveolar Macrophages; Anthrax disease; Antibiotics; Apoptosis; Architecture; Bacillus anthracis; Bacteria; Bacterial Antibiotic Resistance; Biological; Blood Circulation; Breathing; Cell Death; Cells; Chemistry; Cleaved cell; Collaborations; Complement; Computing Methodologies; Country; Cultured Cells; Development; Disease; Effectiveness; Engineering; Enzymes; Epidemic; Fluorescence Resonance Energy Transfer; Human; Immune system; In Vitro; Infection; Institutes; Lead; Matrix Metalloproteinases; Metalloproteases; Mitogen-Activated Protein Kinase Kinases; Patients; Peptide Hydrolases; Peptides; Pharmaceutical Chemistry; Pharmaceutical Preparations; Play; Property; Prophylactic treatment; Recovery; Reporting; Reproduction spores; Research; Research Proposals; Role; Safety; Series; Shock; Signal Transduction; Signaling Protein; Site; Structure; Techniques; Testing; Therapeutic; Toxin; Vaccines; anthrax lethal factor; base; design; drug development; efficacy testing; improved; in vivo; inhibitor/antagonist; interdisciplinary approach; lymph nodes; macrophage; novel; prevent; scaffold; tool

Potent and safe inhibitors of anthrax lethal factor Anthrax is primarily a disease of herbivores caused by gram-positive, aerobic, spore-forming B.anthracis^ Humans are accidental hosts and cases of anthrax have been reported from almost every country. The existence of antibiotic:resistant bacterial strains that arise either naturally or through deliberate engineering further emphasizes the need for alternative therapeutic approaches. Vaccines are typically problematic for prophylactic treatment of large civilian groups, because the inevitable side-effects must somehow be weighed against the chances of epidemics. The progression of anthrax depends on a secreted toxin, LF (lethal factor), a protease that plays a key role in inducing apoptosis of macrophages by cleaving the specific human cell signaling proteins. Anti-toxin approaches that treat infection therapeutically by targeting LF should therefore provide a promising alternative or complement to antibiotics and vaccines. However, further research on the role of LF for the development of Anthrax therapies is hampered by the lack of potent and selective pharmacological tools. Based on these observations, a central hypothesis in our research proposal is that small organic molecules capable of blocking or reducing the activity of LF would render B. Anthracis avirulent, making Anthrax disease treatable in combination with conventional antibiotics. We propose here to develop a novel series of LF inhibitors based on a multidisciplinary approach that involves fragment-based lead design, medicinal chemistry and iterative .structure-based optimizations. In vitro and finally in vivo efficacy studies will be conducted on the most promising agents. Our three specific aims are: (I) To accomplish structure-based design of potent inhibitors capable of selectively blocking the LF cleavage activity without affecting human MMP enzymes. (II) To increase, through derivatizations and iterations, the selectivity, potency and safety of the selected inhibitor scaffolds. (Ill) To test the effectiveness of fine-tuned compounds in protecting the cultured cells and to identify the drug-like lead inhibitors) of LF for continued drug refinement, and in.vivo efficacy studies. Relevance Inhaling B.anthracis spores causes inhalation anthrax, the most deadly form of the disease. As the disease progresses, the spores, engulfed by alveolar macrophages, germinate to generate the bacteria, which spread through the lymph nodes to the bloodstream, eventually leading to systemic fatal shock. To successfully accomplish invasion, B.anthracis has to weaken the host immune system. LF (lethal factor) is a secreted toxin that plays a key role in inducing apoptosis (cell-death) of macrophages by cleaving the specific human cell signaling proteins. Conversely, specific inhibition of LF should prevent macrophage cell- death and promote termination of the disease. The inhibitors of LF we will develop, most likely when used in combination with antibiotics, should facilitate and assure the recovery of patients who harbor the disease.

炭疽致死因素的有效且安全的抑制剂 炭疽主要是由革兰氏阳性，有氧，形成孢子的b.Anthracis^引起的草食动物疾病 人类是偶然的宿主，几乎每个国家都报道了炭疽病病例。这 抗生素的存在：自然或通过故意工程形成的抗性细菌菌株 进一步强调了对替代治疗方法的需求。疫苗通常是有问题的 对大型平民群体的预防治疗，因为不可避免的副作用必须以某种方式 权衡了流行病的机会。炭疽的进展取决于分泌的毒素LF （致命因子），一种蛋白酶，在裂解特定的特定方面在诱导巨噬细胞凋亡中起关键作用 人类细胞信号蛋白。通过靶向LF治疗感染的抗毒素方法 因此，应为抗生素和疫苗提供有希望的替代方案或补充。但是，进一步 缺乏强大和 选择性药理工具。基于这些观察结果，我们的研究建议中的一个中心假设 能够阻断或减少LF活性的小有机分子会导致B.炭疽病。 无毒，使炭疽病与常规抗生素结合使用。我们在这里建议 基于涉及基于碎片的多学科方法，开发一系列新型的LF抑制剂 铅设计，药物化学和基于结构的优化。体外，最终体内 功效研究将对最有前途的药物进行。我们的三个具体目标是：（i） 完成能够选择性阻断LF裂解的有效抑制剂的基于结构的设计 无影响人类MMP酶的活性。 （ii）通过衍生和迭代增加 选定抑制剂支架的选择性，效力和安全性。 （生病）测试微调的有效性 保护培养细胞和鉴定LF的药物样铅抑制剂的化合物持续 药物细化和Vivo功效研究。 关联 吸入b.anththracis孢子会导致吸入炭疽，这是该疾病中最致命的形式。作为疾病 进展，孢子，被肺泡巨噬细胞吞没，发芽以产生细菌，该细菌 通过淋巴结传播到血液，最终导致全身性致命休克。到 成功完成入侵，B.Anthracis必须削弱宿主免疫系统。 LF（致命因素）是 分泌的毒素在诱导巨噬细胞的凋亡（细胞死亡）中起关键作用 特定的人类细胞信号蛋白。相反，特异性抑制LF应防止巨噬细胞 - 死亡并促进疾病的终止。我们将开发的LF的抑制剂，很可能是在使用 与抗生素结合使用，应促进并确保携带该疾病的患者的恢复。