A Bioinorganic Approach to Anthrax Lethal Factor Inhibitors

炭疽致死因子抑制剂的生物无机方法

基本信息

批准号：
7391558
负责人：
SETH M COHEN
金额：
$ 7.58万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-01 至 2010-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7391558
关键词：
Active Sites Address Adverse effects Affinity Anthrax disease Antibiotic Therapy Area Bacillus anthracis Bacteria Binding Biochemical Biological Assay Biological Warfare Bioterrorism Cells Chelating Agents Clinical Clinical Trials Complex Computing Methodologies Disease Disease Outbreaks Drug Kinetics Face Failure Fluorescence Generations Hybrids Hydrolysis Hydroxamic Acids In Vitro International Intervention Ions Laboratories Lead Ligands Matrix Metalloproteinase Inhibitor Matrix Metalloproteinases Metalloproteins Metals Methodology Modeling Mus Musculoskeletal Pain Nature Oral Organic Chemistry Pathogenesis Pathogenicity Pharmaceutical Preparations Play Proteins Purpose Recombinants Role Route Screening procedure Testing Therapeutic Toxin United States Virulence Factors Zinc anthrax lethal factor base chemical stability design hydroxamate improved in vivo inhibitor/antagonist innovation macrophage metalloenzyme novel small molecule

项目摘要

DESCRIPTION (provided by applicant): The major objective of this proposal is to develop novel inhibitors of anthrax lethal factor (LF) by using a comprehensive bioinorganic approach that allows for the mechanistic elucidation of inhibitor-metalloprotein interaction. LF is a hydrolytic zinc-dependent metalloenzyme that is known to play a prominent role in the pathogenesis of Bacillus anthracis. Strains of B. anthracis that are deficient in LF have reduced pathogenicity, making this protein a candidate as the lead virulence factor of anthrax. Anti-toxin therapies are essential to compliment antibiotic treatments, the latter of which are often administered too late due to the asymptomatic nature of anthrax. Several groups have begun to investigate small molecule inhibitors of LF as a route to therapeutics for treating anthrax breakouts. A resurgence in this area has occurred due to international concerns over biowarfare and bioterrorism. Among the most promising inhibitors for LF are previously devised matrix metalloproteinase (MMP) inhibitors, because both MMPs and LF contain a catalytic zinc(II) ion at the active site, which can be directly bound by these inhibitors, thereby suppressing catalytic activity. This common motif has led to the use of MMP inhibitors as inhibitors of LF with encouraging results. Hydroxamic acid-based MMP inhibitors, which make up the vast majority of currently available compounds, have been unsuccessful in clinical trials due to low oral availability, poor pharmacokinetics, and side effects such as musculoskeletal pain. This failure has been due in large part to the low selectivity and affinity of the hydroxamic acid for zinc and the poor chemical stability of the hydroxamic acid group in vivo. Although MMP inhibitors show great promise as LF inhibitors, there remains a need for new compounds, particularly those that provide alternatives to the hydroxamic acid metal chelator. The utilization of a new model-based mechanistic approach that employs synthetic, biochemical, and computational methods to reveal drug-metalloprotein interactions is the focus of the following proposal. Several compounds are proposed as alternatives to hydroxamic acids and have been shown to display improved potency against anthrax LF. Preliminary results show that a LF inhibitor based on our design strategy is potent, soluble, selective, and capable of protecting macrophage cells from anthrax lethal toxin. Further refinement of this approach is expected to yield even more effective LF inhibitors. The proposed project involves the discovery of new compounds to address the threat of anthrax. Molecules will be designed and synthesized to attack a key toxin produced by the anthrax bacteria. In this way, innovative therapeutics for treating anthrax outbreaks will be developed.

描述（由申请人提供）：该提案的主要目标是通过使用全面的生物无机方法来开发炭疽致死因子（LF）的新型抑制剂，该方法可以阐明抑制剂与金属蛋白相互作用的机制。 LF 是一种水解锌依赖性金属酶，已知在炭疽杆菌的发病机制中发挥着重要作用。缺乏 LF 的炭疽芽孢杆菌菌株的致病性降低，使该蛋白成为炭疽主要毒力因子的候选者。抗毒素疗法对于补充抗生素治疗至关重要，由于炭疽的无症状性质，抗生素治疗常常施用得太晚。一些研究小组已经开始研究 LF 的小分子抑制剂，作为治疗炭疽病的治疗途径。由于国际社会对生物战和生物恐怖主义的担忧，这一领域出现了复苏。最有前途的 LF 抑制剂是之前设计的基质金属蛋白酶 (MMP) 抑制剂，因为 MMP 和 LF 的活性位点都含有催化锌 (II) 离子，可以直接与这些抑制剂结合，从而抑制催化活性。这种共同的基序导致使用 MMP 抑制剂作为 LF 抑制剂，并取得了令人鼓舞的结果。基于异羟肟酸的 MMP 抑制剂占目前可用化合物的绝大多数，但由于口服利用率低、药代动力学差以及肌肉骨骼疼痛等副作用，在临床试验中并未成功。这种失败很大程度上是由于异羟肟酸对锌的选择性和亲和力低以及异羟肟酸基团在体内的化学稳定性差。尽管 MMP 抑制剂作为 LF 抑制剂显示出巨大的前景，但仍然需要新的化合物，特别是那些提供异羟肟酸金属螯合剂替代品的化合物。以下提案的重点是利用基于模型的新机械方法，该方法采用合成、生物化学和计算方法来揭示药物-金属蛋白相互作用。几种化合物被提议作为异羟肟酸的替代品，并已被证明对炭疽 LF 具有改进的效力。初步结果表明，基于我们设计策略的 LF 抑制剂是有效的、可溶的、选择性的，并且能够保护巨噬细胞免受炭疽致死毒素的侵害。这种方法的进一步完善预计将产生更有效的 LF 抑制剂。拟议的项目涉及发现新的化合物来应对炭疽的威胁。将设计和合成分子来攻击炭疽细菌产生的关键毒素。通过这种方式，将开发出治疗炭疽暴发的创新疗法。