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）：该提案的主要目的是通过使用综合的生物无机方法来开发新型的炭疽致死因子（LF）抑制剂，该方法允许对抑制剂 - 甲甲基蛋白相互作用的机械阐明。 LF是一种水解锌依赖性的金属酶，已知在炭疽芽孢杆菌的发病机理中起着重要作用。 LF缺乏的炭疽芽孢杆菌的菌株具有降低的致病性，使该蛋白作为炭疽的铅毒力因子。抗毒素疗法对于补充抗生素治疗至关重要，抗生素治疗通常由于炭疽的无症状性质而经常施用太晚。几个小组已经开始研究LF的小分子抑制剂，作为治疗炭疽爆发的治疗疗法的途径。由于国际对生物贸易和生物恐怖主义的关注，这一领域的复兴发生了。在LF的最有希望的抑制剂中，先前设计的基质金属蛋白酶（MMP）抑制剂，因为MMPS和LF都在活性位点均包含催化锌（II）离子，从而可以由这些抑制剂直接绑定，从而抑制催化活性。这种常见基序导致使用MMP抑制剂作为LF的抑制剂，并令人鼓舞。构成当前绝大多数可用化合物的基于羟氨基酸的MMP抑制剂，由于口服较低，药代动力学差和诸如肌肉骨骼疼痛等副作用，在临床试验中已经不成功。这种失败在很大程度上归因于氢氨基酸对锌的选择性低和亲和力以及体内羟氨基酸基团的化学稳定性差。尽管MMP抑制剂作为LF抑制剂表现出巨大的希望，但仍需要新化合物，尤其是那些提供羟基酸金属螯合剂的化合物。采用合成，生化和计算方法来揭示药物 - 超甲蛋白相互作用的新型机械方法的利用是以下建议的重点。提出了几种化合物作为羟丙酸的替代品，并已证明可以提高针对炭疽LF的效力。初步结果表明，基于我们的设计策略的LF抑制剂具有有效，可溶性，选择性，并且能够保护巨噬细胞免受炭疽致死毒素的影响。预计这种方法的进一步完善将产生更有效的LF抑制剂。拟议的项目涉及发现新化合物来应对炭疽的威胁。分子将被设计和合成以攻击炭疽细菌产生的关键毒素。这样，将开发用于治疗炭疽疫情的创新治疗剂。