Small Molecule Inhibitors of Anthrax Lethal Factor

炭疽致死因子小分子抑制剂

• 批准号: 7092076
• 负责人: Norton P Peet
• 金额: $ 71.64万
• 依托单位: MICROBIOTIX, INC
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-15 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7092076
• 关键词: Bacillus anthracis; X ray crystallography; anthrax; anthrax toxin; antibacterial agents; bacterial proteins; bioterrorism /chemical warfare; cell line; chemical structure function; combinatorial chemistry; cytoprotection; drug design /synthesis /production; drug screening /evaluation; laboratory rat; liver cells; macrophage; metalloendopeptidases; microorganism disease chemotherapy; microsomes; nonhuman therapy evaluation; pharmacokinetics; protease inhibitor; small molecule; structural biology

DESCRIPTION (provided by applicant): Aerosolized spores of Bacillus anthracis represent one of the most serious bio-terrorist threats to the security of the United States. New therapeutics based upon novel chemical scaffolds are vital to the biodefense armory because they are likely to be effective against both natural and engineered resistant forms of B. anthracis. Our strategy is to build effective anthrax therapeutics not by targeting the viability of the organism but by targeting the mechanism of pathogenesis directly. Toward this aim, we have identified drug-like small molecule LF inhibitors through a combination of screening of chemical libraries and 3D sub-structure database mining. These inhibitors have been shown to specifically bind to LF with low (M potencies in enzymatic assays and to protect macrophages against challenge with toxin containing LF. The identified inhibitor classes are novel and devoid of non-drug like features such as the hydroxamic acid and peptidic backbone, which are common in many known protease inhibitors. Thus, this validated hit series forms the basis for development of efficacious, safe and orally bioavailable drugs against anthrax. To further enhance the probability of success of this project, the X-ray structure of the inhibitor bound in the active site of LF has been solved thus providing a powerful tool, which we will use to guide the inhibitor refinement process through structure-based drug design. The overall goal of this project is to develop a small molecule LF inhibitor to treat anthrax. In Phase I, we will apply proven techniques of medicinal and combinatorial chemistry; inhibitor-enzyme complex X-ray crystallography and structure-based drug design (SBDD) to rapidly synthesize and evaluate derivatives of this new validated hit series. In an iterative process, we will probe focused compound libraries for features contributing to tighter binding and more potent inhibition of LF by measuring the enzymatic, cellular activity and specificity of derivatives. We will determine the X-ray structures of improved inhibitors bound to the LF active site, and use these data to develop refined pharmacophore models to guide further probing of the structure activity relationship (SAR). In addition, we will assess compounds for optimal ADME (Absorption, Distribution, Metabolism, Elimination) properties (e.g., liver microsome stability, Cyp isoform inhibition and Caco2 permeability). Compounds with sufficient enzymatic, cellular potency and ADME properties will be synthesized at the 1-2 g level and tested for efficacy in a LF induced rat death model. Successful rescue of rats from LF-induced death will qualify compounds as in vivo-validated leads. In Phase II, we will further evaluate these leads for in vivo efficacy, pharmacokinetic properties, toxicity and safety pharmacology, in two species, in order to develop them into pre-IND clinical candidates, suitable for human clinical trials (Phase III).

描述（由申请人提供）：炭疽芽孢杆菌的雾化孢子是对美国安全的最严重的生物恐怖主义威胁之一。基于新型化学支架的新治疗剂对于生物粉丝军械库至关重要，因为它们可能对天然和工程性的炭疽杆菌抗性形式有效。我们的策略是不是通过直接靶向发病机理来建立有效的炭疽治疗剂。为了实现这一目标，我们通过化学文库和3D子结构数据库挖掘的筛选结合了类似药物样的小分子LF抑制剂。这些抑制剂已被证明可以特异性与LF特异性结合（酶测定中的效力，并保护巨噬细胞免受含有LF毒素的挑战的挑战。确定的抑制剂类别是新颖的，并且没有非药物的特征，例如羟氨基酸和诸如羟基酸和肽型链链，在许多已知的蛋白酶中，有效的蛋白酶均受到了这种有效的效果，因此，这些蛋白酶的效果是造成的。针对炭疽病的口服药物。组合化学；抑制剂 - 酶复杂的X射线晶体学和基于结构的药物设计（SBDD）迅速合成和评估该新验证的HIT序列的衍生物，我们将通过迭代的效果进行探测，从X射线结构改善了与LF活性位点结合的抑制剂，并使用这些数据开发精炼的药物团模型来指导结构活性关系（SAR），我们将评估最佳ADME的化合物（例如吸收，分布，代谢，消除）特性酶促，细胞效力和ADME特性将在1-2 g水平上合成，并在LF诱导的大鼠死亡模型中测试了疗效，从LF诱导的死亡中拯救了大鼠。为了将其发展为预先指示的临床候选者，适合人类临床试验（第三阶段）。

项目成果

A Survey of Solvents for the Conrad-Limpach Synthesis of 4-Hydroxyquinolones.

• DOI: 10.1080/00397910802542044
• 发表时间: 2009-01-01
• 期刊: Synthetic communications
• 影响因子: 2.1
• 作者: Brouet JC;Gu S;Peet NP;Williams JD
• 通讯作者: Williams JD

Small molecule inhibitors of anthrax lethal factor toxin.

炭疽致死因子毒素的小分子抑制剂。

• DOI: 10.1016/j.bmc.2013.11.009
• 发表时间: 2014
• 期刊: Bioorganic & medicinal chemistry
• 影响因子: 3.5
• 作者: Williams,JohnD;Khan,AtiyyaR;Cardinale,StevenC;Butler,MichelleM;Bowlin,TerryL;Peet,NortonP
• 通讯作者: Peet,NortonP