Nestorovich Ekaterina M, Bezrukov Sergey M
The Catholic University of America, Department of Biology , Washington, DC , USA +1 202 319 6723 ;
Expert Opin Drug Discov. 2014 Mar;9(3):299-318. doi: 10.1517/17460441.2014.877884. Epub 2014 Jan 22.
Present-day rational drug design approaches are based on exploiting unique features of the target biomolecules, small- or macromolecule drug candidates and physical forces that govern their interactions. The 2013 Nobel Prize in chemistry awarded 'for the development of multiscale models for complex chemical systems' once again demonstrated the importance of the tailored drug discovery that reduces the role of the trial-and-error approach to a minimum. The intentional dissemination of Bacillus anthracis spores in 2001 via the so-called anthrax letters has led to increased efforts, politically and scientifically, to develop medical countermeasures that will protect people from the threat of anthrax bioterrorism.
This article provides an overview of the recent rational drug design approaches for discovering inhibitors of anthrax toxin. The review also directs the readers to the vast literature on the recognized advances and future possibilities in the field.
Existing options to combat anthrax toxin lethality are limited. With the only anthrax toxin inhibiting therapy (protective antigen-targeting with a monoclonal antibody, raxibacumab) approved to treat inhalational anthrax, the situation, in our view, is still insecure. Further, the FDA's animal rule for drug approval, which clears compounds without validated efficacy studies on humans, creates a high level of uncertainty, especially when a well-characterized animal model does not exist. Better identification and validation of anthrax toxin therapeutic targets at the molecular level as well as elucidation of the parameters determining the corresponding therapeutic windows are still necessary for more effective therapeutic options.
当今合理药物设计方法基于利用靶标生物分子、小分子或大分子候选药物的独特特征以及控制它们相互作用的物理力。2013年诺贝尔化学奖授予“复杂化学系统多尺度模型的发展”，再次证明了定制药物发现的重要性，该方法将试错法的作用降至最低。2001年通过所谓的炭疽信件故意传播炭疽芽孢杆菌孢子，在政治和科学上加大了开发医疗对策的力度，以保护人们免受炭疽生物恐怖主义的威胁。
本文概述了近期发现炭疽毒素抑制剂的合理药物设计方法。该综述还引导读者了解该领域已公认的进展和未来可能性的大量文献。
对抗炭疽毒素致死性的现有选择有限。鉴于唯一被批准用于治疗吸入性炭疽的炭疽毒素抑制疗法（用单克隆抗体raxibacumab靶向保护性抗原），我们认为情况仍然不安全。此外，美国食品药品监督管理局（FDA）的药物批准动物规则，即在没有经过验证的人体疗效研究的情况下批准化合物，造成了高度的不确定性，尤其是在不存在特征明确的动物模型时。为了获得更有效的治疗选择，在分子水平上更好地识别和验证炭疽毒素治疗靶点以及阐明确定相应治疗窗口的参数仍然是必要的。
