Kleymann Gerald, Werling Hans-Otto
Bayer Health Care Pharma, Aprather Weg 18 a, D-42096 Wuppertal, Germany.
J Biomol Screen. 2004 Oct;9(7):578-87. doi: 10.1177/1087057104265291.
Efficacy and tolerability are the key criteria for a successful medication in the clinic. Therefore, a new test method to obtain selective and active lead molecules has been developed. Recently, this novel screening strategy enabled a breakthrough in drug discovery in the field of herpes viruses. Here the authors report that this assay is a generally applicable screening test, which allows not only for identifying tolerable and potent antimicrobial agents in compound libraries, but also covers all potential in vitro targets of both the pathogen and the host simultaneously. The test system mimics the smallest unit of a natural infection. Host cells are incubated in the presence of the test sample and are infected with microbes, such as viruses, bacteria, or fungi. Analogous to (lethal challenge) animal models, cell survival is determined. This assay maximizes the chances of success of anti-infective drug discovery, is sensitive, robust, time- and cost-efficient, and especially effective in optimizing screening hits to lead structures and development candidates. In addition to the minimal inhibitory concentration or dose, this test system simultaneously provides the selectivity index, a measure of tolerability in vitro. The authors propose the activity selectivity assay format as a new standard in anti-infective drug discovery and clinical development.
疗效和耐受性是临床中一种成功药物的关键标准。因此，已开发出一种用于获得选择性和活性先导分子的新测试方法。最近，这种新颖的筛选策略在疱疹病毒领域的药物发现中实现了突破。在此，作者报告称该测定法是一种普遍适用的筛选测试，它不仅能够在化合物库中识别出耐受性良好且有效的抗菌剂，还能同时涵盖病原体和宿主的所有潜在体外靶点。该测试系统模拟自然感染的最小单位。将宿主细胞在测试样品存在的情况下进行孵育，然后用微生物（如病毒、细菌或真菌）进行感染。类似于（致死性攻击）动物模型，测定细胞存活率。这种测定法最大限度地提高了抗感染药物发现成功的机会，具有灵敏、稳健、省时且经济高效的特点，尤其在将筛选得到的活性物质优化为先导结构和开发候选物方面效果显著。除了最低抑菌浓度或剂量外，该测试系统还能同时提供选择性指数，这是一种体外耐受性的衡量指标。作者提议将活性选择性测定形式作为抗感染药物发现和临床开发的新标准。
