Pharmacogenomics/natural products + antifungal activity

描述（由申请人提供）： 患有机会性真菌感染的免疫功能低下（AIDS）患者经常遭受高风险， 尽管进行了治疗，但由于缺乏治疗功效或毒性以及对目前可用的药剂的抗性，仍然存在发病率（>70%）和死亡率。该项目的目标是通过整合传统抗真菌药物发现的信息和化合物与药物基因组学方法来提高抗真菌药物的发现。我们的前两个目标是确定天然产物和FDA批准的具有抗真菌活性的药物的药物基因组学特征。这些比较药物基因组学筛选将侧重于致病真菌中的真核细胞（人类）毒性和活性。传统的药物开发过程利用一系列急性和慢性毒性测试来评估安全性。然而，这种方法是耗时的，在动物生命方面是昂贵的，并且通常不是预测性的。药物基因组学是一个有效的工具，允许测量差异表达的基因从真核细胞暴露于抗真菌药物。在数百到数千个基因中观察到的差异表达可以表明化合物如何影响细胞过程。“签名”的细胞过程将用于更有效地指导生物化学和动物试验， NCNPR。我们的第三个目标是建立一个“签名”数据库，并开发一个模型，是一个新的代理的行为预测。确认作用机制和鉴定人体不良副作用是开发新药的主要挑战之一。抗真菌化合物的转录行为或“签名”的数据库可以用生物化学、药理学和毒理学数据建模，以预测新药剂的结果。在其他有前途的化合物的特征中识别潜在的毒性可以允许早期识别那些可能在临床试验中失败的化合物，或者允许研究人员专注于临床前研究。识别具有针对真菌生物体的新作用机制的药剂也是一个潜在的益处。比较有希望的候选药物的“脱靶”特征的程度和特性可以提供对不相关诊断的适应症的洞察。我们的模型的长期益处应该包括可以从我们的模型开发的“治疗阵列”的开发。此阵列 将主要包含来自各种组织部位和酵母的转录物。用来自暴露于新型抗真菌剂的细胞的真核mRNA探测该阵列将预测常见的作用机制以及毒性、活性和抗性的可能性。

DESCRIPTION (provided by applicant): Immunocompromised (AIDS) patients with opportunistic fungal infections frequently suffer high morbidity (>70%) and mortality in spite of therapy, due to a lack of therapeutic efficacy or toxicity, and resistance to currently available agents. The goal of this project is to enhance antimycotic drug discovery by integrating information and compounds derived from traditional antifungal discovery with a pharmacogenomics approach. Our first two objectives will be to identify pharmacogenomic characteristics of natural products and FDA approved drugs with antifungal activity. These comparative pharmacogenomic screenings will focus on eukaryotic cell (human) toxicity and activity in pathogenic fungi. Traditional drug development processes utilize batteries of acute and chronic toxicity tests to evaluate safety. However, this approach is time consuming, costly in terms of animal life, and often not predictive. Pharmacogenomics is an efficient tool, permitting measurements of differentially expressed genes from eukaryotic cells exposed to antifungal agents. The differential expression observed in hundreds to thousands of genes can suggest how a compound affects cellular processes. The cellular processes of "signatures" will be used to more efficiently direct biochemical and animal testing in the NCNPR. Our third objective is to establish a database of "signatures" and develop a model that is predictive of a novel agent's behavior. Confirmation of the mechanism of action and the identification of undesirable secondary effects in man are among the main challenges in developing new drugs. A database of transcriptional behaviors or "signatures" for antimycotic compounds can be modeled with biochemical, pharmacological and toxicological data to predict outcomes of new agents. Recognition of potential toxicities in the signatures of otherwise promising compounds may allow earlier identification of those likely to fail in clinical trials or allow investigators to focus preclinical investigations. Recognition of agents with new mechanisms of action against mycotic organisms is also a potential benefit. Comparing the extent and peculiarities of "off-target" signatures of promising drug candidates could provide insight into indications for an unrelated diagnoses. A long-term benefit of our model should include the development of a "therapeutic array" which could be developed from our model. This array would contain mainly transcripts from various tissue sites and yeast. Probing this array with eukaryotic mRNA from cells exposed to novel antifungals would predict common mechanism of action and likelihood of toxicity, activity and resistance.