Defining New Biological and Chemical Targets With Diazirines

用二氮丙啶定义新的生物和化学目标

• 批准号: RGPIN-2021-02560
• 负责人: Wulff, Jeremy
• 金额: $ 3.5万
• 依托单位: University of Victoria
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=748164
• 关键词: Defining; New; Biological; Chemical; Targets

Medicinal chemistry involves using molecules (drugs) to perturb biological systems. This mostly happens through formation of transient small-molecule-protein complexes, where a drug strongly and selectively binds to its protein target(s). The ability to predictably form association complexes between disease-relevant proteins and drug molecules underpins modern medicine, but identifying such complexes for the first time (i.e. discovering new protein binding pockets whose function can be regulated with drug-like small molecules or probes) has historically been done haphazardly, through target-identification campaigns with molecules of known phenotype or through high-throughput screens with pre-validated protein targets. Because of this, fewer than 500 of the proteins encoded by the 20,000 genes in our genome have approved drugs that selectively target them.1 Thousands of additional, medically relevant proteins cannot be controlled with existing small-molecule therapeutics.2 One of the foundational goals of chemical biology is to solve this limitation by identifying a small-molecule regulator for every member of the human proteome.2,3 To meet this grand challenge, our proposed research program will exploit diazirine-enabled complex molecules to search for protein binding partners at the same time as we exploit diazirine-enabled proteins to prospect for small molecule ligands. In a marked departure from established protocols, we will do so without any requirement for our molecules of interest to possess known phenotypic activity. Instead, we posit that every molecule possessing "drug-like" characteristics and a sufficient degree of molecular complexity will have a suite of proteins to which it binds most strongly. We likewise assert that the identification of small-molecule ligands for hypothesized protein pockets is a valuable undertaking that is likely to lead to new scientific understanding, even when that pocket does not have any known regulatory function. Of course, when new regulatory pockets are identified in disease-relevant proteins, these will have immediate utility for drug development. Our research will thus lead directly to the annotation of new biological targets for medicinal chemistry, and will simultaneously deliver new lead compounds that bind to those targets-setting the stage for multiple future collaborative drug discovery projects. This program represents a bold new direction for our group, yet builds upon expertise in organic synthesis, complex molecule characterization, target identification, chemical biology, and diazirine chemistry acquired by our team over the past 15 years. At the same time the research will allow us to develop new skills in proteomics, and in the site-specific incorporation of noncanonical amino acids. The program will provide a fertile training ground for highly qualified personnel, allowing my lab to build upon our considerable record of accomplishment mentoring and teaching successful scientists.

药物化学涉及使用分子(药物)来扰乱生物系统。这主要是通过形成短暂的小分子-蛋白质复合体发生的，在这种复合体中，药物与其蛋白质靶标强烈和选择性地结合(S)。在疾病相关蛋白质和药物分子之间可预测地形成结合复合体的能力是现代医学的基础，但第一次识别这种复合体(即发现新的蛋白质结合口袋，其功能可以通过类药物小分子或探针调节)历史上一直是随意完成的，通过与已知表型分子的靶标识别运动，或通过具有预先验证的蛋白质靶标的高通量筛选。正因为如此，在我们基因组中20,000个基因编码的蛋白质中，只有不到500个已经批准了选择性地针对它们的药物。1.数以千计的额外的、与医学相关的蛋白质不能用现有的小分子疗法来控制。2化学生物学的基本目标之一是通过为人类蛋白质组的每个成员确定一个小分子调节器来解决这个限制。2、3为了迎接这一重大挑战，我们拟议的研究计划将利用二氮杂环使能的复杂分子来搜索蛋白质结合伙伴，同时我们将利用二氮嗪使能的蛋白质来寻找小分子配体。在与既定方案的明显背离中，我们将这样做，而不需要我们感兴趣的分子具有已知的表型活性。相反，我们假设每个具有“类药物”特征和足够程度的分子复杂性的分子都会有一套它与之结合最强的蛋白质。我们同样断言，为假想的蛋白质口袋识别小分子配体是一项有价值的工作，可能会导致新的科学理解，即使这个口袋没有任何已知的调节功能。当然，当在与疾病相关的蛋白质中发现新的调节口袋时，这些将立即对药物开发产生作用。因此，我们的研究将直接导致药物化学的新生物靶标的注释，并将同时提供与这些靶标结合的新先导化合物-为未来多个合作药物发现项目奠定基础。该项目代表了我们团队的一个大胆的新方向，同时又建立在我们团队在过去15年中获得的有机合成、复杂分子表征、目标识别、化学生物学和二氮杂环化合物化学方面的专业知识。与此同时，这项研究将使我们能够在蛋白质组学和特定部位结合非规范氨基酸方面开发新的技能。该计划将为高素质的人员提供肥沃的培训场地，使我的实验室能够在我们指导和教授成功科学家的可观记录的基础上再接再厉。