Covalent targeting strategies

共价靶向策略

• 批准号: 10513874
• 负责人: John Damon Chodera
• 金额: $ 286.16万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-16 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10513874
• 关键词: Structure

There has been a recent renewed interest in covalent binding small molecules as therapeutic drugs. This interest has been largely driven by recent success and FDA approvals of covalent acting molecules that have highlighted a number of advantages of this class of agents. Perhaps one of the most significant benefits is the fact that covalent drug efficacy is not directly linked to pharmacological properties of the molecules such as adsorption, diffusion, metabolism and secretion (ADME). This is because once a covalent drug binds, the target can only be restored by new protein synthesis. This enables reduced dosing frequency and produces prolonged duration of therapeutic effects. Additionally, covalent targeting of specific amino acid residues on a protein target can produce a high degree of selectivity, even among highly related variants of the same protein. This is particularly relevant for antiviral agents, as covalent targeting of specific residues on viral proteins that cannot be mutated without a high negative fitness cost is likely to result in therapeutics that do not rapidly select for resistance. Therefore, the main goal of this project is to focus recently developed covalent targeting technologies on viral targets, with the goal of generating new classes of highly effective antiviral agents. This includes building and optimizing covalent fragment libraries, performing screens of prioritized ASAP consortium targets, optimization of computational methods to convert reversible binding scaffolds into covalent leads, developing and screening covalent compounds using nanoscale chemistries and phage display, and implementing Proteolysis Targeting Chimeras (PROTACs) strategies using reversible covalent chemistry. The primary deliverable of this project will be novel hits and leads that will feed into projects in the ASAP consortium with the ultimate goal of advancing covalent binding scaffolds into pre-clinical candidates. This will require the development of new methods for covalent ligand discovery and optimization to improve overall performance against the anti-viral targets of this consortium. We expect to generate several promising antiviral compound series (>5) that can be useful as both chemical biology tools for further biological investigation and as advanced leads to be fed into the development pipeline of the consortium. In addition to the benefits for the ASAP consortium, the methodological improvements achieved in this project will also benefit the fields of covalent chemical biology and drug discovery as they can be applied to diverse targets.

最近人们对作为治疗药物的共价结合小分子重新产生了兴趣。这 人们的兴趣很大程度上是由于最近的成功和 FDA 批准的共价作用分子，这些分子已经 强调了此类代理的许多优点。也许最显着的好处之一是 事实上，共价药物的功效与分子的药理学特性并不直接相关，例如 吸附、扩散、代谢和分泌（ADME）。这是因为一旦共价药物结合， 目标只能通过新的蛋白质合成来恢复。这可以减少给药频率并产生 延长治疗效果的持续时间。此外，共价靶向特定氨基酸残基 蛋白质靶标可以产生高度的选择性，即使在同一蛋白质的高度相关的变体中也是如此。 这对于抗病毒药物尤其重要，因为共价靶向病毒蛋白上的特定残基 如果没有较高的负适应成本就无法突变，这可能会导致治疗方法无法迅速实现 选择电阻。因此，该项目的主要目标是关注最近开发的共价靶向 针对病毒靶点的技术，目标是产生新型高效抗病毒药物。这 包括构建和优化共价片段库、执行优先 ASAP 联盟的筛选 目标，优化计算方法以将可逆结合支架转化为共价先导， 使用纳米化学和噬菌体展示开发和筛选共价化合物，以及 使用可逆共价化学实施蛋白水解靶向嵌合体 (PROTAC) 策略。这 该项目的主要交付成果将是新的热门产品和线索，这些将被纳入 ASAP 的项目中 该联盟的最终目标是将共价结合支架推进到临床前候选药物中。这将 需要开发共价配体发现和优化的新方法，以提高整体水平 针对该联盟的抗病毒目标的表现。我们期望产生几种有前途的抗病毒药物 化合物系列（>5）可用作进一步生物学研究的化学生物学工具和 作为先进的线索将被输入到联盟的开发管道中。除了为人们带来的好处之外 ASAP 联盟，该项目中实现的方法改进也将使以下领域受益 共价化学生物学和药物发现，因为它们可以应用于不同的靶标。