Covalent targeting strategies

最近，人们对共价结合小分子作为治疗药物重新产生了兴趣。这 最近成功和FDA批准的共价作用分子已经很大程度上推动了人们的兴趣， 他强调了这类药物的一些优点。也许最重要的好处之一是 共价药物功效与分子的药理学性质不直接相关的事实， 吸附、扩散、代谢和分泌（ADME）。这是因为一旦共价药物结合， 靶点只能通过新蛋白质合成来恢复。这使得能够降低给药频率， 延长疗效持续时间。此外，共价靶向特定氨基酸残基在一个 蛋白质靶标可以产生高度的选择性，甚至在相同蛋白质的高度相关变体之间。 这对于抗病毒剂特别相关，因为共价靶向病毒蛋白上的特定残基， 在没有高负适应性成本的情况下不能突变的基因可能导致不能快速地 选择抵抗。因此，本项目的主要目标是关注最近开发的共价靶向 研究人员正在开发针对病毒靶点的新技术，目标是产生新型高效抗病毒剂。这 包括构建和优化共价片段文库，进行优先ASAP聚生体筛选， 目标，优化计算方法以将可逆结合支架转化为共价引线， 使用纳米级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。的 该项目的主要交付成果将是新的热门产品和线索，这些产品和线索将尽快纳入项目 该联盟的最终目标是将共价结合支架推进到临床前候选物中。这将 需要开发用于共价配体发现和优化的新方法， 针对该联合体的抗病毒靶标的性能。我们希望能产生几种有希望的抗病毒药物 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， 作为先进的导致被送入发展管道的财团。除了对 ASAP财团，该项目中实现的方法学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目标。

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.