Sunkari Yashoda Krishna, Nguyen Thu-Lan, Siripuram Vijay Kumar, Flajolet Marc
Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, 1230 York Avenue, New York, NY 10065, USA.
iScience. 2023 Aug 9;26(9):107573. doi: 10.1016/j.isci.2023.107573. eCollection 2023 Sep 15.
High-power screening (HPS) technologies, such as DNA-encoded library (DEL) technology, could exponentially increase the dimensions of the chemical space accessible for drug discovery. The intrinsic fragile nature of DNA is associated with cumbersome limitations and DNA durability (e.g., depurination, loss of phosphate groups, adduct formation) is compromised in numerous organic chemistry conditions that require empirical testing. An atlas of reaction conditions (temperature, pH, solvent/buffer, ligands, oxidizing reagents, catalysts, scavengers in function of time) that have been systematically tested in multiple combinations, indicates precisely limits useful for DEL construction. More importantly, this approach could be used broadly to effectively evaluate DNA-compatibility of any novel on-DNA chemical reaction, and it is compatible with different molecular methodologies. This atlas and the general approach presented, by allowing novel reaction conditions to be performed in presence of DNA, should greatly help in expanding the DEL chemical space as well as any field involving DNA durability.
高功率筛选（HPS）技术，如DNA编码文库（DEL）技术，可以成倍增加药物发现可及的化学空间维度。DNA固有的脆弱性质伴随着诸多麻烦的限制，并且在许多需要经验测试的有机化学条件下，DNA的耐久性（如脱嘌呤、磷酸基团丢失、加合物形成）会受到损害。一份经过多种组合系统测试的反应条件图谱（温度、pH值、溶剂/缓冲液、配体、氧化试剂、催化剂、不同时间的清除剂）精确地指出了对DEL构建有用的限制条件。更重要的是，这种方法可广泛用于有效评估任何新型DNA上化学反应的DNA兼容性，并且它与不同的分子方法兼容。通过允许在DNA存在的情况下进行新型反应条件，所呈现的这张图谱和通用方法应极大地有助于扩展DEL化学空间以及任何涉及DNA耐久性的领域。
