Martín-Acosta Pedro, Meng Qianli, Klimek John, Reddy Ashok P, David Larry, Petrie Stefanie Kaech, Li Bingbing X, Xiao Xiangshu
Program in Chemical Biology, Department of Chemical Physiology and Biochemistry, Oregon Health & Science University, Portland, OR 97239, USA.
Proteomics Shared Resource, Oregon Health & Science University, Portland, OR 97239, USA.
Acta Pharm Sin B. 2022 May;12(5):2406-2416. doi: 10.1016/j.apsb.2021.12.008. Epub 2021 Dec 22.
Target identification of bioactive compounds is important for understanding their mechanisms of action and provides critical insights into their therapeutic utility. While it remains a challenge, unbiased chemoproteomics strategy using clickable photoaffinity probes is a useful and validated approach for target identification. One major limitation of this approach is the efficient synthesis of appropriately substituted clickable photoaffinity probes. Herein, we describe an efficient and consistent method to prepare such probes. We further employed this method to prepare a highly stereo-congested probe based on naturally occurring triterpenoid betulinic acid. With this photoaffinity probe, we identified tropomyosin as a novel target for betulinic acid that can account for the unique biological phenotype on cellular cytoskeleton induced by betulinic acid.
生物活性化合物的靶点鉴定对于理解其作用机制至关重要，并为其治疗效用提供关键见解。尽管这仍然是一项挑战，但使用可点击光亲和探针的非偏向性化学蛋白质组学策略是一种用于靶点鉴定的有用且经过验证的方法。该方法的一个主要限制是高效合成适当取代的可点击光亲和探针。在此，我们描述了一种高效且一致的方法来制备此类探针。我们进一步采用该方法基于天然存在的三萜类化合物桦木酸制备了一种高度立体拥挤的探针。利用这种光亲和探针，我们鉴定出原肌球蛋白是桦木酸的一个新靶点，这可以解释桦木酸对细胞骨架诱导的独特生物学表型。
