Combining cross-metathesis and activity-based protein profiling: New β-lactone motifs for targeting serine hydrolases

Abstract

β-Lactones are a privileged structural motif as enzyme inhibitors and chemical probes, particularly for the inhibition of enzymes from the serine hydrolase class. Herein, we demonstrate that cross-metathesis (CM) of α-methylene-β-lactones offers rapid access to structurally diverse, previously unexplored β-lactones. Combining this approach with competitive activity-based protein profiling (ABPP) identified lead β-lactone inhibitors/probes for several serine hydrolases, including disease-associated enzymes and enzymes of uncharacterized function. The structural diversity afforded by the α-methylene-β-lactone scaffold thus expands the landscape of serine hydrolases that can be targeted by small-molecule inhibitors and should further the functional characterization of enzymes from this class through the optimization of target-selective probes.

Immunomodulatory lysophosphatidylserines are regulated by ABHD16A and ABHD12 interplay

“…THL can thus serve as a useful scaffold for developing inhibitors with improved activity and/or selectivity for individual serine hydrolases 27 – 29 . With this notion in mind, we assayed recombinant human ABHD16A against a focused library of α-methylene-β-lactones or reduced versions of this parent THL-like scaffold 30 . The compounds (10 μM) were screened by competitive gel-based ABPP and several active ABHD16A inhibitors were identified ( Supplementary Fig.…”

Recent advances of chemical proteomics for protein drug target screening

“…根据反应基团的不同, 探针可分为基于共 ABPP广泛用于药物或小分子靶蛋白的识别 [13] , 该 方法能够直接评估感兴趣的酶活性 [14] , 特异性富集和 表征靶蛋白 [15] , 在新药研发中是一种有力的工具. 目 前, 利用ABPP方法广泛应用于一些重要的蛋白酶家 族的研究, 如丝氨酸水解酶 [16] 、半胱氨酸蛋白酶 [17] 、 氧化还原酶 [18] 、糖苷水解酶 [19] 等. Xiao等人 [20] [23] . Parker等人 [24] [25,26] .…”

Target identification with quantitative activity based protein profiling (ABPP)

“…As a chemical proteomics method that applies active site‐guided probes to comprehensively fish for selective targets, ABPP was first developed to investigate enzymatic activity , and ABPP methods have since been adapted for activity detection in many enzyme classes including serine and cysteine hydrolases and multiple oxidoreductases . ABPP methods have also been successfully used in enzyme inhibitor screening as well as for protein target identification of bioactive small molecules , which will be the primary focus for this review.…”