Natural Product-Derived Activity-Based and Affinity-Based Probes: Tools for Mechanism of Action Studies

Natural products have played a pivotal role in the history of drug discovery, yet mechanistic investigations have often posed significant challenges that impede the development of natural product-derived drugs. Traditional approaches using natural product prototypes as probes for target identification and mechanistic exploration are often hampered by labor-intensive optimization and low sensitivity, whereas the advent of advanced mass spectrometry and mature Activity-Based Protein Profiling (ABPP) strategies has propelled labeled probes derived from natural products to the forefront of research. Such probes enable efficient target identification and visualization, thereby greatly facilitating the elucidation of mechanisms of action. This article systematically introduces commonly used labeling groups, reviews recent applications of labeled probes across various classes of natural products, and aims to provide references for the study of unexplored natural products of similar types. It also outlines the development of novel photoaffinity groups, suggesting that future designs should focus on small size, strong binding affinity, and stable binding, so as to further expand their applications in chemical biology and drug discovery.