Abstract
Combinatorial and modular methods to synthesize small molecule modulators of protein activity have proven to be powerful tools in the development of new drug-like molecules. Over the past decade, these methodologies have been adapted toward utilization in the development of activity- and affinity-based chemical probes, as well as in chemoproteomic profiling. In this review, we will discuss how methods like multicomponent reactions, DNA-encoded libraries, phage displays, and others provide new ways to rapidly screen novel chemical probes against proteins of interest.
Highlights
Chemical tools that covalently modify proteins are of great interest for fundamental biological research as well as for biomedical applications
Combinatorial synthesis of activity- and affinitybased probes was limited to solid phase synthesis
Major advances have been made in the development of modular, solution phase synthesis methods
Summary
Chemical tools that covalently modify proteins are of great interest for fundamental biological research as well as for biomedical applications. Functional chemical probes contain at least the following three elements: (1) a ligand, to confer selectivity toward the proteins of interest, (2) a reporter group (e.g., fluorophore, affinity tag, or bioorthogonal tag for later functionalization) (Speers and Cravatt, 2004), and (3) a reactive group that covalently reacts with the proteins of interest (Figure 1A) (DeGruyter et al, 2017). Which of these probe parts is leading in the probe design is determined by the protein target and dependent on the biological question that is being addressed. This is commonly done when profiling specific proteases by incorporating substituents that target the substrate binding pockets (Greenbaum et al, 2002; Berger et al, 2006; Screen et al, 2010; Geurink et al, 2013; de Bruin et al, 2016; van de Plassche et al, 2020)
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