Deciphering Drug Targets and Actions with Single-Cell and Spatial Resolution

Area of Science:

• Chemical biology
• Genomics
• Molecular biology
• Biotechnology

Background:

• Advances in chemical, molecular, and genetic methods enable whole-proteome and genome drug-target interaction identification.
• Single-cell and spatial omics technologies are transforming the understanding of biological systems' molecular architecture.
• A gap exists in aligning traditional drug action understanding (molecular affinities) with in vivo cellular and spatial tissue heterogeneity.

Purpose of the Study:

• To review state-of-the-art methods for profiling drug-target interactions.
• To discuss emerging multiomics tools for delineating tissue heterogeneity at single-cell resolution.
• To highlight advances in in situ small-molecule drug imaging.

Main Methods:

• Review of current drug-target interaction profiling techniques.
• Exploration of single-cell and spatial omics for tissue heterogeneity analysis.
• Focus on clearing-assisted tissue click chemistry (CATCH) for multiplexable in situ drug imaging.

Main Results:

• Identification of methods to profile drug-target interactions across proteome and genome.
• Characterization of tissue heterogeneity using single-cell and spatial omics.
• Demonstration of high-resolution, multiplexable in situ small-molecule drug imaging via CATCH.

Conclusions:

• Integration of single-cell and spatial omics platforms is crucial for future drug discovery.
• Bridging the gap between molecular affinities and in vivo heterogeneity is key to understanding drug mechanisms.
• The future framework for defining in vivo drug-target interactions will incorporate multiomics data and advanced imaging techniques.