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

Abstract

Recent advances in chemical, molecular, and genetic approaches have provided us with an unprecedented capacity to identify drug-target interactions across the whole proteome and genome. Meanwhile, rapid developments of single-cell and spatial omics technologies are revolutionizing our understanding of the molecular architecture of biological systems. However, a significant gap remains in how we align our understanding of drug actions, traditionally based on molecular affinities, with the in vivo cellular and spatial tissue heterogeneity revealed by these newer techniques. Here, we review state-of-the-art methods for profiling drug-target interactions and emerging multiomics tools to delineate the tissue heterogeneity at single-cell resolution. Highlighting the recent technical advances enabling high-resolution, multiplexable in situ small-molecule drug imaging (clearing-assisted tissue click chemistry, or CATCH), we foresee the integration of single-cell and spatial omics platforms, data, and concepts into the future framework of defining and understanding in vivo drug-target interactions and mechanisms of actions. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 64 is January 2024. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Lysophosphatidylserine: A Signaling Lipid with Implications in Human Diseases

“…Second, despite significant advances in our understanding of the biological phenotypes associated with lyso-PS (e.g., mast cell degranulation, macrophage efferocytosis), little remains known in terms of the protein interactors (or ligands or targets) of lyso-PS in different mammalian cells and tissues. Over the past two decades, chemical proteomics coupled to bioorthogonal reactions has emerged as a powerful functional proteomic strategy to discover protein targets of endogenous ligands and drug candidates in physiological settings and, by doing so, has significantly accelerated our mechanistic knowledge of numerous biological pathways. − Of note, more recently, the development of chemical proteomics platforms using bioorthogonal photoreactive lipid probes has greatly facilitated our understanding of lipid–protein interactions, especially for various signaling lipids (Figure ). − Leveraging such a chemical proteomics strategy by developing bioorthogonal photoreactive lyso-PS probes will go a long way in the identification of protein targets of lyso-PS in various mammalian cells and tissues.…”