Navigating Solute Carrier Transporters-A Comprehensive Review of Functionalized Small Molecule Probes for Target Identification and Characterization.

Abstract

Solute carrier transporters (SLCs) are integral membrane proteins that play pivotal roles in maintaining cellular homeostasis by mediating the transport of a diverse range of substrates across cell membranes. With their involvement in fundamental physiological processes such as nutrient uptake, neurotransmitter signaling, and drug transport, SLCs have emerged as crucial players in health and disease. Dysregulation of SLC function has been implicated in a spectrum of disorders, including metabolic diseases, cancer, and neurological afflictions. Despite their significance, SLCs remain relatively understudied compared to other protein classes, resulting in a gap in understanding their molecular mechanisms of action and potential as therapeutic targets. This review aims to address this gap by providing a comprehensive overview of the diverse array of small-molecule probes utilized in the study of SLCs. Various types of functionalized probes, amongst which fluorescent probes, bivalent probes, covalent inhibitors, affinity-based probes, photoswitchable inhibitors and proteolysis targeting chimeras (PROTACs), have been designed to investigate transporter function, substrate specificity, and regulatory mechanisms. In this review, we describe the principles underlying the design and synthesis of these probes, highlights key examples of their application in elucidating transporter function and regulation, and discuss insights gained from such studies. Furthermore, we examine current challenges and future directions in the development and utilization of small-molecule probes for SLC transporter research. By shedding light on the intricate mechanisms involved in transporter function and regulation, this review not only enhances the understanding of SLCs but also highlights their potential as therapeutic targets in drug discovery and thereby may facilitate systematic implementation of these innovative research approaches and the refinement of existing methodologies.