SLC transporters as therapeutic targets: emerging opportunities

Key Points

  • Membrane transport proteins mediate the transport of molecules across cell membranes and have key roles in human health. More than 100 Mendelian diseases are caused by a defect in a single solute carrier (SLC) transporter.

  • Genetic studies have provided a wealth of information on the roles that SLC transporters play in human health, and in common and rare diseases, enhancing our understanding of the biology of these membrane transporters.

  • High-throughput screening technologies and computational methods may be used to discover novel inhibitors and activators of SLC transporters for therapeutic purposes.

  • Utilizing transporters as drug targets may require indirect methods, such as developing molecules that function as potentiators or correctors, or developing substrates that bypass the transporter.

  • Some currently marketed drugs, including diuretics, neuropsychiatric drugs and antidiabetic drugs, target SLC transporters.

  • Uric acid-, glycine- and bile acid-transport inhibitors are currently in various stages of clinical development for the treatment of various human diseases. First-in-class compounds that target SLC transporters are anticipated to be approved in the near future.

  • Positron emission tomography (PET)-imaging probes may utilize transporters for uptake into cells, enabling transporter function to be visualized in vivo.

Abstract

Solute carrier (SLC) transporters — a family of more than 300 membrane-bound proteins that facilitate the transport of a wide array of substrates across biological membranes — have important roles in physiological processes ranging from the cellular uptake of nutrients to the absorption of drugs and other xenobiotics. Several classes of marketed drugs target well-known SLC transporters, such as neurotransmitter transporters, and human genetic studies have provided powerful insight into the roles of more-recently characterized SLC transporters in both rare and common diseases, indicating a wealth of new therapeutic opportunities. This Review summarizes knowledge on the roles of SLC transporters in human disease, describes strategies to target such transporters, and highlights current and investigational drugs that modulate SLC transporters, as well as promising drug targets.

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Figure 1: Overview of the different types of mutations in SLC transporter genes, and their effects.
Figure 2: SLC transporters implicated in Mendelian diseases, grouped by substrate type.

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Acknowledgements

The authors acknowledge the following funding sources: a US National Institutes of Health (NIH) Training Grant (T32 GM007175) to L.L; an NIH grant (GM61390) to S.W.Y.; an NIH Pharmacogenomics Research Network grant (GM61390) and a Burroughs Wellcome Fund Innovation in Regulatory Sciences grant (1012485, DK103729) to K.M.G.; and a Canadian Institutes of Health Research grant (MOP-89753, DSEN-PREVENT FRN-117588), the Ontario Institutes for Cancer Research, Cancer Care Ontario, and the Program of Experimental Medicine in the Department of Medicine at Western University, in Ontario, Canada, to R.B.K.

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Correspondence to Kathleen M. Giacomini.

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Competing interests

K.M.G. is a co-founder of Apricity Therapeutics and has received grants from Pfizer, Sanofi–Aventis, AstraZeneca and GlaxoSmithKline, and has a patent pending. S.W.Y. is a co-founder of Apricity Therapeutics and has a patent pending. R.B.K. has a patent pending.

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Supplementary information

Supplementary information S1 (table)

SLC transporter-associated Mendelian diseases. The transporters associated with Mendelian diseases and prevalence data on each disease are provided. (PDF 363 kb)

Supplementary information S2 (table)

SLC transporter genes and associated Mendelian diseases. (PDF 1152 kb)

Glossary

Mendelian diseases

Disorders that are caused by mutations in a single gene and follow Mendelian inheritance patterns.

Genome-wide association studies

(GWASs). Studies of multiple genetic variants across the genome in many individuals, looking for association with a given trait. In most GWASs, more than 500,000 genetic variants across the genome are examined for association with a certain trait of some individuals that does not appear in others.

Z′ assay sensitivity factor

A measure of statistical effect size that takes into account the mean and standard deviation of both the positive and the negative controls.

Pharmacophore modelling

Use of a geometric description of the chemical functions of a target protein to generate and use 3D structural information to search for novel active compounds. Models may be generated by either ligand-based or structure-based methods.

Quantitative structure–activity relationship (QSAR) modelling

Use of a regression model to find relationships between the physical or chemical properties and the biological activity of a molecule, based on the assumption that these features are related.

Docking

A computational method used to predict the orientation of molecules during interactions with a target protein.

Homology models

Molecular models of a target protein created from its amino acid sequence and the 3D structure of a homologous protein.

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Lin, L., Yee, S., Kim, R. et al. SLC transporters as therapeutic targets: emerging opportunities. Nat Rev Drug Discov 14, 543–560 (2015). https://doi.org/10.1038/nrd4626

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