Novel drug transporter substrates identification: An innovative approach based on metabolomic profiling, in silico ligand screening and biological validation

Anne T Nies; Jörg König; Patrick Leuthold; Katja Damme; Stefan Winter; Mathias Haag; Satohiro Masuda; Stephan Kruck; Hannelore Daniel; Britta Spanier; Martin F Fromm; Jens Bedke; Ken-Ichi Inui; Matthias Schwab; Elke Schaeffeler

doi:10.1016/j.phrs.2023.106941

Novel drug transporter substrates identification: An innovative approach based on metabolomic profiling, in silico ligand screening and biological validation

Pharmacol Res. 2023 Oct:196:106941. doi: 10.1016/j.phrs.2023.106941. Epub 2023 Sep 27.

Authors

Affiliations

¹ Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany, and University of Tuebingen, Germany; Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tuebingen, Germany.
² Institute of Experimental and Clinical Pharmacology and Toxicology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
³ Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany, and University of Tuebingen, Germany.
⁴ Department of Clinical Pharmacology & Biopharmaceutics, Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan; Department of Clinical Pharmaceutics, Faculty of Pharmaceutical Sciences, Himeji Dokkyo University, Himeji, Japan.
⁵ Department of Urology, University Hospital Tuebingen, Germany.
⁶ TUM School of Life Sciences Weihenstephan, Technical University of Munich, Freising, Germany.
⁷ Kyoto Pharmaceutical University, Kyoto, Japan.
⁸ Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany, and University of Tuebingen, Germany; Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tuebingen, Germany; Departments of Clinical Pharmacology, Pharmacy and Biochemistry, University of Tuebingen, Germany. Electronic address: [email protected].

PMID: 37775020
DOI: 10.1016/j.phrs.2023.106941

Abstract

Solute carrier (SLC) transport proteins are fundamental for the translocation of endogenous compounds and drugs across membranes, thus playing a critical role in disease susceptibility and drug response. Because only a limited number of transporter substrates are currently known, the function of a large number of SLC transporters is elusive. Here, we describe the proof-of-concept of a novel strategy to identify SLC transporter substrates exemplarily for the proton-coupled peptide transporter (PEPT) 2 (SLC15A2) and multidrug and toxin extrusion (MATE) 1 transporter (SLC47A1), which are important renal transporters of drug reabsorption and excretion, respectively. By combining metabolomic profiling of mice with genetically-disrupted transporters, in silico ligand screening and in vitro transport studies for experimental validation, we identified nucleobases and nucleoside-derived anticancer and antiviral agents (flucytosine, cytarabine, gemcitabine, capecitabine) as novel drug substrates of the MATE1 transporter. Our data confirms the successful applicability of this new approach for the identification of transporter substrates in general, which may prove particularly relevant in drug research.

Keywords: 5-Methylcytidine (PubChem CID: 92918); Anserine (PubChem CID: 112072); Capecitabine (PubChem CID: 60953); Cytarabine (PubChem CID: 6253); Cytosine (PubChem CID: 597); Drug screening; Drug transport; Flucytosine (PubChem CID: 3366); Gemcitabine (PubChem CID: 60750); In silico screening; Metabolomics; Multidrug and toxin extrusion protein 1; Proton-coupled peptide transporter 2.

MeSH terms

Animals
Biological Transport
Ligands
Membrane Transport Proteins*
Mice
Solute Carrier Proteins*

Substances

Ligands
Membrane Transport Proteins
Solute Carrier Proteins