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New and Emerging Research on Solute Carrier and ATP Binding Cassette Transporters in Drug Discovery and Development: Outlook From the International Transporter Consortium
Author(s) -
Giacomini Kathleen M.,
Yee Sook W.,
Koleske Megan L.,
Zou Ling,
Matsson Pär,
Chen Eugene C.,
Kroetz Deanna L.,
Miller Miles A.,
Gozalpour Elnaz,
Chu Xiaoyan
Publication year - 2022
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1002/cpt.2627
Subject(s) - transporter , drug discovery , computational biology , atp binding cassette transporter , biology , solute carrier family , function (biology) , membrane transport protein , drug development , bioinformatics , microbiology and biotechnology , pharmacology , drug , biochemistry , gene
Enabled by a plethora of new technologies, research in membrane transporters has exploded in the past decade. The goal of this state‐of‐the‐art article is to describe recent advances in research on membrane transporters that are particularly relevant to drug discovery and development. This review covers advances in basic, translational, and clinical research that has led to an increased understanding of membrane transporters at all levels. At the basic level, we describe the available crystal structures of membrane transporters in both the solute carrier (SLC) and ATP binding cassette superfamilies, which has been enabled by the development of cryogenic electron microscopy methods. Next, we describe new research on lysosomal and mitochondrial transporters as well as recently deorphaned transporters in the SLC superfamily. The translational section includes a summary of proteomic research, which has led to a quantitative understanding of transporter levels in various cell types and tissues and new methods to modulate transporter function, such as allosteric modulators and targeted protein degraders of transporters. The section ends with a review of the effect of the gut microbiome on modulation of transporter function followed by a presentation of 3D cell cultures, which may enable in vivo predictions of transporter function. In the clinical section, we describe new genomic and pharmacogenomic research, highlighting important polymorphisms in transporters that are clinically relevant to many drugs. Finally, we describe new clinical tools, which are becoming increasingly available to enable precision medicine, with the application of tissue‐derived small extracellular vesicles and real‐world biomarkers.