Abstract
Solute carrier (SLC) transporters play important roles in regulating the movement of small molecules and ions across cellular membranes. In mammals, they play an important role in regulating the uptake of nutrients and vitamins from the diet, and in controlling the distribution of their metabolic intermediates within the cell. Several SLC families also play an important role in drug transport and strategies are being developed to hijack SLC transporters to control and regulate drug transport within the body. Through the addition of amino acid and peptide moieties several novel antiviral and anticancer agents have been developed that hijack the proton-coupled oligopeptide transporters, PepT1 (SCL15A1) and PepT2 (SLC15A2), for improved intestinal absorption and renal retention in the body. A major goal is to understand the rationale behind these successes and expand the library of prodrug molecules that utilise SLC transporters. Recent co-crystal structures of prokaryotic homologues of the human PepT1 and PepT2 transporters have shed important new insights into the mechanism of prodrug recognition. Here, I will review recent developments in our understanding of ligand recognition and binding promiscuity within the SLC15 family, and discuss current models for prodrug recognition.
Highlights
Solute carrier (SLC) transporters are important determinants of drug pharmacokinetics and are increasingly being identified as important therapeutic targets in their own right [1,2]
One approach to address this challenge has been the development of prodrugs that target the intestinal peptide transporter, PepT1 (SLC15A1), which is highly expressed in the brush border membrane of the small intestine [4,5] (Figure 1A)
Within the repertoire of intestinal SLC transporters, PepT1 stands out as displaying the most extreme promiscuity [25]. This characteristic, coupled with the similarity of both amino acid side chains to functional groups of drug molecules and the size of di- and tri-peptides to small molecule therapeutics [11], has resulted in PepT1 being a major focus of prodrug design strategies [26,27,28]
Summary
Solute carrier (SLC) transporters play important roles in regulating the movement of small molecules and ions across cellular membranes. In mammals, they play an important role in regulating the uptake of nutrients and vitamins from the diet, and in controlling the distribution of their metabolic intermediates within the cell. Several SLC families play an important role in drug transport and strategies are being developed to hijack SLC transporters to control and regulate drug transport within the body. I will review recent developments in our understanding of ligand recognition and binding promiscuity within the SLC15 family, and discuss current models for prodrug recognition
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