ArticleProceedings of the National Academy of Sciences of the United States of America2019
Structural basis for prodrug recognition by the SLC15 family of proton-coupled peptide transporters.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 67 citations in OpenAlex.
- Dipeptide Transport Systems at the Interface of Peptide Metabolism and Drug Delivery in Cancer.International journal of molecular sciences · 2026Review
- Energetic and structural control of polyspecificity in a multidrug transporter.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Enhanced lymphatic transportation of SLN by mimicking oligopeptide transportation route.Asian journal of pharmaceutical sciences · 2025Article
- Understanding, inhibiting, and engineering membrane transporters with high-throughput mutational screens.Cell chemical biology · 2025Review
- Energetics of substrate transport in proton-dependent oligopeptide transporters.Communications chemistry · 2024Article
- Structural basis for antibiotic transport and inhibition in PepT2.Nature communications · 2024Article
- Article
- FOCUS on NOD2: Advancing IBD Drug Discovery with a User-Informed Machine Learning Framework.ACS medicinal chemistry letters · 2024Article
- Structural basis for antibiotic transport and inhibition in PepT2, the mammalian proton-coupled peptide transporter.Research square · 2024Article
- The Application of Prodrugs as a Tool to Enhance the Properties of Nucleoside Reverse Transcriptase Inhibitors.Viruses · 2023Review
- Proton-Coupled Oligopeptide Transport (Slc15) in the Brain: Past and Future Research.Pharmaceutical research · 2023Review
- Minimal Out-of-Equilibrium Metabolism for Synthetic Cells: A Membrane Perspective.ACS synthetic biology · 2023Review
- Transporter-Mediated Drug Delivery.Molecules (Basel, Switzerland) · 2023Review
- Extracellular domain of PepT1 interacts with TM1 to facilitate substrate transport.Structure (London, England : 1993) · 2022Article
- Proton coupling and the multiscale kinetic mechanism of a peptide transporter.Biophysical journal · 2022Article
- Peptide transporter structure reveals binding and action mechanism of a potent PEPT1 and PEPT2 inhibitor.Communications chemistry · 2022Article
- Gutsy science: In vitro systems of the human intestine to model oral drug disposition.Pharmacology & therapeutics · 2022Review
- Mutagenesis and functional analysis of SotB: A multidrug transporter of the major facilitator superfamily fromFrontiers in microbiology · 2022Article
- Structural snapshots of human PepT1 and PepT2 reveal mechanistic insights into substrate and drug transport across epithelial membranes.Science advances · 2021Article
- The Transporter-Mediated Cellular Uptake and Efflux of Pharmaceutical Drugs and Biotechnology Products: How and Why Phospholipid Bilayer Transport Is Negligible in Real Biomembranes.Molecules (Basel, Switzerland) · 2021Review
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2 authors at 1 institution in 1 country.
Funding
Abstract
A major challenge in drug development is the optimization of intestinal absorption and cellular uptake. A successful strategy has been to develop prodrug molecules, which hijack solute carrier (SLC) transporters for active transport into the body. The proton-coupled oligopeptide transporters, PepT1 and PepT2, have been successfully targeted using this approach. Peptide transporters display a remarkable capacity to recognize a diverse library of di- and tripeptides, making them extremely promiscuous and major contributors to the pharmacokinetic profile of several important drug classes, including beta-lactam antibiotics and antiviral and antineoplastic agents. Of particular interest has been their ability to recognize amino acid and peptide-based prodrug molecules, thereby providing a rational approach to improving drug transport into the body. However, the structural basis for prodrug recognition has remained elusive. Here we present crystal structures of a prokaryotic homolog of the mammalian transporters in complex with the antiviral prodrug valacyclovir and the peptide-based photodynamic therapy agent, 5-aminolevulinic acid. The valacyclovir structure reveals that prodrug recognition is mediated through both the amino acid scaffold and the ester bond, which is commonly used to link drug molecules to the carrier's physiological ligand, whereas 5-aminolevulinic acid makes far fewer interactions compared with physiological peptides. These structures provide a unique insight into how peptide transporters interact with xenobiotic molecules and provide a template for further prodrug development.
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