Skip to main content
bioRxiv
  • Home
  • About
  • Submit
  • ALERTS / RSS
Advanced Search
New Results

Structural basis for prodrug recognition by the SLC15 family of proton coupled peptide transporters

View ORCID ProfileGurdeep S. Minhas, View ORCID ProfileSimon Newstead
doi: https://doi.org/10.1101/454116
Gurdeep S. Minhas
1Department of Biochemistry, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Gurdeep S. Minhas
Simon Newstead
1Department of Biochemistry, University of Oxford, South Parks Road, Oxford, OX1 3QU, UK
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • ORCID record for Simon Newstead
  • Abstract
  • Full Text
  • Info/History
  • Metrics
  • Supplementary material
  • Preview PDF
Loading

Abstract

A major challenge in drug development is the optimisation 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 recognise a diverse library of di‐ and tri-peptides, making them extremely promiscuous and major contributors to the pharmacokinetic profile of several important drug classes, including beta-lactam antibiotics, anti-viral and antineoplastic agents. Of particular interest has been their ability to recognise 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 homologue 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 to physiological peptides. These structures provide a unique insight into how peptide transporters interact with xenobiotic molecules and provide a template for further prodrug development.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
Back to top
PreviousNext
Posted October 26, 2018.
Download PDF

Supplementary Material

Email

Thank you for your interest in spreading the word about bioRxiv.

NOTE: Your email address is requested solely to identify you as the sender of this article.

Enter multiple addresses on separate lines or separate them with commas.
Structural basis for prodrug recognition by the SLC15 family of proton coupled peptide transporters
(Your Name) has forwarded a page to you from bioRxiv
(Your Name) thought you would like to see this page from the bioRxiv website.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Share
Structural basis for prodrug recognition by the SLC15 family of proton coupled peptide transporters
Gurdeep S. Minhas, Simon Newstead
bioRxiv 454116; doi: https://doi.org/10.1101/454116
Digg logo Reddit logo Twitter logo Facebook logo Google logo LinkedIn logo Mendeley logo
Citation Tools
Structural basis for prodrug recognition by the SLC15 family of proton coupled peptide transporters
Gurdeep S. Minhas, Simon Newstead
bioRxiv 454116; doi: https://doi.org/10.1101/454116

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Subject Area

  • Biochemistry
Subject Areas
All Articles
  • Animal Behavior and Cognition (4109)
  • Biochemistry (8813)
  • Bioengineering (6517)
  • Bioinformatics (23456)
  • Biophysics (11788)
  • Cancer Biology (9205)
  • Cell Biology (13318)
  • Clinical Trials (138)
  • Developmental Biology (7433)
  • Ecology (11407)
  • Epidemiology (2066)
  • Evolutionary Biology (15145)
  • Genetics (10433)
  • Genomics (14041)
  • Immunology (9169)
  • Microbiology (22152)
  • Molecular Biology (8808)
  • Neuroscience (47558)
  • Paleontology (350)
  • Pathology (1428)
  • Pharmacology and Toxicology (2491)
  • Physiology (3730)
  • Plant Biology (8079)
  • Scientific Communication and Education (1437)
  • Synthetic Biology (2220)
  • Systems Biology (6037)
  • Zoology (1252)