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

BioRxiv : the Preprint Server for Biology
Gurdeep S Minhas, Simon Newstead

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 ...Continue Reading

Related Concepts

Aminolevulinic Acid
Antineoplastic Agents
Antiviral Agents
Drug Carriers
Intestinal Absorption
Ligands
Monobactams
Peptides
Photochemotherapy
Prodrugs

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