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

Gurdeep S Minhas,Simon Newstead

doi:10.1073/pnas.1813715116

Gurdeep S Minhas, Simon Newstead

Open Access

https://doi.org/10.1073/pnas.1813715116

Copy DOI

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.

Highlights

A major challenge in drug development is the optimization of intestinal absorption and cellular uptake
The oral bioavailability of valacyclovir improved to >50% for the prodrug derivative valacyclovir compared with 15% for the parent drug acyclovir, which was attributed to its recognition and transport by PepT1 [11, 12]
Combined with the previous peptide-bound structures, we present a pharmacophore model for prodrug recognition, which facilitates a structure-based route to further drug development targeted at the SLC15 family

Summary

Introduction

A major challenge in drug development is the optimization of intestinal absorption and cellular uptake. 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. PepT1 exhibits a remarkably promiscuous binding site and is known to transport many different drug molecules These include, but are not limited to, angiotensin converting enzyme inhibitors, beta-lactam antibiotics, an N-methyl-D-aspartate receptor antagonist PD-15874, and 5-aminolevulinic acid, an endogenous nonprotein amino acid currently being evaluated as a photodynamic therapeutic agent for the treatment of bladder cancer and esophageal carcinoma [7]. We present the structure of a bacterial homolog of PepT1 bound to both an antiviral prodrug, valacyclovir, and anticancer drug 5-aminolevulinic acid These structures enable a pharmacophore model to be developed that will aid future prodrug design

Methods

Results

Discussion

Conclusion