Peptide transporters are the major route of dietary peptide absorption in the small intestine and kidneys. In humans they belong to the Solute Carrier (SLC) 15 gene family and are called PepT1 and PepT2. Both PepT1 and PepT2 are of significant pharmaceutical interest due to their ability to actively uptake a number of clinically important drugs, such as beta-lactam antibiotics, antivirals and HIV protease inhibitors. Recent developments in drug delivery technology have targeted PepT1 and PepT2 to improve the pharmacokinetic properties of several drug molecues, including their uptake and retention within the body. Following attachment of amino acids or small peptides to a drug that has poor absorption properties, these so-called peptide pro drugs are now recognized by PepT1 and transported into the body following oral administration. The potential of utilizing PepT1 and PepT2 as universal drug delivery and retention systems represents a profound and transformative new development in engineered drug bioavailiabity.
A key research aim is to provide novel insights into the molecular details underpinning the observed peptide and drug recognition properties within the SLC15 peptide transporter family and use this to develop novel strategies for drug delivery.
Since determining the first crystal structure of a peptide transporter in 2011 we have continued to expand our understanding of this important SLC family, recently reviewed here. In particular our co-crystal structures with di- and tri-peptide ligands revealed a novel multi-site binding mode, which may help to explain the promiscuous nature of the binding site.
Recently we determined the crystal structure of the extracellular domain of the mammalian transporters, PepT1 and PepT2.
To understand the molecular basis for substrate recognition we also determined the crystal structure of the plant nitrate transporter, NRT1.1. Although a member of the SLC15 family, this protein has adapted to recognise nitrate in place of peptides, yet still retains much of the proton coupling machinary. Our structure and associated biochemical work also revealed a phosphorylation driven kinetic switch, that functions in vivo to regulate the Km of nitrate transport.
We are continuing to discover more details concerning the molecular basis for proton coupled peptide transport. Our recent work on the role of water wires shows how protons are moved within the binding site and our discovery that certain members of the family can transport peptides using variable proton stoichiometries may help to explain why peptide transport in eukaryotes is still proton coupled. Our current work is focused on drug complexes and the recognition of xenobiotics.