Elucidating the molecular mechanism of drug transport through structural studies of peptide transport proteins.

The design of drugs for oral administration is common practice in the pharmaceutical industry due to ease of patient administration, storage, distribution and patient compliance. Many drugs however are poorly absorbed in the gastrointestinal (GI) tract, the main route by which orally administered drugs enter the blood stream. One successful approach to overcome this obstacle has been the design of prodrugs. Prodrugs are modified drug compounds that target nutrient transporters in the GI tract. Of these, oligopeptide transporters are the most promising targets as they are highly expressed in the GI tract and are already responsible for the uptake of antibiotics. This prodrug strategy has already been successful in improving the oral bioavailability of a number of medically important antivirals. The role of this research proposal is to gain an understanding of the underlying mechanism by which these peptide transporters function. Such information will enable a more rational extension of the initial prodrug approach with benefits for both patients and the pharmaceutical industry alike.

The proton oligopeptide cotransporter family, SLC15, is a family of integral membrane proteins that utilise the proton motive force to power the uptake of short chain peptides and peptidomimetics into a variety of cells. These proteins are the major routes of dietry nitrogen absorption from the small intestine and nitrogen re-absorption from the glomerular filtrate in the kidney. They are of broad pharmaceutical interest due to their ability to actively uptake a number of pharmaceutically important drugs, such as the beta-lactam antibiotics, certain antivirals and HIV protease inhibitors.
The aim of this proposal is to elucidate the molecular mechanism by which the SLC15 family of integral membrane proteins function and to gain a deeper understanding of drug transport and oral bioavailability. This research has significant clinical utility, as oral administration is currently the most successful route for drug administration. An understanding, at the molecular level, of how drugs are both recognised and transported across the gut epithelium will aid in more rational drug design and should have significant translational potential.
I plan to achieve these goals principally through the insights gained from X-ray crystallography. X-ray crystallography is particularly powerful in this regard as it allows currently unparalleled insights into molecular form and function. Functional studies will also be undertaken and directed by the insights obtained from the structural models. This will be a collaborative project with both eukaryotic and prokaryotic transporters being studied.
Using the expertise I have gained in the laboratory of Prof. So Iwata I am currently in the process of determining the first crystal structure of a peptide transport protein. The insights gained from this structure will make a significant contribution to our understanding of drug uptake in the human gastrointestinal tract. Through collaborations with medicinal chemists and physiologists I plan to extend this research to include the human members of this transport family. During my post-doctoral research I helped develop a rational platform for optimising membrane protein transporters for structural studies. This included screening for solubility, monodispersity and thermal stability in different detergents using small quantities of protein to allow rapid and cost effective identification of suitable targets. These methods have worked successfully for the bacterial peptide transport proteins and I now plan to utilise these methods to work on the mammalian SLC15 family members.