EPSAM

I graduated in 2008 with a BSC with honours in Chemistry with Forensic science from Keele University. I am currently in the third year of my AstraZeneca CASE studenship researching the use of the human PepT1 transporter as a route to improve the oral bioavailability of Pharmaceuticals.

Affiliations:

• Bailey and Phillips Research group
• Keele synthesis and medicinal chemistry cluster
• Academy of Pharmaceutical sciences
• Royal society of chemistry

Supervisors

• Prof. Pat Bailey - Keele University
• Dr Kevin Foote - AstraZeneca

Collaborators

• Kate Harris, Stuart Pearson, Lee Ashworth – AstraZeneca
• Dr David Meredith – Oxford Brookes University
• Prof. Randy Mrsny – University of Bath

The design and synthesis of drug carrier molecules to improve the oral bioavailability of hPepT1

Lead supervisor:  Prof Pat Bailey

PepT1 (SLC15A1) is a low affinity high capacity, di- and tri-peptide transmembrane transporter. It is found in the highest concentrations at the villi tips of the brush border membrane in the small intestines.  As well as transporting oligopeptides, PepT1 has also been discovered to transport wide range of xenobiotics including, β–lactams and ACE inhibitors. This broad substrate capacity makes PepT1 ideal as a vehicle for the targeted delivery of xenobiotic prodrugs.

The use of our patented, hydrolysis resistant, PepT1 recognised carriers allows prodrugs to be created of gastric irritating or poorly absorbed drugs. The prodrugs can then be absorbed through the wall of the small intestine via the PepT1 co-transport mechanism. The use of an ether, ester or hydroxyimine bond as a linker between the carrier and the drug allows for effective metabolism of the prodrug back into its active form. The presence of the thio-amide bond within the carrier maintains binding affinity, but ensures that metabolism by peptidases in the GI tract cannot occur.

The discovery that PepT1 is over-expressed in pancreatic adenocarcinoma cell lines, AsPc-1 and Capan-2,4 has also led to research being undertaken into targeted anti-cancer therapy, via our thiodipeptide. We believe that through the use of the PepT1 carrier method, a wider range of pharmaceuticals may be brought to the market via the oral route. By determining the limits of the PepT1 transporter for drug moiety attachments, it is hoped that not only can new drugs be formulated using this technique, but that existing drugs can be reassessed.