Drug transport through human peptide transporters

The human proton-coupled oligopeptide transporters PepT1 and PepT2 play a crucial role not only in the absorption of dietary nitrogen in the form of di- and tri-peptides, but also in absorption and retention of structurally similar drugs, such as beta-lactam antibiotics.

Recent structural studies on bacterial homologues have highlighted the roles for key protein residues involved in transport, and molecular dynamics (MD) simulations have been used to gain insight into the free energy landscape of the alternating access mechanism of conformational changes during transport.

The molecular basis of the transporter’s substrate promiscuity, that is why some molecules are transported but not others, remains poorly understood, however.

In this project, we aim in the first instance to use MD to probe how binding of transported drugs affects the transporter on a molecular level.

This will enable us to construct a pharmacophore model for transport to cover the wider chemical space of drugs, by helping us understand key substrate–transporter interactions which initiate transport.

We will test these computational predictions in transport assays, and collaborate with synthetic chemists to design better substrates for transport. These studies will help the design of drugs and prodrugs with better pharmacokinetic properties.