Mammalian peptide transporters as targets for advanced drug design and delivery. (360G-Wellcome-102890_Z_13_Z)

£1,644,734

My research seeks to develop a mechanistic understanding of peptide and drug transport in the human body via the mammalian PepT1 and PepT2 proteins, members of the proton coupled peptide transporter family of plasma membrane transporters. PepT1 and PepT2 are responsible for the absorption and retention of dietary protein in the form of small peptides and also for the majority of beta-lactam antibiotic transport in the small intestine. The US Food and Drug Administration recently identified PepT1 and PepT2 as clinically important transport proteins, further underlining their important role in drug transport. A growing number of antiviral and anticancer drugs have been modified to utilize PepT1 to improve their absorption following oral administration. PepT1 and PepT2 represent excellent targets for the efficient and controlled delivery of drugs into the human body as their peptide binding site can accommodate a wide range of molecules of differing size, hydrophobicity and charge, enabli ng chemically diverse peptides and drug molecules to be transported. My research into the structure and function of the bacterial homologues provides very promising evidence that PepT1 and PepT2 can be targeted more intelligently if we only had the necessary molecular insight into how peptides and drugs are recognized and transported. My research goal is to provide this insight using state-of-the-art structural, biochemical and functional analysis with the long-term vision of improving the bioav ailability of new and existing drugs by targeting them for transport via PepT1 and PepT2. To achieve this I need to address the following questions: 1. Does drug transport via PepT1 and PepT2 operate with the same mechanism as that for natural peptides or via an alternative mechanism? 2. How are binding and transport linked and what features of the protein and binding site determine ligand affinity, specificity and transport rate? 3. Can we improve the recognition of transported beta-l actam antibiotics and apply this knowledge to new classes of drug molecule such as antivirals? 4. What role does post-translational regulation have in controlling peptide transport in the mammalian cell and what are the implications for our understanding of eukaryotic membrane protein function? These questions form part of an integrated and coherent work program that address the relationship between peptide and drug transport through PepT1 and PepT2. Without the insights gained from crystal structures, insightful biochemical analysis and in vitro kinetic data investigating the effects of post translational regulation on human peptide transport, our ability to understand the roles played by PepT1 and PepT2 in drug transport will be inadequate, limiting our ability to utilize these proteins for improving drug transport in the future.

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Grant Details

Amount Awarded 1644734
Applicant Surname Newstead
Approval Committee Science Interview Panel
Award Date 2013-12-03T00:00:00+00:00
Financial Year 2013/14
Grant Programme: Title Investigator Award in Science
Internal ID 102890/Z/13/Z
Lead Applicant Prof Simon Newstead
Partnership Value 1644734
Planned Dates: End Date 2019-12-31T00:00:00+00:00
Planned Dates: Start Date 2014-06-01T00:00:00+00:00
Recipient Org: Country United Kingdom
Region South East