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(BBSRC DTP) Synthetic biology and specificity of membrane transporters for drugs and xenobiotics

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  • Full or part time
    Prof D Kell
    Dr P Day
  • Application Deadline
    No more applications being accepted
  • Competition Funded PhD Project (European/UK Students Only)
    Competition Funded PhD Project (European/UK Students Only)

Project Description

It is now becoming clear [1,2] that xenobiotics (including pharmaceutical drugs) do not enter cells by ‘passive’ transport across any untrammelled phospholipid bilayer, but must and do hitchhike on membrane transporters (SoLute Carriers, SLCs) that normally exist for the transport of intermediary metabolites [3] and natural products [4]. Consequently, the distribution of administered drugs, which underpins their (lack of) efficacy and/or toxicity, is determined by the distribution and specificity of SLCs. The big need [5] is to understand which transporters are used by particular xenobiotics and vice versa, and the aim of this project is to find out.

This statement is true both for the pharmaceutical drugs that we have mainly studied to date and for the uptake of the substrates and efflux of products that are the subject of the biotransformations research in SYNBIOCHEM. The means by which we do that involve manipulation of the expression levels and sequences (see SpeedyGenes at http://dbkgroup.org/publications/) of transporters and the study of the effects thereon of candidate uptake molecules. By varying the molecules we obtain a so-called Quantitative Structure-Activity
Relationship (QSAR) that allows us to predict the uptake of any small molecule of known structure. In parallel, we use machine learning methods to understand the effect of protein sequence variations on the QSARs, to help determine and indeed to design and build those sequences that are best for as-yet-untested or poorly active transporter substrates. Assays of drug uptake are by mass spectrometry or, where appropriate, by competition against the uptake of fluorescent substrates, the latter conveniently performed in 384-well plate format in our newly commissioned (BBSRC ALERT 2017 competition) Intellicyt iQue PLUS instrument.

The interdisciplinary project will provide world-class training in modern molecular and synthetic biology, in high-throughput assay technology, and in the computational (‘cheminformatic’) analysis of large structureactivity and sequence-activity datasets, within the open source KNIME environment (www.knime.org/).

Qualification
Applications are invited from UK/EU nationals only. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.

Contact for further Information
For more details contact Professor Doug Kell ([email protected])

http://dbkgroup.org/publications/

Funding Notes

This project is to be funded under the BBSRC Doctoral Training Programme. If you are interested in this project, please make direct contact with the Principal Supervisor to arrange to discuss the project further as soon as possible. You MUST also submit an online application form - full details on how to apply can be found on the BBSRC DTP website www.manchester.ac.uk/bbsrcdtpstudentships

References

[1] Kell DB, Dobson PD, Bilsland E, Oliver SG: The promiscuous binding of pharmaceutical drugs and their transporter-mediated uptake into cells: what we (need to) know and how we can do so. Drug Disc Today 2013;18:218-239.

[2] Kell DB, Oliver SG: How drugs get into cells: tested and testable predictions to help discriminate between transporter-mediated uptake and lipoidal bilayer diffusion. Front Pharmacol 2014; 5:231.

[3] O'Hagan S, Swainston N, Handl J, Kell DB: A ‘rule of 0.5′ for the metabolite-likeness of approved pharmaceutical drugs. Metabolomics 2015; 11:323-339.

[4] O'Hagan S, Kell DB: Consensus rank orderings of molecular fingerprints illustrate the ‘most genuine’ similarities between marketed drugs and small endogenous human metabolites, but highlight exogenous natural products as the most important ‘natural’ drug transporter substrates. ADMET & DMPK 2017; 5:85-125.

[5] César-Razquin A, Snijder B, Frappier-Brinton T, Isserlin R, Gyimesi G, Bai X, Reithmeier RA, Hepworth D, Hediger MA, Edwards AM, Superti-Furga G: A call for systematic research on solute carriers. Cell 2015;162:478-487..

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