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Development of novel tools that bind intrinsically disordered regions to manipulate clinically important targets


Project Description

Dual award PhD in Synthetic and Systems Biology - Manchester and Tsinghua University.

The University of Manchester and China’s Tsinghua University have come together to offer a unique dual degree PhD programme in Synthetic and Systems Biology, with successful applicants spending four life-changing years across Manchester and Beijing. The first-of-its-kind dual award PhD programme brings together two globally-renowned institutions at the forefront of research in this area: the Manchester Institute of Biotechnology (MIB) at The University of Manchester, and the Center for Synthetic and Systematic Biology (CSSB) at Tsinghua University in Beijing, China.

Students will spend two years at Manchester and two years at Tsinghua University, with supervisors in both locations. At the end of the four-year full-time programme, you will receive a dual PhD, one award and two certificates.

Project Description:
The project will use novel approaches to identify sites within intrinsically disordered regions of high-value protein targets that are vulnerable to inhibition. From here conformation-specific monoclonal antibodies and antibody mimetics will be developed that allow the selective manipulation of the function of these high-value protein targets.
The controlled manipulation of proteins that contain intrinsically disordered regions is a largely untapped area that offers extensive opportunities to improve our understanding of cellular processes and, importantly, to develop next-generation therapeutics. Examples include many intracellular proteins like transcription factors, protein kinases and protein phosphatases that are central to many cancers, and many extracellular proteins like APP, prion protein and fibronectin that are central to neurodegeneration and cellular spreading. These classes of proteins make up a substantial proportion of current drug discovery portfolios in the pharmaceutical and biotech sectors. The selective modulation of the activity of these proteins through manipulation of their intrinsically disordered regions is a highly attractive approach since it circumvents the well-known problems of trying to target active sites that are insufficiently distinct from those of many related proteins, leading to low specificity, and trying to interfere directly with large protein-protein interfaces.
We have very recently developed technology for the identification of unique transient structured elements within intrinsically disordered regions of proteins, which can be targeted by either classical small molecule therapeutics, or by biotherapeutics, such as monoclonal antibodies or their mimetics. The approach uses our recently introduced quantitative chemical denaturant titration NMR methodology, and a combination of stable isotope and spin-labelling, to identify and determine the stability of local transient structured regions of amino acid residues that are unrelated to the conformational requirements for function. The relevant conformational ensembles are then defined using computational model building and selection approaches, utilising the experimental measurements as constraints. Once the regions involved in non-functional transient structure have been identified, their population is substantially amplified through the introduction of covalent linkages between amino acid residues near to their centres. The resulting molecules provide novel haptens that greatly increase the probability of inducing or selecting relevant conformation-specific antibodies or their mimetics. Once in hand, these antibodies/mimetics provide tools to selectively manipulate the behaviour of intrinsically disordered proteins, thereby providing novel experimental agents to test the role of these proteins in a cellular environment. In addition, the cross-linked molecules provide sensitive species for the screening of small molecule ligands using traditional approaches.

https://www.research.manchester.ac.uk/portal/en/researchers/jonathan-waltho(1cfad6dd-fc22-4452-b8fc-87dfa035be6a).html
http://www.chem.tsinghua.edu.cn/publish/chemen/2141/2011/20110403163131080656841/20110403163131080656841_.html

Academic background of candidates
Applicants should hold (or be about to obtain) a minimum 2:1 bachelor’s degree (or overseas equivalent), a master’s degree (including an integrated masters degree) or extensive research experience - such as an industry placement - in a relevant discipline. Applicants can be internal or external to The University of Manchester. For applicants whose first language is not English, we require a minimum IELTS score of 6.5TOEFL 90.

programme name: synbiodual

Funding Notes

This is a 4 year fully funded studentship covering tuition fees and stipend (£15,009 in 2019-20 while in Manchester, and a commensurate stipend while at Tsinghua). You will also receive an annual Research Training Support Grant towards project running costs/consumables while in Manchester, and flight allowance for travelling to Tsinghua will be covered.

References

1. Milanesi L, Waltho JP, Hunter CA, Shaw DJ, Beddard GS, Reid GD, Dev S, Volk M. Proc. Nat. Acad. Sci. USA (2012) 109 19563-8.
2. Macek P, Embrey KJ, Holdgate GA, Nissink JWM, Panova S, Cliff MJ, Waltho JP, Davies RA. J. Biol. Chem. (2018) 293 9301-9310.
3. Panova S, Cliff MJ, Macek P, Blackledge M, Ringkjøbing Jensen M, Nissink JWM, Embrey KJ, Davies R, Waltho JP. Structure (2019) 27 1-10.
4. Cai H, Chen MS, Sun ZY, Zhao YF, Kunz H, Li YM. Angew. Chemie (2013) 52 6106-10.
5. Chen H, Zhang Y, Li Q, Zhao YF, Chen YX, Li YM. J. Org. Chem. (2018) 83 7528-33.

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