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Structure based design of novel warheads for use in peptide-drug conjugates


Project Description

Chronic Myelomonocytic Leukaemia (CMML) is an orphan disease defined by myeloid dysplasia, myeloproliferation and a malignant expansion of classical monocytes. There is no generally effective treatment beyond allogeneic stem cell transplantation, which is an option for only a small minority of patients. For the majority prognosis is dismal, with median survival of 15-20 months following diagnosis.

Chemotherapeutic approaches in CMML (and other leukaemias) frequently fail due to a lack of specificity, or insufficient activity against earlier disease initiating/sustaining progenitor cells protected in the bone marrow niche. We are seeking to address this unmet need by developing a new class of peptide-drug conjugates that mobilize CMML progenitor cells from the bone marrow and selectively kill all CMML cells throughout the disease clone in the bloodstream.

This project will focus on the structure-based design and synthesis of a new class of warheads for inclusion in these peptide-drug conjugates. This will involve;

1) Medicinal chemistry techniques to design the novel warheads and linkers (i.e. Pymol, property based design).
2) Synthetic organic chemistry techniques to prepare and characterise the warheads.
3) Protein conjugation and characterisation of the conjugates by e.g. SEC, MALDI MS.
4) Biological evaluation using established methods; cell culture, flow cytometry and colorimetric assays.

Through this work we will establish the role of the chemical linker and the physicochemical properties of the warhead in determining the activity and retention of the active species in leukaemia cell lines and patient samples.

For international students we also offer a unique 4 year PhD programme that gives you the opportunity to undertake an accredited Teaching Certificate whilst carrying out an independent research project across a range of biological, medical and health sciences. For more information please visit http://www.internationalphd.manchester.ac.uk.

Funding Notes

Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree (or equivalent) in Chemistry, Medicinal Chemistry or a closely related area / subject.

This project has a Band 2 fee. Details of our different fee bands can be found on our website (View Website). For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (View Website).

Informal enquiries may be made directly to the primary supervisor.


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