Professor Bazbek Davletov
Chair in Biomedical Science
Department of Biomedical Science
Room D225 Alfred Denny building
Brief career history
We routinely generate new secretion- and translation-inhibiting biomedicines and characterise their functional effects on primary sensory neurons. Successful targeting and delivery into neurons will pave the way for utilization of known potent enzymes in treatment of neurological disorders. In addition, the results of this study will be important for the design of new multifunctional therapies encompassing antibodies, their fragments, small molecule drugs and siRNAs.
Images courtesy of Davletov lab 2015
A detailed description of my projects:
Project 1: Developing long-lasting analgesic drugs
We plan to obtain evidence in cell cultures that RSPs can block release of pain-signalling molecules from pain-conducting neurons and then to test RSPs for their ability to influence sensory biology in rodent models. Proving the analgesic potential of specific RSP versions will be required to bring the benefits of basic research to clinical practice. We expect that successful RSP molecules will be helpful in treating different kinds of chronic pain not only in humans but also in animals.
Project 2: Targeting translation in cancer treatment
Translation-inhibiting enzymes (Tie-s) is an emerging class of anti-cancer drugs provided they can be targeted into the cytosol of specific cancer cells. Generally, targeting can be achieved by attaching Tie-s to antibodies, growth factors or other ligands which preferentially bind to cancer cells. The anti-proliferative enzymatic activity of Tie-s, however, can only take place in the cytosol which is protected by cellular membranes. Following binding to cancer cells, Tie-s will be processed in the endosomal-lysosomal pathway. To escape degradation, Tie-s must be able to rapidly exit endosomes into the cellular cytosol.
We recently introduced a ‘protein stapling’ technique which potentially allows conjugation of any cancer-inhibiting enzyme to any proven cell-targeting agent. The advantage of this system is that the staple itself can serve as a point where we can add further functionality, such as endosomal escape. Several peptides have been developed which can break endosomes allowing access into the cell interior. Our ‘protein stapling’ system provides a unique opportunity to combine endosome breaking agents with translation-inhibiting and cell-targeting proteins. Successful targeting of functional Tie-s will pave the way for utilization of these potent enzymes in cancer treatment. In addition, the results of this study will be important for the design of new multifunctional cancer therapies encompassing antibodies, their fragments, enzymes and siRNAs.
Undergraduate and postgraduate taught modules
Postgraduate PhD Opportunity
Botulinum drugs for migraine treatment
Funding status: Competition funded project European/UK students only
This project is eligible for a department scholarship. These scholarships are awarded on a competitive basis – find out more on our funding webpage.
This project is open for UK, European and worldwide applicants.
Migraine is a common neurological condition, affecting one in five women and one in fifteen men. Current treatments for migraine are often inadequate, and therapeutic advances have been slow. In 2010, quarterly injections of Botulinum neurotoxin type A (Botox®) were approved as a preventative treatment for chronic migraine sufferers. However, only 50% of migraine sufferers report measurable improvement. Botulinum neurotoxin is a potent paralysing agent and thus its efficacy in migraine treatment will always be limited.
Mechanistically, botulinum neurotoxin targets neuronal populations and cleaves intraneuronal SNAP25 protein to cause long-lasting blockade of neurotransmitter release. The project aims to develop a non-paralysing botulinum drug which has improved ability to inhibit release of neuropeptides implicated in migraine. We will use our invented protein-stapling technique to engineer synthetic versions of botulinum neurotoxin which will be analysed in neuronal cells for their targeting and enzymatic efficacies.
The project will involve molecular and cell biological techniques and also in vivo experimentation. Results of this study will help to understand better the biological action of botulinum neurotoxins and most importantly pave the way for new therapeutics to treat a wide range of neurological disorders. This project has the potential to bring about a new approach to treat millions of migraine sufferers.
Keywords: Biochemistry, Biomedical Engineering, Biophysics, Biotechnology, Cell Biology / Development, Genetics, Medical/Clinical Science, Molecular Biology, Neuroscience/Neurology, Pharmacology, Structural Biology, Chemical Engineering, Macromolecular Chemistry, Pharmaceutical Chemistry, Synthetic Chemistry, Biophysics, Nanotechnology
For informal enquiries about the project or application process, please feel free to contact me:
For further information about these projects and how to apply, see our PhD Opportunities page:
- Rust A, Doran C, Hart R, Binz T, Stickings P, Sesardic D, Peden AA & Davletov B (2017) A cell line for detection of botulinum neurotoxin type B. Frontiers in Pharmacology, 8(NOV). View this article in WRRO
- Mangione AS, Obara I, Maiarú M, Geranton SM, Tassorelli C, Ferrari E, Leese C, Davletov B & Hunt SP (2016) Nonparalytic botulinum molecules for the control of pain. PAIN, 157(5), 1045-1055. View this article in WRRO
- Rust A, Leese C, Binz T & Davletov B (2016) Botulinum neurotoxin type C protease induces apoptosis in differentiated human neuroblastoma cells. Oncotarget. View this article in WRRO
- Rust A, Hassan HHA, Sedelnikova S, Niranjan D, Hautbergue G, Abbas SA, Partridge L, Rice D, Binz T & Davletov B (2015) Two complementary approaches for intracellular delivery of exogenous enzymes. Scientific Reports, 5, 12444-12444. View this article in WRRO
- Ferrari E, Gu C, Niranjan D, Restani L, Rasetti-Escargueil C, Obara I, Geranton SM, Arsenault J, Goetze TA, Harper CB, Nguyen TH, Maywood E, O'Brien J, Schiavo G, Wheeler DW, Meunier FA, Hastings M, Edwardson JM, Sesardic D, Caleo M, Hunt SP & Davletov B (2013) Synthetic self-assembling clostridial chimera for modulation of sensory functions.. Bioconjug Chem, 24(10), 1750-1759. View this article in WRRO
- Arsenault J, Ferrari E, Niranjan D, Cuijpers SAG, Gu C, Vallis Y, O'Brien J & Davletov B (2013) Stapling of the botulinum type A protease to growth factors and neuropeptides allows selective targeting of neuroendocrine cells.. J Neurochem, 126(2), 223-233. View this article in WRRO
- Darios F, Niranjan D, Ferrari E, Zhang F, Soloviev M, Rummel A, Bigalke H, Suckling J, Ushkaryov Y, Naumenko N, Shakirzyanova A, Giniatullin R, Maywood E, Hastings M, Binz T & Davletov B (2010) SNARE tagging allows stepwise assembly of a multimodular medicinal toxin.. Proc Natl Acad Sci U S A, 107(42), 18197-18201.
- Darios F, Ruipérez V, López I, Villanueva J, Gutierrez LM & Davletov B (2010) Alpha-synuclein sequesters arachidonic acid to modulate SNARE-mediated exocytosis.. EMBO Rep, 11(7), 528-533.
- Ferrari E, Darios F, Zhang F, Niranjan D, Bailes J, Soloviev M & Davletov B (2010) Binary polypeptide system for permanent and oriented protein immobilization.. J Nanobiotechnology, 8, 9. View this article in WRRO