Professor Bazbek Davletov

Professor Bazbek DavletovChair in Biomedical Science

Department of Biomedical Science
The University of Sheffield
Western Bank
Sheffield S10 2TN
United Kingdom

Room D225 Alfred Denny building
Telephone: +44 (0) 114 222 5111
email: b.davletov@sheffield.ac.uk

CMIAD


Neuroscience


Cell Biology and Cancer


General

Brief career history

  • 2012-present: Chair in Biomedical Science, Department of Biomedical Science, University of Sheffield, UK.
  • 1998-2012: Programme Leader, Medical Research Council, The MRC Laboratory of Molecular Biology, Cambridge, UK.
  • 1995-1997: Wellcome Trust Research Fellow, Imperial College, London.
  • 1988-1991: Research Associate, Institute of Bioorganic Chemistry, Moscow.

Educational qualifications:

  • 1992-1994: PhD, University of Texas Southwestern Medical Center, Dallas, USA. Supervisor: Prof Thomas Sudhof, Nobel Prize in Physiology and Medicine 2013. 11 joint publications.
  • 1980-1985: BA, MSc in Biochemistry, Moscow State University, Russia.

Research interests

We are developing new technologies for delivery of biomedicinal enzymes into neurons. Neuronal disorders are a huge burden to our society and include many untreatable conditions such as chronic pain, epilepsy and neurodegeneration. We recently introduced a ‘protein stapling’ technique which potentially allows conjugation of any therapeutic enzyme to any proven cell-targeting agent. The advantage of this system is that it can incorporate other functionalities such as multiple targeting or endosome-disrupting agents.


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.


Mouse sensory neurons in culture

P75_Ganglioside

Human SIMA neuroblastoma cells

GT1bgreenSNAP25red_DRG

Images courtesy of Davletov lab 2015

Major scientific accomplishments:

  • Discovery of non-paralysing neuronal blockers for treatment of pain and brain disorders (2011-13).
  • Development of ‘protein stapling’ technology for molecular assembly, cell targeting, enzyme immobilization (2009-2010).
  • Elucidation of molecular mechanisms underlying synaptic neurotransmission (1998-2008).
  • Identification of receptors for spider neurotoxins – neurexin and latrophilin (1988-91, 1995-97).
  • Identification of protein domains involved in synaptic neurotransmission (1992-94).

In the news:

'Scientists find way to refine Botox for new uses' - Reuters

Inventions and patents

Patent family entitled “Complexing System” with Priority in United Kingdom and the United States from the 12th of August 2009, also covering Europe, China, India, Singapore, Canada, Australia.

ResearchGate


Full publications

Research

A detailed description of my projects:

Project 1: Developing long-lasting analgesic drugs

This project aims to develop new long-lasting pain relief. Around 12% of adults suffer from severe, disabling chronic pain which occurs due to over-reactive neurons. At present, the use of drugs to treat chronic pain is rarely curative and often limited by intolerable side effects. A key feature of our approach is the use of retargeted SNAP25 proteases (RSPs) to selectively silence specific types of neurons for prolonged periods of time. This strategy has evolved from my studies of neuronal communication which universally depends on a protein called SNAP25.

We demonstrated that specific cleavage of this protein can lead to a prolonged silencing of neurons with full recovery after several months. My laboratory recently developed RSPs which have a more selective action. Specifically, several of our products target central and sensory neurons but not neuromuscular junctions. This feature makes RSPs more attractive in treating various chronic neuronal disorders since neuronal silencing can be achieved without muscle paralysis.

Group members:

  • Charlotte Leese, Postdoctoral Fellow
  • Ciara Doran, Postdoctoral Fellow
  • Rosalyn Hart, PhD Student
  • Rebecca Bresnahan, PhD Student
  • Jaqueline Price, Lab Manager
  • Muna Nuh Ali, MSc Student
  • Sajid Shah, MSc Student

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.

SNARE stapling

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.

TetBotMouseDRG_CleavedSNAP25greenTubulinRed

Funding:

  • Medical Research Council
  • BBSRC
  • NC3R

Collaborators:

  • Stephen Hunt (University College London)
  • Frederic Meunier (University of Brisbane, Australia)
  • Robert Zorec (University of Ljubljana, Slovenia)
  • Rashid Giniatullin (University of Kuopio, Finland)
  • Thea Sesardic (National Institute for Biological Standards and Control, London)
Teaching

Undergraduate and postgraduate taught modules

Level 2:

  • BMS238 Cell and Molecular Biology

Level 3:

  • BMS376 Membrane Trafficking
  • BMS349 Extended Library Project
  • BMS369 Laboratory Research Project
Opportunities

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.

Project Description

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

Contact information

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:

PhD Opportunities

Selected publications

Journal articles