Professor Bazbek Davletov

Professor Bazbek DavletovChair in Biomedical Science
Department of Biomedical Science
Room D225, Denny building
The University of Sheffield
Western Bank, Sheffield S10 2TN
United Kingdom

Telephone: +44 (0) 114 222 5111

email: b.davletov@sheffield.ac.uk


General

GT1bgreenSNAP25red_DRGCareer 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 working on biomolecular assembly, neuronal blockers, medicines for chronic pain, anti-cancer biological drugs.

In addition, the Davletov group is part of the Centre for Membrane Interactions and Dynamics (CMIAD).

CMIAD

Mouse sensory neurons in culture

P75_Ganglioside

Human SIMA neuroblastoma cells

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.

Recent publications

For more publications see:

ResearchGate

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. 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

Positions Available

Postgraduate PhD Opportunities

1. Developing drugs for long-lasting pain relief

This project aims to develop new approach for long-lasting pain relief. Around 12% of adults suffer from severe chronic pain which include cancer, inflammatory and neuropathic pain. Available drugs to treat persistent pain are rarely curative and bring intolerable side effects in a long run. A key feature of our approach is the use of re-targeted botulinum proteases to selectively silence specific types of neurons for months-long periods of time after local injections.

This strategy has evolved from my studies of neuronal communication which universally depends on SNARE proteins. We and others demonstrated that specific cleavage of these proteins can lead to prolonged silencing of neurons with full recovery after several months. My laboratory recently engineered botulinum molecules which have a more selective action. Specifically, several of our molecules target central and sensory neurons but not neuromuscular junctions. This feature makes novel botulinum molecules attractive in treating various chronic neuronal disorders since neuronal silencing can be achieved without side-effects.

We plan to obtain evidence in cell cultures that these botulinum molecules can block release of pain-signalling molecules from sensory neurons and then to test them for their ability to cause long-lasting analgesia in rodent models. Proving the analgesic potential of specific botulinum drugs will be required to translate the benefits of basic research to clinical practice.

References

  • Mangione AS, Obara I, Maiarú M, Geranton SM, Tassorelli C, Ferrari E, Leese C, Davletov B, Hunt SP. ‘Non-paralytic botulinum molecules for the control of pain. Pain 157:1045-55.
  • 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 F, Hastings M, Edwardson JM, Sesardic D, Caleo M, Hunt SP & Davletov B ‘A synthetic self-assembling clostridial chimera for modulation of sensory functions’ Bioconjug Chem 24, 1750−1759.
  • Arsenault J, Ferrari E, Niranjan D, Cuijpers SAG, Gu C, Vallis Y, O'Brien J & Davletov B. ‘Stapling of the botulinum type A protease to growth factors and neuropeptides allows selective targeting of neuroendocrine cells’ J Neurochem 126, 223-33.

2. New therapeutics for motor neuron diseases

Motor neuron diseases such as Parkinson’s and Amyotrophic Lateral Sclerosis (ALS) often lead to autonomic dysfunctions including difficulty swallowing. Dysphagia (swallowing difficulties) is a major risk factor in motor neuron diseases because of lung infections and choking due to saliva production.

Currently, botulinum neurotoxin provides the most reliable, long-lasting partial reduction in salivation. The major obstacle in the use of botulinum neurotoxin stems from its dangerous paralysing properties restricting its application in patients which are already suffering from muscle weakness. We recently developed several non-paralysing botulinum molecules which we need to evaluate in relevant rodent models.

The successful PhD applicant will learn the production of botulinum-based drugs, develop quantitative method for measuring saliva production and investigate the novel therapeutics in rodents. The successful completion of this project will open new avenues for the treatment of motor neuron disease patients ultimately improving the quality of life for people with motor neuron diseases throughout the world.

References

  • Mangione AS, Obara I, Maiarú M, Geranton SM, Tassorelli C, Ferrari E, Leese C, Davletov B, Hunt SP.
    ‘Non-paralytic botulinum molecules for the control of pain.
    Pain 157:1045-55.
  • 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 F, Hastings M, Edwardson JM, Sesardic D, Caleo M, Hunt SP & Davletov B
    ‘A synthetic self-assembling clostridial chimera for modulation of sensory functions’
    Bioconjug Chem 24, 1750−1759.
  • Arsenault J, Ferrari E, Niranjan D, Cuijpers SAG, Gu C, Vallis Y, O'Brien J & Davletov B
    ‘Stapling of the botulinum type A protease to growth factors and neuropeptides allows selective targeting of neuroendocrine cells’
    J Neurochem 126, 223-33.

For further information about these projects and how to apply, see our PhD Opportunities page:

PhD Opportunities

Members

Davletov lab 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