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 Opportunities
Targeting the exocytotic machinery to treat chronic pain
An early and key event in pain signaling and its subsequent chronification is the increased excitability of peripheral nociceptors and enhanced exocytosis of neurotransmitters. Underpinning this hyper-excitability is the increased trafficking of ion channels to the plasma membrane. Both the delivery of additional ion channels to the membrane and release of neurotransmitters from secretory vesicles is dependent upon vesicular membrane fusion events driven by the assembly of functional SNARE complexes.
Botulinum neurotoxins are endopeptidases that cleave and inactivate SNAREs thereby preventing vesicle fusion. This project aims to explore and develop the therapeutic potential of novel botulinums (nBots), created in the Davletov lab, to produce long lasting block of pain induced hyper-excitability and neurotransmission in nociceptors. While much is known about the SNAREs involved in regulating vesicle fusion during neurotransmitters release, little is known about SNAREs involved in the delivery of ion channels to the plasma membrane in health or disease.
(1) Use protein engineering to generate bespoke nBots targeted to subpopulations of sensory neurons using receptor-based ligands (for details see (Arsenault, J., et al. (2013). J Neurochem 126(2): 223-233)
(2) Use in vitro methods to evaluate and compare the SNARE cleaving capacity and targeting of nBots with native toxins
(3) Perform detailed functional analysis (electrophysiology, live cell imaging) analysis of the effects of selected nBots on inflammation-induced hyper-excitability and ion channel activity in nociceptors in vitro and in vivo.
Funding for this Studentship is provided through an MRC CASE Industrial studentship awarded to EPS/BD at University of Sheffield and Lisa Broad (Eli Lilly and Company, UK). The project is designed to provide the student with experience of collaborative research with a non‐academic partner and offer an outstanding student an experience of two distinct research cultures and provide access to a wider than usual range of technology, facilities and expertise.
As part of the studentship, the student will be expected to spend a minimum of three months with the non-academic partner. Full student support is provided for UK resident students who have been resident in the UK and Islands for the full three-year period before the first day of the first academic year of the course; the main purpose for your residence in the UK and Islands must not have been to receive full-time education during any part of the three-year period.
Keywords: Biotechnology, Cell Biology / Development, Neuroscience/Neurology, Pharmacology
2. 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.
3. 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.
For further information about these projects and how to apply, see our PhD Opportunities page:
- 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
- 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, 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
- 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