Professor Bazbek Davletov
School of Biosciences
Chair in Biomedical Science

+44 114 222 5111
Full contact details
School of Biosciences
D225
Alfred Denny Building
Western Bank
Sheffield
S10 2TN
- Profile
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- 2012-present: Chair in Biomedical Science, School of Biosciences, 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.
Rational development of drugs involves understanding molecular principles of the cellular processes one would like to target. I started my career in neurobiology by asking a basic question: What is the molecular machinery that allows neurons to communicate with each other? In the 1980s, scientists knew that neurons release neurotransmitters but the mechanisms of secretion were not known. I used the most potent neuronal secretagogue – a protein called alpha-latrotoxin, the main ingredient of the black widow spider venom – to isolate its neuronal receptors.
These receptors happened to be membrane proteins responsible for interlinking neurons: neurexins and latrophilins. I then investigated in depth synaptic proteins which either bind or are cleaved by neurotoxins: synaptotagmin, syntaxin, SNAP25 and VAMP proteins. These synaptic proteins constitute the fine-tuned release machinery responsible for secretion of neurotransmitters and are the targets of botulinum neurotoxins. My research demonstrated step-by-step protein interactions that are crucial for vesicle fusion and neurotransmitter release.
My work on synaptic proteins and neurotoxins gave rise to several translational ideas, and I engaged top experts to forge fruitful collaborations in cancer, pain and botulinum fields. With Prof. Brindle at Cambridge University, we demonstrated that synaptotagmin protein could be used to indicate success in cancer treatment. With Prof. Hunt at London University, we demonstrated that engineered botulinum molecules could provide long-lasting pain relief in animal models of pain. With Drs Sesardic and Stickings at Medicines and Healthcare products Regulatory Agency, we developed novel neurotoxin detection assays, required to replace animal use in related biomedical fields.
- Qualifications
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- 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
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My laboratory is working on the development of 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 engineered botulinum neurotoxin 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 SNARE proteins.
We demonstrated that specific cleavage of these proteins can lead to a prolonged silencing of neurons with full recovery after several months. My laboratory recently developed a wide range of botulinum molecules with selective actions. Specifically, several of our products target central and sensory neurons but not neuromuscular junctions. This feature makes engineered botulinum molecules more attractive in treating various chronic neuronal disorders since neuronal silencing can be achieved without muscle paralysis.
We investigate botulinum action on SNARE proteins in cell cultures and to that end, we developed new cell-based assays for testing botulinum and tetanus toxins. This is an important biomedical avenue since it will allow saving thousands of mice from lethal tests used by major pharmaceutical companies.
Proving the analgesic potential of novel botulinum products is conducted in collaboration with internationally recognised pain experts to bring the benefits of basic research to clinical practice. We expect that successful botulinum molecules will be helpful in treating different kinds of chronic pain not only in humans but also in animals.
- Publications
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Show: Featured publications All publications
Featured publications
Journal articles
- Double-binding botulinum molecule with reduced muscle paralysis: Evaluation in in vitro and in vivo models of migraine. Toxicon, 190, S5-S5.
- Selective neuronal silencing using synthetic botulinum molecules alleviates chronic pain in mice.. Science Translational Medicine, 10(450). View this article in WRRO
- A cell line for detection of botulinum neurotoxin type B. Frontiers in Pharmacology, 8, 796-796. View this article in WRRO
- Nonparalytic botulinum molecules for the control of pain. PAIN, 157(5), 1045-1055. View this article in WRRO
- Botulinum neurotoxin type C protease induces apoptosis in differentiated human neuroblastoma cells. Oncotarget, 7, 33220-33228. View this article in WRRO
- Two complementary approaches for intracellular delivery of exogenous enzymes. Scientific Reports, 5, 12444-12444. View this article in WRRO
- Synthetic self-assembling clostridial chimera for modulation of sensory functions.. Bioconjug Chem, 24(10), 1750-1759. View this article in WRRO
- Stapling of the botulinum type A protease to growth factors and neuropeptides allows selective targeting of neuroendocrine cells. Journal of Neurochemistry, 126(2), 223-233.
- 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
- SNARE tagging allows stepwise assembly of a multimodular medicinal toxin.. Proc Natl Acad Sci U S A, 107(42), 18197-18201.
All publications
Journal articles
- Vesicle fusion as a target process for the action of sphingosine and its derived drugs. International Journal of Molecular Sciences, 23(3).
- Characterisation of tetanus monoclonal antibodies as a first step towards the development of an in vitro vaccine potency immunoassay. Biologicals, 71, 31-41.
- Long-term amelioration of persistent pain states with a novel botulinum–Substance P construct and reinstatement of analgesia with a second injection of the construct. Toxicon, 190, S45-S46.
- Double-binding botulinum molecule with reduced muscle paralysis: Evaluation in in vitro and in vivo models of migraine. Toxicon, 190, S5-S5.
- Double-binding botulinum molecule with reduced muscle paralysis : evaluation in in vitro and in vivo models of migraine. Neurotherapeutics. View this article in WRRO
- Duplication of clostridial binding domains for enhanced macromolecular delivery into neurons. Toxicon: X, 5. View this article in WRRO
- Multiple sclerosis drug FTY-720 toxicity is mediated by the heterotypic fusion of organelles in neuroendocrine cells. Scientific Reports, 9(1). View this article in WRRO
- Duplication of neuronal binding domains derived from clostridial neurotoxins greatly enhances intraneuronal delivery of therapeutics. Toxicon, 156, S68-S68.
- Selective neuronal silencing using synthetic botulinum molecules alleviates persistent pain states. Toxicon, 156, S72-S72.
- Discovery of novel botulinum pain therapeutics: A binary approach. Toxicon, 156, S20-S20.
- An enzymatic reporter cell line for detection of botulinum neurotoxin type B. Toxicon, 156, S25-S25.
- Emerging evidence for the modulation of exocytosis by signalling lipids. FEBS Letters, 592(21), 3493-3503. View this article in WRRO
- Selective neuronal silencing using synthetic botulinum molecules alleviates chronic pain in mice.. Science Translational Medicine, 10(450). View this article in WRRO
- Burkholderia Lethal Factor 1, a Novel Anti-Cancer Toxin, Demonstrates Selective Cytotoxicity in MYCN-Amplified Neuroblastoma Cells. Toxins, 10(7), 261-261. View this article in WRRO
- Structural and Aggregation Properties of Alpha-Synuclein Linked to Phospholipase A2 Action. Protein & Peptide Letters, 25(4), 368-378.
- A cell line for detection of botulinum neurotoxin type B. Frontiers in Pharmacology, 8, 796-796. View this article in WRRO
- Sphingomimetic multiple sclerosis drug FTY720 activates vesicular synaptobrevin and augments neuroendocrine secretion. Scientific Reports, 7. View this article in WRRO
- Nonparalytic botulinum molecules for chronic pain management. Toxicon, 123, S21-S21.
- Sigma-1 receptor expression in the dorsal root ganglion: Reexamination using a highly specific antibody. Neuroscience, 331, 148-157.
- Nonparalytic botulinum molecules for the control of pain. PAIN, 157(5), 1045-1055. View this article in WRRO
- Botulinum neurotoxin type C protease induces apoptosis in differentiated human neuroblastoma cells. Oncotarget, 7, 33220-33228. View this article in WRRO
- Angiotensin II activates different calcium signaling pathways in adipocytes. Archives of Biochemistry and Biophysics, 593, 38-49.
- Two complementary approaches for intracellular delivery of exogenous enzymes. Scientific Reports, 5, 12444-12444. View this article in WRRO
- Control of Autophagosome Axonal Retrograde Flux by Presynaptic Activity Unveiled Using Botulinum Neurotoxin Type A. The Journal of Neuroscience, 35(15), 6179-6194. View this article in WRRO
- Unexpected Transcellular Protein Crossover Occurs During Canonical DNA Transfection. Journal of Cellular Biochemistry, 115(12), 2047-2054. View this article in WRRO
- A multiple sclerosis drug sheds light on astrocyte biology.. Acta Physiol (Oxf), 212(1), 8-10.
- Botulinum protease-cleaved SNARE fragments induce cytotoxicity in neuroblastoma cells.. J Neurochem, 129(5), 781-791. View this article in WRRO
- Synthetic self-assembling clostridial chimera for modulation of sensory functions.. Bioconjug Chem, 24(10), 1750-1759. View this article in WRRO
- Cortical spreading depression induces oxidative stress in the trigeminal nociceptive system.. Neuroscience, 253, 341-349.
- Synaptotagmin interaction with SNAP-25 governs vesicle docking, priming, and fusion triggering.. J Neurosci, 33(36), 14417-14430.
- Stapling of the botulinum type A protease to growth factors and neuropeptides allows selective targeting of neuroendocrine cells. Journal of Neurochemistry, 126(2), 223-233.
- 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
- Lipid metabolites enhance secretion acting on SNARE microdomains and altering the extent and kinetics of single release events in bovine adrenal chromaffin cells.. PLoS One, 8(9), e75845. View this article in WRRO
- Fingolimod--a sphingosine-like molecule inhibits vesicle mobility and secretion in astrocytes.. Glia, 60(9), 1406-1416.
- Presynaptic neurotoxins: an expanding array of natural and modified molecules.. Cell Calcium, 52(3-4), 234-240.
- VAMP4 directs synaptic vesicles to a pool that selectively maintains asynchronous neurotransmission.. Nature Neuroscience, 15(5), 738-745. View this article in WRRO
- Assembly of protein building blocks using a short synthetic peptide.. Bioconjug Chem, 23(3), 479-484.
- Re-assembled botulinum neurotoxin inhibits CNS functions without systemic toxicity.. Toxins (Basel), 3(4), 345-355. View this article in WRRO
- Erratum: Lipid-protein interactions in exocytotic release of hormones and neurotransmitters (Clinical Lipidology (2010) 5: 5 (747-761)). Clinical Lipidology, 6(4), 493-494.
- SNARE tagging allows stepwise assembly of a multimodular medicinal toxin.. Proc Natl Acad Sci U S A, 107(42), 18197-18201.
- Alpha-synuclein, lipids and Parkinson's disease.. Prog Lipid Res, 49(4), 420-428.
- Lipid function at synapses.. Curr Opin Neurobiol, 20(5), 543-549.
- Alpha-synuclein sequesters arachidonic acid to modulate SNARE-mediated exocytosis.. EMBO Rep, 11(7), 528-533.
- Lipid-protein interactions in exocytotic release of hormones and neurotransmitters. Clinical Lipidology, 5(5), 747-761.
- Binary polypeptide system for permanent and oriented protein immobilization.. J Nanobiotechnology, 8, 9. View this article in WRRO
- N-terminal acetylation of the neuronal protein SNAP-25 is revealed by the SMI81 monoclonal antibody.. Biochemistry, 48(40), 9582-9589.
- Sphingosine facilitates SNARE complex assembly and activates synaptic vesicle exocytosis.. Neuron, 62(5), 683-694.
- DOC2B acts as a calcium switch and enhances vesicle fusion.. J Neurosci, 28(27), 6794-6806.
- Cross-linking of phospholipid membranes is a conserved property of calcium-sensitive synaptotagmins.. J Mol Biol, 380(1), 42-50.
- Real-time assay for monitoring membrane association of lipid-binding domains.. Anal Biochem, 377(1), 83-88.
- Detection of cell death in tumors by using MR imaging and a gadolinium-based targeted contrast agent.. Radiology, 246(3), 854-862.
- Munc18-1 is critical for plasma membrane localization of syntaxin1 but not of SNAP-25 in PC12 cells.. Mol Biol Cell, 19(2), 722-734.
- Phospholipases and fatty acid signalling in exocytosis.. J Physiol, 585(Pt 3), 699-704.
- Neurexin Ibeta and neuroligin are localized on opposite membranes in mature central synapses.. J Neurochem, 103(5), 1855-1863.
- SPECT imaging of myocardial infarction using 99mTc-labeled C2A domain of synaptotagmin I in a porcine ischemia-reperfusion model.. Nucl Med Biol, 34(8), 917-923.
- Beta-strand recombination in tricalbin evolution and the origin of synaptotagmin-like C2 domains.. Proteins, 68(3), 770-778.
- Regulation of SNARE fusion machinery by fatty acids.. Cell Mol Life Sci, 64(13), 1597-1608.
- Tight coupling of the t-SNARE and calcium channel microdomains in adrenomedullary slices and not in cultured chromaffin cells.. Cell Calcium, 41(6), 547-558.
- A paramagnetic nanoprobe to detect tumor cell death using magnetic resonance imaging.. Nano Lett, 7(5), 1419-1423.
- Conserved prefusion protein assembly in regulated exocytosis. Comparative Biochemistry and Physiology Part A: Molecular & Integrative Physiology, 146(4), S105-S105.
- Mechanism of arachidonic acid action on syntaxin-Munc18.. EMBO Rep, 8(4), 414-419.
- Alpha-synuclein adopts an alpha-helical conformation in the presence of polyunsaturated fatty acids to hinder micelle formation.. Biochemistry, 45(51), 15610-15616.
- SNAP25 is a pre-synaptic target for the depressant action of reactive oxygen species on transmitter release.. J Neurochem, 98(6), 1789-1797.
- Omega-3 and omega-6 fatty acids stimulate cell membrane expansion by acting on syntaxin 3.. Nature, 440(7085), 813-817.
- The synaptic vesicle protein 2C mediates the uptake of botulinum neurotoxin A into phrenic nerves.. FEBS Lett, 580(8), 2011-2014.
- Synuclein proteins of the pufferfish Fugu rubripes: sequences and functional characterization.. Biochemistry, 45(8), 2599-2607.
- Conserved prefusion protein assembly in regulated exocytosis.. Mol Biol Cell, 17(1), 283-294.
- Beyond BOTOX: advantages and limitations of individual botulinum neurotoxins. American Journal of Ophthalmology, 140(6), 1173-1173.
- Promiscuous interaction of SNAP-25 with all plasma membrane syntaxins in a neuroendocrine cell.. Biochem J, 392(Pt 2), 283-289.
- Beyond BOTOX: advantages and limitations of individual botulinum neurotoxins.. Trends Neurosci, 28(8), 446-452.
- Self-assembly of SNARE fusion proteins into star-shaped oligomers.. Biochem J, 388(Pt 1), 75-79.
- Arachidonic acid allows SNARE complex formation in the presence of Munc18.. Chem Biol, 12(5), 545-553.
- A molecular basis underlying differences in the toxicity of botulinum serotypes A and E.. EMBO Rep, 5(11), 1090-1095.
- Mutation E46K increases phospholipid binding and assembly into filaments of human alpha-synuclein.. FEBS Lett, 576(3), 363-368.
- Detection of apoptosis using the C2A domain of synaptotagmin I.. Bioconjug Chem, 15(5), 983-987.
- Synaptotagmin interaction with the syntaxin/SNAP-25 dimer is mediated by an evolutionarily conserved motif and is sensitive to inositol hexakisphosphate.. J Biol Chem, 279(13), 12574-12579.
- Comparative analysis of tandem C2 domains from the mammalian synaptotagmin family.. Biochem J, 378(Pt 2), 681-686.
- A common mechanism for the regulation of vesicular SNAREs on phospholipid membranes.. Biochem J, 377(Pt 3), 781-785.
- High affinity interaction of syntaxin and SNAP-25 on the plasma membrane is abolished by botulinum toxin E.. J Biol Chem, 279(1), 644-651.
- Sculpting a domain by splicing.. Nat Struct Mol Biol, 11(1), 4-5.
- Getting muscles moving again after botulinum toxin: novel therapeutic challenges.. Trends Mol Med, 9(7), 291-299.
- Mechanism of calcium-independent synaptotagmin binding to target SNAREs.. J Biol Chem, 278(8), 5501-5504.
- SNAREs and control of synaptic release probabilities.. FASEB J, 17(2), 130-135.
- Action of complexin on SNARE complex.. J Biol Chem, 277(44), 41652-41656.
- Vesicular restriction of synaptobrevin suggests a role for calcium in membrane fusion.. Nature, 415(6872), 646-650.
- Non-invasive detection of apoptosis using magnetic resonance imaging and a targeted contrast agent.. Nat Med, 7(11), 1241-1244.
- Tetramerisation of α-latrotoxin by divalent cations is responsible for toxin-induced non-vesicular release and contributes to the Ca2+-dependent vesicular exocytosis from synaptosomes. Biochimie, 82(5), 453-468.
- Norepinephrine exocytosis stimulated by α-latrotoxin requires both external and stored Ca2+ and is mediated by latrophilin, G proteins and phospholipase C. Philosophical Transactions of the Royal Society B: Biological Sciences, 354(1381), 379-386.
- Calcium-dependent membrane penetration is a hallmark of the C2 domain of cytosolic phospholipase A2 whereas the C2A domain of synaptotagmin binds membranes electrostatically.. J Biol Chem, 273(30), 19093-19096.
- Vesicle exocytosis stimulated by α-latrotoxin is mediated by latrophilin and requires both external and stored Ca2+. EMBO Journal, 17(14), 3909-3920.
- α-Latrotoxin receptor, latrophilin, is a novel member of the secretin family of G protein-coupled receptors. Journal of Biological Chemistry, 272(34), 21504-21508.
- Bipartite Ca2+-binding motif in C
2 domains of synaptotagmin and protein kinase C. Science, 273(5272), 248-251. - Isolation and biochemical characterization of a Ca2+-independent α- latrotoxin-binding protein. Journal of Biological Chemistry, 271(38), 23239-23245.
- Structure of the first C
2 domain of synaptotagmin I: A novel Ca2+/phospholipid-binding fold. Cell, 80(6), 929-938. - High affinity binding of α-latrotoxin to recombinant neurexin Iα. Journal of Biological Chemistry, 270(41), 23903-23905.
- Distinct Ca2+ and Sr2+ binding properties of synaptotagmins: Definition of candidate Ca2+ sensors for the fast and slow components of neurotransmitter release. Journal of Biological Chemistry, 270(42), 24898-24902.
- Synaptotagmin I is a high affinity receptor for clathrin AP-2: Implications for membrane recycling. Cell, 78(5), 751-760.
- Interaction of synaptotagmin with the cytoplasmic domains of neurexins.. Neuron, 10(2), 307-315.
2 domain from synaptotagmin I is sufficient for high affinity Ca2+/phospholipid binding. Journal of Biological Chemistry, 268(35), 26386-26390.
A single C- Neurexins.. Cold Spring Harb Symp Quant Biol, 57, 483-490.
- Binding of synaptotagmin to the α-latrotoxin receptor implicates both in synaptic vesicle exocytosis. Nature, 353(6339), 65-68.
- Human adrenoceptor system response to the development of high altitude pulmonary arterial hypertension. Journal of Molecular and Cellular Cardiology, 21(SUPPL. 1), 175-179.
- Botulinum Neurotoxin F Subtypes Cleaving the VAMP-2 Q58–K59 Peptide Bond Exhibit Unique Catalytic Properties and Substrate Specificities. Toxins, 10(8), 311-311. View this article in WRRO
- The Use of Plant-Derived Ribosome Inactivating Proteins in Immunotoxin Development: Past, Present and Future Generations. Toxins, 9(11), 344-344. View this article in WRRO
Conference proceedings papers
- Protein Conjugation to Nanoparticles by Designer Affinity Tags. Materials Today: Proceedings, Vol. 4(7) (pp 6923-6929)
- On-Demand Assembly of Macromolecules Used for the Design and Application of Targeted Secretion Inhibitors. Peptides Across the Pacific: The Proceedings of the Twenty-Third American and the Sixth International Peptide Symposium
- Cleaved Intracellular SNARE Peptides are Implicated in a Novel Cytotoxicity Mechanism of Botulinum Serotype C. Peptides Across the Pacific: The Proceedings of the Twenty-Third American and the Sixth International Peptide Symposium
- Functional Characterization of Putative Synaptotagmin-Binding Interfaces in SNAP-25. Biophysical Journal, Vol. 100(3) (pp 407a-407a)
- Double-binding botulinum molecule with reduced muscle paralysis: Evaluation in in vitro and in vivo models of migraine. Toxicon, 190, S5-S5.
- Research group
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Group members:
- Charlotte Leese, Postdoctoral Fellow
- Ciara Doran, Postdoctoral Fellow
- Claire Christmas, Postdoctoral Fellow
- Deniz Simsek, PhD Student
- Eve Corrie, PhD Student
- Tatum Askey, MSc Student
Collaborators:
- Stephen Hunt (University College London)
- Rashid Giniatullin (University of Kuopio, Finland)
- Paul Stickings (National Institute for Biological Standards and Control, London)
- Silvia Fragoeira, Merck Animal Health
- Ron Broide, Allergan
- Grants
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- Medical Research Council
- NC3R
- Teaching activities
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Undergraduate and postgraduate taught modules
- BMS109 Introduction to Biomedical Science
- BMS110 Research Topics in Biomedicine
- BMS242/243 Cell & Molecular Biology
- BMS349 Dissertation module
- BMS397 Laboratory projects
- BMS401/6051 Masters course
- BMS402/6052 Laboratory projects
- BMS403/6053 Critical Analysis of Current Science