Professor Bazbek Davletov

Department of Biomedical Science

Chair in Biomedical Science

b.davletov@sheffield.ac.uk
+44 114 222 5111

Full contact details

Professor Bazbek Davletov
Department of Biomedical Science
D225
Alfred Denny Building
Western Bank
Sheffield
S10 2TN
Profile
  • 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.

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.

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.

Publications

Show: Featured publications All publications

Journal articles

All publications

Journal articles

Conference proceedings papers

  • Abdullahi RA, Lloyd J, Jones M, Lambru G, Al-Kaisy A, Davletov B & Andreou A (2019) Long term actions of a recombinant advanced Botulinum toxin (BiTox-AA) molecule in migraine animal models. CEPHALALGIA, Vol. 39 (pp 230-230) RIS download Bibtex download
  • AbuukarAbdullahi R, Lloyd JO, Jones MG, Lambru G, Al-Kaisy A, Davletov B & Andreou AP (2018) Long-term effects of the non-paralytic botulinum toxin A molecule BiTox in migraine animal models. JOURNAL OF HEADACHE AND PAIN, Vol. 19 RIS download Bibtex download
  • Andreou AP, AbuukarAbdullahi R, Lloyd JO, Jones M, Lambru G, Al-Kaisy A & Davletov B (2018) Long-term Effects of the Non-paralytic Botulinum Toxin a Molecule Bitox in a Migraine Animal Model. HEADACHE, Vol. 58(8) (pp 1335-1336) RIS download Bibtex download
  • Ma W, Aboagye-Mensah D, Soloviev M, Davletov B & Ferrari E (2017) Protein Conjugation to Nanoparticles by Designer Affinity Tags. Materials Today: Proceedings, Vol. 4(7) (pp 6923-6929) RIS download Bibtex download
  • Paraskevopoulou M, Perez JT, Miedzik A, Chamberlain J, Lambru G, Davletov B & Andreou AP (2016) NON-PARALYTIC BOTULINUM MOLECULES FOR THE CONTROL OF MIGRAINE. CEPHALALGIA, Vol. 36 (pp 135-135) RIS download Bibtex download
  • Wang T, Martin S, Papadopulos A, Harper C, Mavlyutov T, Niranjan D, Glass N, Cooper-White J, Sibarita J-B, Choquet D , Davletov B et al (2015) Control of autophagosome axonal retrograde flux by presynaptic activity unveiled using botulinum neurotoxin type-A. JOURNAL OF NEUROCHEMISTRY, Vol. 134 (pp 165-165) RIS download Bibtex download
  • Torres-Perez JV, Chamberlain J, Miedzik AA, Nagy I, Davletov B & Andreou AP (2015) Non-paralytic botulinum chimeras increase the activation threshold of the trigeminovascular system in migraine models. CEPHALALGIA, Vol. 35 (pp 4-4) RIS download Bibtex download
  • Arsenault J, Ferrari E, Niranjan D & Davletov B (2013) 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 RIS download Bibtex download
  • Arsenault J, Cuijpers SAG, Ferrari E, Niranjan D, O'Brien JA & Davletov B (2013) 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 RIS download Bibtex download
  • Arsenault J, Ferrari E, Niranjan D & Davletov B (2012) Retargeted Botulinum Neurotoxins using SNARE protein stapling capable of selectively silencing neuroendocrine cells. JOURNAL OF PEPTIDE SCIENCE, Vol. 18 (pp S154-S154) RIS download Bibtex download
  • Mohrmann R, De Wit H, Connell E, Davletov B, Verhage M & Sørensen JB (2011) Functional Characterization of Putative Synaptotagmin-Binding Interfaces in SNAP-25. Biophysical Journal, Vol. 100(3) (pp 407a-407a) RIS download Bibtex download
  • Arsenault J, O'Brien J, Ferrari E, Niranjan D, Ruiperez V & Davletov B (2011) SNARE based peptide linking as an efficient strategy to retarget botulinum neurotoxin's enzymatic domain to specific neurons using diverse neuropeptides as targeting domains. BIOPOLYMERS, Vol. 96(4) (pp 466-466) RIS download Bibtex download
  • Broersen K & Davletov B (2007) Lipids and alpha-synuclein aggregation in Parkinson's disease. MOVEMENT DISORDERS, Vol. 22(12) (pp VI-VI) RIS download Bibtex download
  • Voigl B, Hlavacka A, Craxton M, Davletov B, Menzel D & Baluska F (2005) Plant Synaptotagmins: effectors of calcium-regulated endocytosis and exocytosis in plants?. EUROPEAN JOURNAL OF CELL BIOLOGY, Vol. 84 (pp 131-131) RIS download Bibtex download
  • Bajohrs M, Rickman C, Binz T & Davletov B (2004) The interaction of SNAP-25 with syntaxin1 and syntaxin2 accounts for the differential toxicity of botulinum toxin A and E. MOLECULAR BIOLOGY OF THE CELL, Vol. 15 (pp 71A-71A) RIS download Bibtex download
Research group

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

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)
Grants
  • Medical Research Council
  • NC3R
Teaching activities

Undergraduate and postgraduate taught modules

Undergraduate:

  • BMS110 Research Topics in Biomedicine
  • BMS242/243 Cell & Molecular
  • Level 3 Practical and Dissertation Module