Monthly Lab Focus – Davletov Group
Scientific Questions we are addressing:
- Targeting technologies for drug delivery
- Mechanisms of botulinum neurotoxins action on neurons
- Design of non-paralysing botulinum constructs for long-lasting pain alleviation
- Targeting protein translation in cancer and chronic pain
- Design of multifunctional biomolecules
Techniques we use:
- Bacterial protein expression and purification
- Protein modification and stapling reactions
- Cell culture and cell labelling
- Cell death and neurite outgrowth assays
- Dorsal root ganglion neuronal cultures
- Fluorescence microscopy analysis of neurons and neuroblastoma cells
- In vivo tests of new non-paralysing constructs
Images courtesy of Davletov lab 2015.
Lay Summary of research within the lab
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.
Our novel biomolecular constructs for long-lasting control of pain attracted attention of national and international press and radio. Notably:
- Interview on US WAMC Radio. Prof Bazbek Davletov explains why Botox could be the next great pain medication.
- Scientists modify Botox for the treatment of pain
Selected Recent Publications:
- Mangione AS, Obara I, Maiarú M, Geranton SM, Tassorelli C, Ferrari E, Leese C, Davletov B, Hunt SP. (2016) Non-paralytic botulinum molecules for the control of pain. Pain, Epub ahead of print January 5
- 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.
- Wang T, Martin S, Papadopulos A, Harper CB, Mavlyutov TA, Niranjan D, Glass NR, Cooper-White JJ, Choquet D, Davletov B & Meunier FA (2015) Control of autophagosome axonal retrograde flux by presynaptic activity unveiled using botulinum neurotoxin type A. Journal of Neuroscience, 35(15), 6179-6194.
- Arsenault J, Cuijpers SAG, Niranjan D, Davletov B (2014) Unexpected transcellular protein crossover occurs during canonical DNA transfection. Journal of Cellular Biochemistry, 115(12), 2047-2054.
- Arsenault J, Cuijpers SAG, Ferrari E, Niranjan D, O'Brien JA, Davletov B, Rust A, Leese C & Binz T (2014) Botulinum protease-cleaved SNARE fragments induce cytotoxicity in neuroblastoma cells. Journal of Neurochemistry, 129(5), 781-791.
- Davletov B (2014) A multiple sclerosis drug sheds light on astrocyte biology. Acta Physiol (Oxf) 212(1):8-10.
- Arsenault J, Ferrari E, Niranjan D, Cuijpers SA, 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.
- 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 (2013) A synthetic self-assembling clostridial chimera for modulation of sensory functions. Bioconjug Chem. 24:1750-59 (featured on the journal cover).
- Mohrmann R, de Wit H, Connell E, Pinheiro PS, Leese C, Bruns D, Davletov B, Verhage M & Sørensen JB (2013) Synaptotagmin Interaction with SNAP-25 Governs Vesicle Docking, Priming, and Fusion Triggering. J Neurosci, 33(36), 14417-14430.
- Shatillo A, Koroleva K, Giniatullina R, Naumenko N, Slastnikova AA, Aliev RR, Bart G, Atalay M, Gu C, Khazipov R, Davletov B, Grohn O & Giniatullin R (2013) Cortical spreading depression induces oxidative stress in the trigeminal nociceptive system. Neuroscience 253:341-9
- 2015 – BMS Third year PhD symposium award by Aleks Rust
- 2015 – BMS First year PhD symposium award by Rose Hart
- 2015 – BMS PhD retreat 3rd place poster award by Rose Hart
- Medical Research Council
- 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)