Projects per year
Personal profile
Research interests
My research interests lie at the interface of chemistry and biology, utilising synthetic organic chemistry to investigate biological systems. I am involved in the design, synthesis and use of substrate derivatives as tools to study enzymes of biological and medical importance, with a particular emphasis on carbohydrate processing enzymes. These studies range from detailed investigations into the catalytic mechanisms of enzymes, to the use of this information in the design and synthesis of compounds as potential drug candidates. Some of the current research projects in my group include:
Inhibitors of HIV Integrase
HIV integrase is an enzyme expressed by the HIV virus. Integrase catalyses the incorporation of viral DNA into the genome of the host and as such, is essential for the survival and proliferation of the virus. Integrase is seen as a promising target for the chemotherapeutic treatment of HIV, yet little is known about the precise chemical mechanism through which the enzyme catalyses the integration of viral DNA.
My group is using chemically modified oligonucleotides in combination with protein X-ray crystallography (collaboration with Prof. Gideon Davies, University of York) to characterise crucial DNA-protein binding interactions, as well as the conformation changes the enzyme undergoes upon binding of viral and host DNA. This work will give us a detailed understanding of the catalytic mechanism of HIV integrase.
Information gained on the catalytic mechanism will then used to design and synthesise ‘mechanism-based’ inhibitors specific for HIV integrase.
Mechanism-based Inhibitors of Influenza Neuraminidases
Neuraminidases are enzymes that catalyse the removal of sialic acid residues from various glycoconjugates. The activity of these enzymes is known to be essential for the virulence and survival of several pathogens including the influenza virus. Consequently, influenza neuraminidase has emerged as a target enzyme for the development of anti-viral therapeutics. Indeed two neuraminidase inhibitors are currently marketed as drugs for influenza, namely Relenza® and Tamiflu®. However, it has recently emerged that strains of avian influenza, or 'Bird Flu', have already shown resistance to Tamiflu®. As many today consider that a new and devastating influenza pandemic is inevitable, there is an urgent need to develop new classes of antiviral compounds less susceptible to drug-induced resistance. Work in the laboratory of Prof. Steve Withers (UBC, Vancouver) has shown that fluorinated sialic acid analogues act as ‘mechanism-based’ inactivators to inhibit influenza neuraminidases. These compounds inhibit influenza neuraminidases by specifically targeting crucial residues of the enzyme essential for catalysis. As the neuraminidase is unable to tolerate mutations to these essential residues, drug-induced resistance is less likely to evolve in response to compounds.
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Network
Projects
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Investigations into the physico-chemical stability of multi-drug combinations in palliate care
16/10/17 → 15/10/21
Project: UK industry
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IAA - Exploitation of Novel Protein Conjugation Chemistry
Engineering and Physical Sciences Research Council
1/06/18 → 31/03/20
Project: Research council
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GCRF - Safe Drugs for Developing Countries
Engineering and Physical Sciences Research Council
18/07/16 → 17/03/17
Project: Research council
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KTP with Qualasept Limited
1/12/14 → 30/11/17
Project: Central government, health and local authorities
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The Development of Novel Protein Therapeutics Utilising an Innate Immune Response (Linked to RC-BB1163)
21/05/14 → 20/01/15
Project: Research council
Research Output
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High PD-1/PD-L1 Checkpoint Interaction Infers Tumor Selection and Therapeutic Sensitivity to Anti-PD-1/PD-L1 Treatment
Sanchez-Magraner, L., Miles, J., Baker, C. L., Applebee, C., Lee, D-J., Elsheikh, S., Lashin, S., Withers, K., Watts, A., Parry, R., Edmead, C., Lopez, J. I., Mehta, R., Italiano, A., Ward, S. G., Parker, P. J. & Larijani, B., 31 Oct 2020, In: Cancer Research. 80, 19, p. 4244-4257 14 p.Research output: Contribution to journal › Article › peer-review
4 Downloads (Pure) -
Structural Stabilisation of Disulphide-Linked Fluid-Phase C3d Dimers by Sbi Suggests a Novel B cell Subversion Strategy by Staphylococcus aureus
Wahid, A., Dunphy, R., Gibson, B., Back, C., Hallam, T., Alkhawaja, B., Harris, C., Crennell, S., Watts, A., Marchbank, K. & Van Den Elsen, J., Oct 2019, p. 437.Research output: Contribution to conference › Paper
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Utilization of Staphylococcal Immune Evasion Protein Sbi as a Novel Vaccine Adjuvant
Yang, Y., Back, C., Gräwert, M., Wahid, A., Denton, H., Kildani, R., Paulin, J., Wörner, K., Kaiser, W., Svergun, D., Sartbaeva, A., Watts, A., Marchbank, K. J. & Van Den Elsen, J., 11 Jan 2019, In: Frontiers in Immunology. 9, p. 1-17 17 p., 3139.Research output: Contribution to journal › Article › peer-review
Open AccessFile3 Citations (Scopus)68 Downloads (Pure) -
Immunogenic compositions comprising Sbi protein and uses thereof
Van Den Elsen, J., Watts, A. & Marchbank, K. J., 31 May 2018, Patent No. PCT/EP2017/080321, 31 May 2018Research output: Patent
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Structural and functional analysis of anti-influenza activity of 4-, 7-, 8- and 9-deoxygenated 2,3-difluoro-N-acetylneuraminic acid derivatives
McKimm-Breschkin, J. L., Barrett, S., Pilling, P. A., Hader, S., Watts, A. & Streltsov, V., 8 Mar 2018, In: Journal of Medicinal Chemistry. 61, 5, p. 1921–1933 13 p.Research output: Contribution to journal › Article › peer-review
Open AccessFile3 Citations (Scopus)37 Downloads (Pure)