Projects per year
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.
Expertise related to UN Sustainable Development Goals
In 2015, UN member states agreed to 17 global Sustainable Development Goals (SDGs) to end poverty, protect the planet and ensure prosperity for all. This person’s work contributes towards the following SDG(s):
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16/10/17 → 31/01/23
Project: UK industry
1/06/18 → 31/03/20
Project: Research council
Staphylococcal complement evasion protein Sbi stabilises C3d dimers by inducing an N-terminal helix swapDunphy, R., Wahid, A., Back, C., Martin, B., Watts, A., Dodson, C., Crennell, S. & Van Den Elsen, J., 25 May 2022, In: Frontiers in Immunology. 13, 892234.
Research output: Contribution to journal › Article › peer-reviewOpen Access8 Downloads (Pure)
Wahid, A., Dunphy, R., Macpherson, A., Gibson, B., Kulik, L., Whale, K., Back, C., Hallam, T., Alkhawaja, B., Martin, B., Meschede, I., Laabei, M., Lawson, A., Holers, V. M., Watts, A., Crennell, S., Harris, C., Marchbank, K. & Van Den Elsen, J., 9 Aug 2021, In: Frontiers in Immunology. 12, 714055.
Research output: Contribution to journal › Article › peer-reviewOpen AccessFile2 Citations (SciVal)12 Downloads (Pure)
BIS(2-HALOACETAMIDO)-COMPOUNDS FOR USE AS LINKING AGENTS AND RESULTANT PRODUCTS WHICH COMPRISE ANTIBODIES, HALF-ANTIBODIES AND ANTIBODY FRAGMENTSWatts, A. & Alkhawaja, B., 30 Dec 2020, IPC No. C07K16/00, A61K47/00, C07C233/00, C07C247/04, Patent No. WO2020260514, Priority date 25 Jun 2019, Priority No. GB201909103A
Research output: Patent
High PD-1/PD-L1 Checkpoint Interaction Infers Tumor Selection and Therapeutic Sensitivity to Anti-PD-1/PD-L1 TreatmentSanchez-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-reviewOpen AccessFile14 Citations (SciVal)11 Downloads (Pure)
Structural Stabilisation of Disulphide-Linked Fluid-Phase C3d Dimers by Sbi Suggests a Novel B cell Subversion Strategy by Staphylococcus aureusWahid, 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