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Targeting protein-protein interactions in inflammation and cancer (O’CONNELLMU19SCIVC)

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  • Full or part time
    Prof M O'Connell
    Dr A Beekman
  • Application Deadline
    No more applications being accepted
  • Funded PhD Project (European/UK Students Only)
    Funded PhD Project (European/UK Students Only)

Project Description

Protein-protein interactions (PPI) play an essential role in cellular processes. There are several thousands of PPIs in cells, ranging in complexity and until recently, were considered undruggable. However, due to recent research advances, they are emerging as important therapeutic targets in chronic inflammatory diseases and cancer. We are particularly interested in understanding and characterising PPIs and developing small molecules that target them, including interactions involving the intracellular proteins Nrf2, p53 and MCL-1. The transcription factor Nrf2 plays a key role in sensing oxidative stress. Nrf2 activation leads to cytoprotective and anti-inflammatory effects in vitro and in vivo1. It binds to Keap1 in the cytosol and small Maf proteins in the nucleus. We have previously shown that disruption of the Nrf2/Keap1 interaction leads to anti-inflammatory effects in immune cells, suggesting this PPI is a valid therapeutic target in inflammatory diseases2,3. In cancer, Nrf2 has dual effects, as although it protects cells from mutation, once tumors have developed, they may hijack this pathway to protect themselves and induce resistance to cytotoxic drugs Disruption of the Nrf2/small Maf PPI may therefore be beneficial in cancer. We have also developed strategies to target other PPIs in cancer and developed small molecules targeting p53/Mdm2 and MCL-1/Noxa4,5. In this multidisciplinary project, the student will investigate and characterise PPIs that are important in chronic inflammatory diseases and cancer. They will also screen small molecules in silico and investigate the effects of novel small molecules on selected PPIs. The student will gain expertise in cell culture and several cell and molecular biology techniques, in silico screening, data analysis and structure activity relationships in addition to generic research skills.

For more information on the supervisor for this project, please go here: https://people.uea.ac.uk/m_oconnell
The type of programme – PhD
The start date of the project – October 2019
Acceptable first degree in Pharmacology and Drug Discovery, Pharmacology, Biological Sciences or other related area and requires a 1st in Pharmacology or related subject.

Funding Notes

This PhD studentship is funded for 3 years by the Faculty of Science and is open to UK/EU applicants only. Funding comprises home/EU tuition fees and an annual stipend of £15,009

References

1. O’Connell MA, Hayes JD (2015). The Keap1/Nrf2 pathway in health and disease: from the bench to the clinic. Biochem Soc Trans 43, 687-89.

2. Steel R, O’Connell MA, Searcey M (2018). Perfluorarene-based peptide macrocycles that inhibit the Nrf2/Keap1 interaction. Bioorg Med Chem Letts 28, 2728-2731.
3. Steel R, Cowan J, Payerne E, O'Connell MA, Searcey M (2012). Anti-inflammatory effect of a cell penetrating peptide targeting the Nrf2/Keap1 interaction. ACS Med Chem Letts 3, 407-410.

4. Beekman AM, O’Connell MA, Howell L (2017). Peptide directed binding; a strategy for the discovery of new, selective protein-protein interaction modulators, exemplified with apoptosis regulating Mcl-1/Noxa. Angew Chem Int Ed Engl 56, 10446-10450.

5. Beekman AM, Cominetti MMD, Walpole SJ, Prabhu S, O’Connell MA, Angulo J, Searcey M (2019). Identification of selective protein-protein interaction inhibitors using efficient in silico peptide-directed ligand design. Chem Sci 10, 4502-4508.



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