Lesley A. Howell

Queen Mary University of London

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Mark Searcey

University of East Anglia

Peter J. McCormick

Queen Mary University of London

Maria A. O’Connell

University of East Anglia

Andrew M. Beekman

University of East Anglia

Enric I. Canela

Universitat de Barcelona

Estefanía Moreno

Universitat de Barcelona

Sergi Ferré

National Institute on Drug Abuse

Vicent Casadó

Universitat de Barcelona

Joaquín Botta

William Harvey Research Institute

Carmen Lluís

Universitat de Barcelona

Cooperative Institutions

University of East Anglia

Universitat de Barcelona

Norwich Research Park

Biomedical Research Networking Center on Neurodegenerative Diseases

Centro de Investigación Biomédica en Red

Instituto de Salud Carlos III

Institut de Biomedicina de la Universitat de Barcelona

National Institute on Drug Abuse

Norwich University

National Institutes of Health

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When being off-track is a way of being on-track: a hermeneutic phenomenological approach to research and research supervision

Steven P. Segal Claire Jankelson Bradley Rolfe John Walker Rachelle Arkles

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Design and Characterization of Superpotent Bivalent Ligands Targeting Oxytocin Receptor Dimers via a Channel-Like Structure

Journal of Medicinal Chemistry (2016)

Marta Busnelli Gunnar Kleinau Markus Muttenthaler Stoytcho Stoev Maurice Manning

Dimeric/oligomeric states of G-protein coupled receptors have been difficult to target. We report here bivalent ligands consisting of two identical oxytocin-mimetics that induce a three order magnitude boost in G-protein signaling of oxytocin receptors (OTRs) in vitro and a 100- and 40-fold gain in potency in vivo in the social behavior of mice and zebrafish. Through receptor mutagenesis and interference experiments with synthetic peptides mimicking transmembrane helices (TMH), we show that such superpotent behavior follows from the binding of the bivalent ligands to dimeric receptors based on a TMH1-TMH2 interface. Moreover, in this arrangement, only the analogues with a well-defined spacer length (∼25 Å) precisely fit inside a channel-like passage between the two protomers of the dimer. The newly discovered oxytocin bivalent ligands represent a powerful tool for targeting dimeric OTR in neurodevelopmental and psychiatric disorders and, in general, provide a framework to untangle specific arrangements of G-protein coupled receptor dimers.

Bivalent (engine)

Oxytocin receptor

10.1021/acs.jmedchem.6b00564

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Peptide‐Directed Binding for the Discovery of Modulators of α‐Helix‐Mediated Protein–Protein Interactions: Proof‐of‐Concept Studies with the Apoptosis Regulator Mcl‐1

Angewandte Chemie (2017)

Andrew M. Beekman Maria A. O’Connell Lesley A. Howell

Abstract Targeting PPIs with small molecules can be challenging owing to large, hydrophobic binding surfaces. Herein, we describe a strategy that exploits selective α‐helical PPIs, transferring these characteristics to small molecules. The proof of concept is demonstrated with the apoptosis regulator Mcl‐1, commonly exploited by cancers to avoid cell death. Peptide‐directed binding uses few synthetic transformations, requires the production of a small number of compounds, and generates a high percentage of hits. In this example, about 50 % of the small molecules prepared showed an IC 50 value of less than 100 μ m, and approximately 25 % had IC 50 values below 1 μ m to Mcl‐1. Compounds show selectivity for Mcl‐1 over other anti‐apoptotic proteins, possess cytotoxicity to cancer cell lines, and induce hallmarks of apoptosis. This approach represents a novel and economic process for the rapid discovery of new α‐helical PPI modulators.

10.1002/ange.201705008

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Citations (1)

Rac1 plays a role in CXCL12 but not CCL3-induced chemotaxis and Rac1 GEF inhibitor NSC23766 has off target effects on CXCR4

Cellular Signalling (2017)

Shirley C. Mills Lesley A. Howell Andrew M. Beekman Leanne Stokes Anja Müeller

CDC42

Jurkat cells

10.1016/j.cellsig.2017.10.006

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Citations (21)

Highlighting the Contributions of Marginalized Chemists in the Chemistry Curriculum

Journal of Chemical Education (2023)

Israt-Zahan Chowdhury Aisha Sharif Lesley A. Howell Tippu S. Sheriff

There is widespread interest in diversifying and decolonizing the chemistry curricula in higher education. However, this is not reflected in the curricula taught to students prior to coming to university. We describe the results of an online survey of 185 secondary school/college teachers and students (>18 years) and, separately, 79 members of the public (of all ages) in the United Kingdom on their knowledge of historical chemists and scientists. The results of the survey revealed a notable disparity in recognition between White male scientists and scientists from African American and other backgrounds. Almost 90% of the respondents to our online survey said that the contributions of Black, Asian, and minority ethnic (BAME) scientists are not highlighted adequately in the English national curriculum. Furthermore, over 85% of the participants believed that the national curriculum should be revised to include the achievements of underrepresented scientists. We describe how we addressed this by cocreating (with undergraduate students) teacher resources to highlight the contributions of underrepresented scientists and the feedback received. Overall, our research underscores the need for a more inclusive approach to teaching chemistry in secondary schools and colleges. It highlights the demand for a curriculum that recognizes and celebrates the significant contributions made by scientists from diverse backgrounds.

10.1021/acs.jchemed.2c00771

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Citations (3)

Luteinising hormone receptor signalling is reliant on formation of distinct multi-receptor complexes

Endocrine Abstracts (2023)

Abigail Walker Thomas Hopkins Lesley A. Howell Zara Farooq Peter J. McCormick

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Signalling

10.1530/endoabs.94.oc4.5

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Unveiling the “Three-Finger Pharmacophore” Required for p53-MDM2 Inhibition by Saturation-Transfer Difference (STD) NMR Initial Growth-Rates Approach

Chemistry - A European Journal (2016)

Jesús Angulo Sarah A. Goffin Daivik Gandhi Mark Searcey Lesley A. Howell

Inhibitors of the p53-MDM2 protein-protein interaction are emerging as a new and validated approach to treating cancer. Herein, we describe the synthesis and inhibitory evaluation of a series of isoquinolin-1-one analogues, and highlight the utility of an initial growth-rates saturation-transfer difference (STD) NMR approach supported by protein-ligand docking to investigate p53-MDM2 inhibition. The approach is illustrated by the study of compound 1, providing key insights into the binding mode of this kind of MDM2 ligands and, more importantly, readily unveiling the previously proposed three-finger pharmacophore requirement for p53-MDM2 inhibition.

Docking (animal)

10.1002/chem.201600114

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Citations (9)

Identification of Small‐Molecule Inhibitors of the Antiapoptotic Protein Myeloid Cell Leukaemia‐1 (Mcl‐1)

ChemMedChem (2015)

Andrew M. Beekman Maria A. O’Connell Lesley A. Howell

Abstract Protein–protein interactions (PPIs) control many cellular processes in cancer and tumour growth. Of significant interest is the role PPIs play in regulating apoptosis. The overexpression of the antiapoptosis regulating Bcl‐2 family of proteins is commonly observed in several cancers, leading to resistance towards both radiation and chemotherapies. From this family, myeloid cell leukemia‐1 (Mcl‐1) has proven the most difficult to target, and one of the leading causes of treatment resistance. Exploiting the selective PPI between the apoptosis‐regulating protein Noxa and Mcl‐1, utilising a fluorescence polarization assay, we have identified four small molecules with the ability to modulate Mcl‐1. The identified compounds were computationally modelled and docked against the Mcl‐1 binding interface to obtain structural information about their binding sites allowing for future analogue design. When examined for their activity towards pancreatic cell lines that overexpress Mcl‐1 (MiaPaCa‐2 and BxPC‐3), the identified compounds demonstrated growth inhibition, suggesting effective Mcl‐1 modulation.

10.1002/cmdc.201500488

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Citations (17)

ChemInform Abstract: Synthesis and Evaluation of 9‐Aminoacridines Derived from Benzyne Click Chemistry.

ChemInform (2010)

Lesley A. Howell Aaron Howman Maria A. O’Connell Anja Müeller Mark Searcey

Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Aryne

10.1002/chin.201007136

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Peptide-Directed Binding for the Discovery of Modulators of α-Helix-Mediated Protein-Protein Interactions: Proof-of-Concept Studies with the Apoptosis Regulator Mcl-1

Angewandte Chemie International Edition (2017)

Andrew M. Beekman Maria A. O’Connell Lesley A. Howell

Targeting PPIs with small molecules can be challenging owing to large, hydrophobic binding surfaces. Herein, we describe a strategy that exploits selective α-helical PPIs, transferring these characteristics to small molecules. The proof of concept is demonstrated with the apoptosis regulator Mcl-1, commonly exploited by cancers to avoid cell death. Peptide-directed binding uses few synthetic transformations, requires the production of a small number of compounds, and generates a high percentage of hits. In this example, about 50 % of the small molecules prepared showed an IC

10.1002/anie.201705008

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Citations (13)