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Professor Brindle studies protein function, structure, and adaptability.

He uses evolutionary and protein engineering techniques to develop novel proteins for medicine and biotechnology, and to investigate viral evolution, vaccine and drug resistance.

We evolve and engineer proteins to better understand biology and to create new protein functionality

Our current research is centered around two themes:

• Creating new protein functions for medical and biotechnology applications
• Discovering mechanisms by which viruses modify their ability to bind host cells and to acquire vaccine and drug resistance

We use a wide range of methodologies including directed protein evolution, deep mutational scanning and protein engineering. Some examples of recent and ongoing work include:

Selective inhibitors for vascular disease

We have evolved the binding selectivity of a receptor ectodomain to create highly selective inhibitors for the ligand Ang2 (; ), a protein that activates vascular inflammation and has pathological roles in several diseases, including heart failure, diabetic retinopathy and HHT. In this work we also discovered key roles for specific residues in the receptor binding interface that enables the Ang2 receptor to be directly regulated by different ligands.

Viral evolution

Our directed evolution work on the receptor-binding domain of SARS-CoV2 spike protein () has provided insights into mutations affecting spike protein binding to its cellular receptor ACE2. Importantly, we identified a strong negative epistasis between the N501Y and Q498H mutations, that limits the ways the virus can mutate depending on whether it has the N501Y or Q498H mutation.

Improving detection of viral and other proteins

Using directed evolution and protein engineering we have modified the SARS-CoV2 receptor ACE2 to create very high affinity forms of the receptor that can be used to capture virus and retain it for many hours. We used these to demonstrate proof-of-concept for a novel capture technology to increase sensitivity of detecting viruses and proteins in biological and environmental samples ().

Vaccine and drug resistance

We are using deep mutational scanning (DMS) to identify and predict mutations that can lead to therapeutic resistance in viral and other proteins. The ability to be able to predict and test which mutations in a protein lead to therapeutic resistance is important for designing better vaccines and drugs, optimising treatments and containment of resistant microbial variants.

Bate, N, Lane, D, Evans, SE, Salim, F, Allcock, NS, Haigh, R, Sale, JE, Jones, DJL, Brindle, NPJ (2025). “Engineered Receptor Capture Combined with Mass Spectrometry Enables High-Throughput Detection and Quantitation of SARS-CoV-2 Spike Protein” JACS Au. 5, 747–55.

Bate, N., Savva, CG, Moody, PCE, Brown, EA, Ball, JK, Schwabe, JWR, Sale, JE and Brindle, NPJ (2022). "In vitro evolution predicts emerging CoV-2 mutations with high affinity for ACE2 and cross-species binding." PLOS Pathogens 18: e1010733.

Bate, N., J. Lodge, J and Brindle, NPJ (2021). "Intrinsic differences in the mechanisms of Tie2 binding to angiopoietins exploited by directed evolution to create an Ang2-selective ligand-trap." J Biol Chem 297: 100888.

Alharbi, A., Thompson, J. P., Brindle, N. P. & Stover, C. M (2019) “Ex vivo modelling of the formation of inflammatory platelet-leucocyte aggregates and their adhesion on endothelial cells, an early event in sepsis” Clin. Exp. Med. 19, 321-337.

Issa, E, Moss, AJ, Fischer, M, Kang, M, Ahmed, S, Farah, H, Bate, N, Giakomidi, D & Brindle NPJ (2018) “Development of an orthogonal Tie2 ligand resistant to inhibition by Ang2” Molecular Pharmaceutics 15, 3962-3968.

Alawo, DOA, Tahir, TA, Fischer,M, Bates, D, Amirova, SR & Brindle, NPJ (2017). "Regulation of Angiopoietin Signalling by Soluble Tie2 Ectodomain and Engineered Ligand Trap." Sci Reports 7(1): 3658.

Fischer, M., M. Kang and N. P. Brindle (2016). "Using experimental evolution to probe molecular mechanisms of protein function." Protein Sci 25(2): 352-359.

Tahir, TA, Singh, H & Brindle NPJ. The RNA binding protein hnRNP-K mediates post –transcriptional regulation of Uncoupling Protein-2 by angiopoietin-1. Cell Signal (2014) 26 1379-1384.

Brindle, NP, Sale, JE, Arakawa, H, Buerstedde, JM, Nuamchit, T, Sharma, S, Steele, KH. Directed evolution of an Angiopoietin-2 ligand trap by somatic hypermutation and cell surface display. J Biol Chem (2013) 288, 33205-33212.

Singh H, Hansen TM, Patel N, Brindle NPJ. The molecular balance between receptor tyrosine kinases Tie1 and Tie2 is dynamically controlled by VEGF and TNFα and regulates angiopoietin signalling. PLoS ONE (2012) 7(1): e29319.

Singh, H, Tahir, TA, Alawo, DOA, Issa, E & Brindle NPJ. Molecular control of angiopoietin signaling. Biochem Soc Trans (2011) 39 1592-1596.

Hansen, TM, Singh, H, Tahir, TA & Brindle NPJ (2010) “Effects of Angiopoietin-1 and -2 on the receptor tyrosine kinase Tie2 are differentially regulated at the endothelial cell surface” Cellular Signalling 22 527-532.

Kopp, PM, Bate, N, Hansen, TM, Brindle, NP, Praekelt, U, Debrand, E, Coleman, S, Mazzeo, D, Goult, BT, Gingras, AR, Pritchard, CA, Critchley, DR, Monkley, SJ (2010) “Studies on the morphology and spreading of human endothelial cells define key inter- and intramolecular interactions for talin1” European Journal of Cell Biology 89 661-673.

BSc (Hons) University of Leeds

PhD University of Manchester

FHEA