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6. Development of stapled NONO‐associated peptides reveals unexpected cell permeability and nuclear localisation.

Author

Young, Reginald, Huang, Tiancheng, Luo, Zijie, Tan, Yaw Sing, Kaur, Amandeep, and Lau, Yu Heng

Abstract

The non‐POU domain‐containing octamer‐binding protein (NONO) is a nucleic acid‐binding protein with diverse functions that has been identified as a potential cancer target in cell biology studies. Little is known about structural motifs that mediate binding to NONO apart from its ability to form homodimers, as well as heterodimers and oligomers with related homologues. We report a stapling approach to macrocyclise helical peptides derived from the insulin‐like growth factor binding protein (IGFBP‐3) that NONO interacts with, and also from the dimerisation domain of NONO itself. Using a range of chemistries including Pd‐catalysed cross‐coupling, cysteine arylation and cysteine alkylation, we successfully improved the helicity and observed modest peptide binding to the NONO dimer, although binding could not be saturated at micromolar concentrations. Unexpectedly, we observed cell permeability and preferential nuclear localisation of various dye‐labelled peptides in live confocal microscopy, indicating the potential for developing peptide‐based tools to study NONO in a cellular context. [ABSTRACT FROM AUTHOR]

Published
2024
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12. Structural polymorphism in protein cages and virus-like particles.

Author

Lie, Felicia, Szyszka, Taylor N., and Lau, Yu Heng

Abstract

Protein cages and virus-like particles are often thought of as highly uniform structures that obey strict geometric rules for self-assembly. Yet, there is a growing number of examples where different architectures can emerge from the same native cage system through minor changes in experimental conditions or protein sequence. Access to diverse architectures can help tune the engineering of protein cages for biotechnology applications where shape and symmetry often affects function. In this review, we highlight the underappreciated diversity of polymorphic architectures that can be formed by protein cages and virus-like particles, categorising examples by their method of formation. [ABSTRACT FROM AUTHOR]

Published
2023
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15. Encapsulin Nanocompartments for Biomanufacturing Applications

Author

Szyszka, Taylor, Adamson, Lachlan, and Lau, Yu Heng

Subjects
0304 Medicinal and Biomolecular Chemistry, 0601 Biochemistry and Cell Biology
Abstract

Enzyme scaffolding is an emerging technique for enhancing yield and efficiency of biomanufacturing processes for generating high-value products. Of the many scaffolds available for in vivo and cell-free applications, encapsulin protein nanocompartments have garnered recent attention due to their desirable properties as a scaffold, such as robust self-assembly, high thermal stability, and the inherent ability to package and display enzymatic cargo. In this chapter, we discuss basic and advanced methods for encapsulin engineering, as well as the many encapsulin-based biomanufacturing systems that have been built. We subsequently discuss how these advances can be applied to increasingly complex encapsulin systems and look to the future of biomanufacturing in tunable protein nanocompartments.

Published
2022

17. Pore structure controls stability and molecular flux in engineered protein cages

Author

Adamson, Lachlan S. R., primary, Tasneem, Nuren, additional, Andreas, Michael P., additional, Close, William, additional, Jenner, Eric N., additional, Szyszka, Taylor N., additional, Young, Reginald, additional, Cheah, Li Chen, additional, Norman, Alexander, additional, MacDermott-Opeskin, Hugo I., additional, O’Mara, Megan L., additional, Sainsbury, Frank, additional, Giessen, Tobias W., additional, and Lau, Yu Heng, additional

Published
2022
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22. Pore structure controls stability and molecular flux in engineered protein cages

Author

Adamson, Lachlan S. R., primary, Tasneem, Nuren, additional, Andreas, Michael P., additional, Close, William, additional, Jenner, Eric N., additional, Szyszka, Taylor N., additional, Young, Reginald, additional, Cheah, Li Chen, additional, Norman, Alexander, additional, MacDermott-Opeskin, Hugo I., additional, O’Mara, Megan L., additional, Sainsbury, Frank, additional, Giessen, Tobias W., additional, and Lau, Yu Heng, additional

Published
2021
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25. Molecular Display on Protein Nanocompartments: Design Strategies and Systems Applications.

Author

Szyszka, Taylor N., Jenner, Eric N., Tasneem, Nuren, and Lau, Yu Heng

Subjects
ENCAPSULATION (Catalysis), ENZYMES, SYNTHETIC biology, CAPSIDS, CHEMISTRY
Abstract

The design of biomimetic systems in the laboratory is a long‐sought goal for systems chemists and synthetic biologists alike. Fundamental to this design is the generation of self‐assembled structures capable of mimicking compartmentalisation, which includes the encapsulation of molecular cargo as well as the display of molecules on the exterior. Protein nanocompartments are fast becoming popular scaffolds for these systems due to their robust self‐assembly, ability to encapsulate non‐native cargo, and amenability to surface modifications. In this Review, we discuss the primary methods for displaying a wide array of molecular motifs on compartment surfaces. We discuss benefits and drawbacks of each type of display and examine three recent case studies wherein molecular display was a critical design element in the construction of multi‐enzyme chemical systems. The analyses and case studies presented in this Review aim to provide a critical summary of the technologies currently used for molecular display to add another dimension to the design of chemical systems and nanoreactors. [ABSTRACT FROM AUTHOR]

Published
2022
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26. Stapled peptides as a new technology to investigate protein-protein interactions in human platelets

Author

Iegre, Jessica, Ahmed, Niaz S, Gaynord, Josephine S, Wu, Yuteng, Herlihy, Kara M, Tan, Yaw Sing, Lopes-Pires, Maria E, Jha, Rupam, Lau, Yu Heng, Sore, Hannah F, Verma, Chandra, O' Donovan, Daniel H, Pugh, Nicholas, Spring, David R, Iegre, Jessica [0000-0002-9074-653X], Gaynord, Josephine S [0000-0002-4091-8030], Tan, Yaw Sing [0000-0002-2522-9421], O' Donovan, Daniel H [0000-0002-8400-2198], Pugh, Nicholas [0000-0002-6916-4199], Spring, David R [0000-0001-7355-2824], and Apollo - University of Cambridge Repository

Subjects
Biomedical, Basic Science, Hematology, 0601 Biochemistry and Cell Biology, Cardiovascular
Abstract

Platelets are blood cells with numerous crucial pathophysiological roles in hemostasis, cardiovascular thrombotic events and cancer metastasis. Platelet activation requires the engagement of intracellular signalling pathways that involve protein-protein interactions (PPIs). A better understanding of these pathways is therefore crucial for the development of selective anti-platelet drugs. New strategies for studying PPIs in human platelets are required to overcome limitations associated with conventional platelet research methods. For example, small molecule inhibitors can lack selectivity and are often difficult to design and synthesise. Additionally, development of transgenic animal models is costly and time-consuming and conventional recombinant techniques are ineffective due to the lack of a nucleus in platelets. Herein, we describe the generation of a library of novel, functionalised stapled peptides and their first application in the investigation of platelet PPIs. Moreover, the use of platelet-permeable stapled Bim BH3 peptides confirms the part of Bim in phosphatidyl-serine (PS) exposure and reveals a role for the Bim protein in platelet activatory processes. Our work demonstrates that functionalised stapled peptides are a complementary alternative to conventional platelet research methods, and could make a significant contribution to the understanding of platelet signalling pathways and hence to the development of anti-platelet drugs.

Published
2018

27. Toolbox of Diverse Linkers for Navigating the Cellular Efficacy Landscape of Stapled Peptides

Author

Wu, Yuteng, primary, Kaur, Amandeep, additional, Fowler, Elaine, additional, Wiedmann, Mareike M., additional, Young, Reginald, additional, Galloway, Warren R. J. D., additional, Olsen, Lasse, additional, Sore, Hannah F., additional, Chattopadhyay, Anasuya, additional, Kwan, Terence T.-L., additional, Xu, Wenshu, additional, Walsh, Stephen J., additional, de Andrade, Peterson, additional, Janecek, Matej, additional, Arumugam, Senthil, additional, Itzhaki, Laura S., additional, Lau, Yu Heng, additional, and Spring, David R., additional

Published
2019
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28. Water-soluble, stable and azide-reactive strained dialkynes for biocompatible double strain-promoted click chemistry

Author

Sharma, Krishna, primary, Strizhak, Alexander V., additional, Fowler, Elaine, additional, Wang, Xuelu, additional, Xu, Wenshu, additional, Hatt Jensen, Claus, additional, Wu, Yuteng, additional, Sore, Hannah F., additional, Lau, Yu Heng, additional, Hyvönen, Marko, additional, Itzhaki, Laura S., additional, and Spring, David R., additional

Published
2019
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30. Stapled peptides as a new technology to investigate protein–protein interactions in human platelets

Author

Iegre, Jessica, primary, Ahmed, Niaz S., additional, Gaynord, Josephine S., additional, Wu, Yuteng, additional, Herlihy, Kara M., additional, Tan, Yaw Sing, additional, Lopes-Pires, Maria E., additional, Jha, Rupam, additional, Lau, Yu Heng, additional, Sore, Hannah F., additional, Verma, Chandra, additional, O' Donovan, Daniel H., additional, Pugh, Nicholas, additional, and Spring, David R., additional

Published
2018
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31. Development of a Multifunctional Benzophenone Linker for Peptide Stapling and Photoaffinity Labelling

Author

Wu, Yuteng, Olsen, Lasse B., Lau, Yu Heng, Jensen, Claus Hatt, Rossmann, Maxim, Baker, Ysobel R., Sore, Hannah F., Collins, Súil, Spring, David R., Rossmann, Maxim [0000-0001-8811-3277], Sore, Hannah [0000-0002-6542-0394], Spring, David [0000-0001-7355-2824], and Apollo - University of Cambridge Repository

Subjects
Molecular Structure, Communication, Proto-Oncogene Proteins c-mdm2, Photoaffinity Labels, stapled peptide, Ligands, linker, Communications, Benzophenones, Cross-Linking Reagents, MDM2, click chemistry, Peptides, photoaffinity labeling
Abstract

Photoaffinity labelling is a useful method for studying how proteins interact with ligands and biomolecules, and can help identify and characterise new targets for the development of new therapeutics. We present the design and synthesis of a novel multifunctional benzophenone linker that serves as both a photo‐crosslinking motif and a peptide stapling reagent. Using double‐click stapling, we attached the benzophenone to the peptide via the staple linker, rather than by modifying the peptide sequence with a photo‐crosslinking amino acid. When applied to a p53‐derived peptide, the resulting photoreactive stapled peptide was able to preferentially crosslink with MDM2 in the presence of competing protein. This multifunctional linker also features an extra alkyne handle for downstream applications such as pull‐down assays, and can be used to investigate the target selectivity of stapled peptides.

Published
2016

32. Cyclisation strategies for stabilising peptides with irregular conformations

Author

Vu, Quynh Ngoc, Young, Reginald, Sudhakar, Haritha Krishna, Gao, Tianyi, Huang, Tiancheng, Tan, Yaw Sing, and Lau, Yu Heng

Abstract

Cyclisation is a common synthetic strategy for enhancing the therapeutic potential of peptide-based molecules. While there are extensive studies on peptide cyclisation for reinforcing regular secondary structures such as α-helices and β-sheets, there are remarkably few reports of cyclising peptides which adopt irregular conformations in their bioactive target-bound state. In this review, we highlight examples where cyclisation techniques have been successful in stabilising irregular conformations, then discuss how the design of cyclic constraints for irregularly structured peptides can be informed by existing β-strand stabilisation approaches, new computational design techniques, and structural principles extracted from cyclic peptide library screening hits. Through this analysis, we demonstrate how existing peptide cyclisation techniques can be adapted to address the synthetic design challenge of stabilising irregularly structured binding motifs.

Published
2021
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36. Large-scale recoding of a bacterial genome by iterative recombineering of synthetic DNA

Author

Lau, Yu Heng, primary, Stirling, Finn, additional, Kuo, James, additional, Karrenbelt, Michiel A. P., additional, Chan, Yujia A., additional, Riesselman, Adam, additional, Horton, Connor A., additional, Schäfer, Elena, additional, Lips, David, additional, Weinstock, Matthew T., additional, Gibson, Daniel G., additional, Way, Jeffrey C., additional, and Silver, Pamela A., additional

Published
2017
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37. Rapid genome recoding by iterative recombineering of synthetic DNA

Author

Lau, Yu Heng, primary, Stirling, Finn, additional, Kuo, James, additional, Karrenbelt, Michiel A.P., additional, Chan, Yujia A., additional, Riesselman, Adam, additional, Horton, Connor A., additional, Schaefer, Elena, additional, Lips, David, additional, Weinstock, Matthew T., additional, Gibson, Daniel G., additional, Way, Jeffrey C., additional, and Silver, Pamela A., additional

Published
2017
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40. Molecular Switches for any pH: A Systematic Study of the Versatile Coordination Behaviour of Cyclam Scorpionands.

Author

Lau, Yu Heng, Clegg, Jack K., Price, Jason R., Macquart, Rene B., Todd, Matthew H., and Rutledge, Peter J.

Subjects
*MOLECULAR switches, *TRANSITION metal complexes, *ACTIVE metals, *FUNCTIONAL groups, *REACTIVITY (Chemistry)
Abstract

Abstract: Molecular switches have many potential applications in nanoscience and biomedicine. Transition metal complexes that can be switched from an inert, unreactive state to a catalytically active one by a simple change in conditions (e.g. pH shift) or by binding to a specific biomolecular target—so‐called target‐activated metal complexes (TAMCs)—hold particular allure as a means of harnessing the potent but at times indiscriminate reactivity of metal‐based drugs. Towards this goal, we have prepared a series of ten structurally related ligands, each of which bears a different pendant side‐arm functional group appended to a common macrocyclic core, along with copper(II) and nickel(II) complexes of these cyclam‐based “molecular scorpionands”. X‐ray crystal structures reveal a variety of binding modes between pendant side‐arm and metal centre that depend on the constituent donor atoms. To investigate the switchability of side‐arm coordination in solution, spectrophotometric pH titrations were carried out for all 20 metal complexes. The majority of the complexes undergo spectroscopic changes that are consistent with a switch in pendant coordination state at a specific pH. This ligand series represents a comprehensive model platform from which to build pH‐switchable metal complexes for applications in nanoscience and biomedicine. [ABSTRACT FROM AUTHOR]

Published
2018
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46. Functionalised staple linkages for modulating the cellular activity of stapled peptides

Author

Lau, Yu Heng, primary, de Andrade, Peterson, additional, Quah, Soo-Tng, additional, Rossmann, Maxim, additional, Laraia, Luca, additional, Sköld, Niklas, additional, Sum, Tze Jing, additional, Rowling, Pamela J. E., additional, Joseph, Thomas L., additional, Verma, Chandra, additional, Hyvönen, Marko, additional, Itzhaki, Laura S., additional, Venkitaraman, Ashok R., additional, Brown, Christopher J., additional, Lane, David P., additional, and Spring, David R., additional

Published
2014
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