Christopher BROWN

Protein and Peptide Engineering and Research Laboratory (P2ERL)

PhD - University of Edinburgh, UK

LinkedIn: https://sg.linkedin.com/in/christopher-john-brown-3bab944a

SUMMARY

Christopher J. Brown is a Principal Investigator at the Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), co-leading the P2ERL (Protein and Peptide Engineering and Research Lab).

Over the last 20 years, Christopher has carried out his research in Singapore and has had a keen interest in understanding the parameters that underpin macrocyclic peptide cell permeability. An important focus of his current work is to develop libraries to discover new binding sites using phenotypic screens to nucleate the development of tools for target site validation and hit discovery. For example, discovering novel helical peptide interaction sites that can take advantage of the known ‘rules’ for stapled peptide development, which elicit desirable phenotypic effects.

Christopher’s research has been highly collaborative, leading to many beneficial interactions and collaboration with other A*STAR research entities (Bioinformatics Institute (BII), Institute of Sustainability for Chemicals, Energy and Environment (ISCE²)) and with external partners (MSD, IPSEN).

Christopher graduated from the University of Leeds (UK) and obtained an MRes from the University of York (UK). He then carried out his Ph.D. studies in the Structural Biochemistry group at the University of Edinburgh (UK) with Professor Malcolm Walkinshaw, before leaving for Singapore to carry out his early postdoctoral studies with Sir David Lane at the p53Lab in IMCB, where he then progressed to Principal Investigator in the p53lab, prior his current role.

AWARDS & GRANTS

2024 NRF Competitive Research Programme (CRP)
2023 GAP Funding
2021 STDR Pilot

RESEARCH

Protein and Peptide Engineering and Research Laboratory (P2ERL)
Our team's primary focus is on discovering novel modalities, such as macrocyclic peptides and mini-proteins, to perturb intracellular biological interactions of therapeutic interest. Specifically, we target macromolecular surfaces that are challenging for small molecules to bind. We employ various display technologies, including chemically modified phage and yeast libraries, to efficiently explore chemical and structural space and discover these molecules. Characterization is performed using biophysical and structural methods. We have also begun to explore the application of lentiviral based libraries to deliver protein fragments to perturb phenotypes of interest with the aim of identifying novel druggable sites.

Our research interests include developing techniques to enhance the functionality of these molecules and enable targeted delivery for target validation and therapeutic modeling studies. For example, our research has explored the use of mini-proteins in 3D cellular culture and animal systems to model potential cellular effects. Molecules exhibiting desirable properties can serve as scaffolds for therapeutic development, guiding the design of novel treatments. Additionally, we have investigated the fusion of mini-proteins with protein domains of orthogonal functionality, such as E3 ligases, to enable extended modes of inhibition and catalytic degradation of multiple target molecules.

PUBLICATIONS

Design-rules for stapled peptides with in vivo activity and their application to Mdm2/X antagonists.
Chandramohan, A., Josien, H., Yuen, T.Y. et al.
Nat Commun 15, 489 (2024).
Engineering an autonomous VH domain to modulate intracellular pathways and to interrogate the eIF4F complex.
Frosi, Y., Lin, YC., Shimin, J. et al.
Nat Commun 13, 4854 (2022).
Development of a novel peptide aptamer that interacts with the eIF4E capped-mRNA binding site using peptide epitope linker evolution (PELE).
Frosi Y, Ng S, Lin YC, Jiang S, Ramlan SR, Lama D, Verma CS, Asial I, Brown CJ.
RSC Chem Biol. 2022 May 19;3(7):916-930.
Structural insights reveal a recognition feature for tailoring hydrocarbon stapled-peptides against the eukaryotic translation initiation factor 4E protein.
Lama D, Liberatore AM, Frosi Y, Nakhle J, Tsomaia N, Bashir T, Lane DP, Brown CJ, Verma CS, Auvin S.
Chem Sci. 2019 Jan 7;10(8):2489-2500.
Enhancing Specific Disruption of Intracellular Protein Complexes by Hydrocarbon Stapled Peptides Using Lipid Based Delivery.
Thean D, Ebo JS, Luxton T, Lee XC, Yuen TY, Ferrer FJ, Johannes CW, Lane DP, Brown CJ.
Sci Rep. 2017 May 11;7(1):1763.
Stapled peptides with improved potency and specificity that activate p53.
Brown CJ, Quah ST, Jong J, Goh AM, Chiam PC, Khoo KH, Choong ML, Lee MA, Yurlova L, Zolghadr K, Joseph TL, Verma CS, Lane DP.
ACS Chem Biol. 2013 Mar 15;8(3):506-12.

PATENTS

Engineering peptides using peptide epitope linker evolution (WO2023182945A2)
The present invention relates to methods of engineering and identifying a peptide aptamer that binds to a target protein of interest, and peptide aptamers engineered and identified using these methods and methods to identify a candidate peptide or nucleic acid that binds to a target protein in a live cell. The peptide aptamers defined herein may be useful for treating a condition associated with dysregulated cap-dependent translation, dysregulated DNA replication, dysregulated DNA repair and/or dysregulated mRNA translation such as cancer, diseases associated with a viral infection and obesity.
P53 activator peptidomimetic macrocycles (WO2020257133)
Peptidomimetic macrocycles that comprise all-D configuration α-amino acids and bind mouse double minute 2 (MDM2 aka E3 ubiquitin-protein ligase) and MDMX (aka MDM4) are described. These all-D configuration α-amino acid peptidomimetic macrocycles are protease resistant, cell permeable without inducing membrane disruption, and intracellularly activate p53 by binding MDM2 and MDMX thereby antagonizing MDM2 and MDMX binding to p53. These peptidomimetic macrocycles may be useful in anticancer therapies, particularly in combination with chemotherapy or radiation therapy.

Christopher BROWN

A*STAR celebrates International Women's Day