Christopher BROWN

Protein and Peptide Engineering and Research Laboratory (P2ERL)

PhD - Edinburgh

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

SUMMARY

Dr. Christopher BROWN holds a PhD in Structural Biochemistry from the University of Edinburgh, UK, where he worked under the guidance of Professor Malcolm Walkinshaw. He graduated from the University of Leeds, UK, and obtained an MRes from the University of York, UK, before pursuing his doctoral degree. Following his PhD, Dr. Brown undertook postdoctoral training with Professor Sir David Lane at IMCB, and was subsequently appointed Principal Investigator in the p53lab. He currently co-leads P2ERL alongside his colleague Dr. Farid Ghadessy.

With 18 years of research experience in Singapore, Dr. Brown has bridged the gap between academia and industry, contributing to projects ranging from small molecule discovery to macrocyclic peptides and engineered protein domains.

AWARDS & GRANTS

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

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
Nat Commun. 2024 Jan 12;15(1):489.
Engineering an autonomous VH domain to modulate intracellular pathways and to interrogate the eIF4F complex
Nat Commun. 2022 Aug 18;13(1):4854.
Development of a novel peptide aptamer that interacts with the eIF4E capped-mRNA binding site using peptide epitope linker evolution (PELE)
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
Chem Sci. 2019 Jan 7;10(8):2489-2500.
Enhancing Specific Disruption of Intracellular Protein Complexes by Hydrocarbon Stapled Peptides Using Lipid Based Delivery
Sci Rep. 2017 May 11;7(1):1763.
Stapled peptides with improved potency and specificity that activate p53
ACS Chem Biol. 2013 Mar 15;8(3):506-12.

PATENTS

c-terminal extended p53 activator crosslinked peptidomimetic macrocycles against mdm2/mdmx (WO2023096947)
Crosslinked peptidomimetic macrocycles that either contain a an alkene or alkyne staple and a poly-amino acid C -terminal tail. These crosslinked peptidomimetic macrocycles have improved binding to MDM2 and MDMX (aka MDM4), 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.
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.
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.

Christopher BROWN

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