The main focus of our group is to discover novel modalities such as macrocyclic peptides and mini-proteins
in order to perturb intracellular biological interactions of therapeutic interest. In particular we focus
on protein-protein interactions that are considered to be intractable to small molecule antagonism. We
use a variety of display technologies such as chemically modified phage and yeast libraries to efficiently
search chemical and structural space to discover and isolate these molecules, which are then characterised
using biophysical and structural methods. However, in general macrocyclic peptides and mini-proteins
are inherently cell impermeable and require further chemical optimization and utilization of cell delivery
methods. Therefore another key interest of our group is to explore alternative approaches to circumvent
this issue and to develop cellular based assays to quantitate successful target engagement with in cell.
Once cell permeability has been established in tandem with a preliminary structure activity relationship,
we believe that these molecules can serves as initial hits in therapeutic lead development programs.
An attractive use of the development of novel mini-proteins is that these modalities can be expressed
in cells and animal systems to model the potential cellular effects of these compounds. This should
allow the development of more efficient assays and the identification of ‘biomarkers’ that can be used
to guide these molecules through the early iterative stages of therapeutic lead development. The
group is actively involved in the IAF funded Peptide Engineering Program (PEP), in partnership with BII
and ICES, which seeks to develop techniques that will optimize and increase the efficiency of macrocycle
peptide discovery and lead development. In addition, we actively seek collaboration with industrial and
academic partners to pursue targets of high scientific and medical interest. Recent and current partners
have included IPSEN, MBL and MSD.
Christopher J Brown - Group Leader
Siti Radhiah Ramlan
- Monitoring flux in signaling pathways through measurements of 4EBP1-mediated eIF4F Complex assembly.
Yuri Frosi, Rachael Usher, Dawn Thean Gek Lian,
David P. Lane
Christopher J. Brown. BMC Biology. Accepted.
- 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,
Brown CJ, Verma CS, Auvin S.
Chem Sci. 2019 Jan 7;10(8):2489-2500.
- The MDM2/MDMX-p53 antagonist PM2 radiosensitizes wild-type p53 tumorsD Spiegelberg, AC Mortensen, S Lundsten,
DP Lane, M Nestor. Cancer research 78 (17), 5084-5093.
- Macrocyclic α helical peptide therapeutic modality: A perspective of learnings and challenges. Sawyer
TK, Partridge AW, Kaan HYK, Juang YC, Lim S, Johannes C, Yuen TY, Verma C, Kannan S, Aronica P, Tan
YS, Sherborne B, Ha S, Hochman J, Chen S, Surdi L, Peier A, Sauvagnat B, Dandliker PJ,
Brown CJ, Ng S, Ferrer F,
Bioorg Med Chem. 2018 Jun 1;26(10):2807-2815.
- Enhancing Specific Disruption of Intracellular Protein Complexes by Hydrocarbon Stapled Peptides Using
Lipid Based Delivry. Thean D, Ebo JS, Luxton T, Lee XC, Yuen TY, Ferrer FJ, Johannes CW,
Sci Rep. 2017 May 11;7(1):1763.
- Rational optimization of conformational effects induced by hydrocarbon staples in peptides and their
binding interfaces. Lama D, Quah ST, Verma CS, lakshminarayanan R, Beuerman RW,
Sci Rep. 2013 Dec 13;3:3451.
- 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,
ACS Chem Biol. 2013 Mar 15;8(3):506-12.
- Crystallographic and mass spectrometric characterisation of eIF4E with N7-alkylated cap derivatives.
Brown CJ, McNae I, Fischer PM,
J Mol Biol. 2007 Sep 7;372(1):7-15.