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, Lane DP, 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, CJ Brown, 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, Lane DP. 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, Lane DP, Brown CJ. 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, Lane DP, Brown CJ. 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, Lane DP. 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, Walkinshaw MD. J Mol Biol. 2007 Sep 7;372(1):7-15.