Dr James Baker

Research Overview

Our research group is focused on developing new methods in organic synthesis and chemical biology, and harnessing them in the design of therapeutics, clinical tools and probes of biological systems. We are particularly interested in investigating new approaches to the chemical modification of proteins, the construction and application of homogeneous antibody conjugates, and the photochemical control of biomolecules.

A New Chemical Platform for Protein Modification

Reagents that can selectively modify individual amino acids are of widespread use in the study and manipulation of proteins. We have developed the Next Generation Maleimide (NGM) reagents as a powerful new chemical platform for protein conjugation (collaboration with Prof Steve Caddick). These reagents offer major advantages over the current state-of-the-art. They undergo rapid and highly selective conjugation to single cysteine residues or to reduced disulfide bonds, allowing site-selective modification of proteins to afford superior homogeneous bioconjugates. By re-bridging reduced disulfides the NGMs allow targeting of these accessible residues whilst retaining the stabilising structural bridges (see figure below).

We are investigating applications of this versatile NGM platform in the construction of protein conjugates for therapeutic applications; most significantly in the area of antibody conjugates (collaboration with Prof Steve Caddick and Prof Kerry Chester – UCL Cancer Institute). Using antibodies as therapeutics and diagnostics is one of the most promising areas of research into new healthcare products. Antibodies represent the fastest growing class of therapeutics, with over 30 approved for clinical use to date and over 150 in clinical development. Two particularly promising classes of antibody based therapeutics are antibody-drug conjugates (ADCs) and bispecifics, commonly referred to as ‘magic-bullet’ therapies due to their ability to seek and destroy just diseased cells within the body (e.g. cancer cells). However, a major hindrance to the area is the lack of suitable chemical methods for the construction of homogeneous, well defined, antibody conjugates, which we are seeking to overcome with the NGM platform.

New method protein modification 130%

Select publications in this area

[1] Bromomaleimides; new reagents for the selective and reversible modification of cysteine, L. M. Tedaldi, M. E. B. Smith, R. Nathani, J. R. Baker, Chem. Commun., 2009, 6583-6585. doi:10.1039/b915136b

[2] Protein modification, bioconjugation, and disulfide bridging using bromomaleimides, M. E. B. Smith, F. F. Schumacher, C. P. Ryan, L. M. Tedaldi, D. Papaioannou, G. Waksman, S. Caddick, J. R. Baker, J. Am. Chem. Soc., 2010, 132, 1960-1965. doi:10.1021/ja908610s

[3] In Situ Maleimide Bridging of Disulfides and a New Approach to Protein PEGylation, F. F. Schumacher, M. Nobles, C. P. Ryan, M. E. B. Smith, A. Tinker, S. Caddick, J. R. Baker, Bioconjugate Chem., 2011, 22, 132-136. doi:10.1021/bc1004685

[4] Tunable reagents for multi-functional bioconjugation: reversible or permanent chemical modification of proteins and peptides by control of maleimide hydrolysis, C. P. Ryan, M. E. B. Smith, F. F. Schumacher, D. Grohmann, D. Papaioannou, G. Waksman, F. Werner, J. R. Baker, S. Caddick, Chem. Commun., 2011, 47, 5452-5454. doi:10.1039/C1CC11114K

[5] Homogeneous antibody fragment conjugation by disulfide bridging introduces 'spinostics', F. F. Schumacher, V. A. Sanchania, B. Tolner, Z. V. F. Wright, C. P. Ryan, M. E. B. Smith, J. M. Ward, S. Caddick, C. W. M. Kay, G. Aeppli, K. A. Chester, J. R. Baker, Sci. Rep., 2013, 3, 1525. doi:10.1038/srep01525

[6] Homogeneous Bispecifics by Disulfide Bridging, E. A. Hull, M. Livanos, E. Miranda, M. E. B. Smith, K. A. Chester, J. R. Baker, Bioconjugate Chem., 2014, 25, 1395-1401. doi:10.1021/bc5002467

[7] Next generation maleimides enable the controlled assembly of antibody-drug conjugates via native disulfide bond bridging, F. F. Schumacher, J. P. M. Nunes, A. Maruani, V. Chudasama, M. E. B. Smith, K. A. Chester, J. R. Baker, S. Caddick, Org. Biomol. Chem., 2014, 12, 7261-7269. doi:10.1039/c4ob01550a

Photochemical method development for organic synthesis and chemical biology

Photochemistry is a powerful tool for organic synthesis and also in the study of biological systems (and increasingly in therapeutics e.g. photodynamic therapy). It enables reactions to be carried out that are impossible via standard thermal pathways, whilst also providing spatial and temporal control over ‘where’ and ‘when’ reactions take place. We aim to exploit the power of photochemistry in the synthesis of complex small molecule scaffolds and to control the activity of biomolecules, particularly peptides and proteins (see figure below).

Broadening the scope of viable synthetic photocycloadditions. The widespread application of photochemistry in organic synthesis is hindered in part by the unpredictable yields of products obtained in reactions. We are exploring new methodology to offer greater control of [2+2] photocycloadditions, which enables the rapid construction of complex molecules incorporating highly strained cyclobutanes and cyclobutenes.

The design and synthesis of photoactivatable tools of the GABAA ion channel (collaboration with Professor Trevor Smart, UCL pharmacology). The GABAA receptor is a chloride ion channel which has gamma-aminobutyric acid as its activating ligand. We are designing and synthesising new photoactive analogues of GABAA ligands, to serve as tools to study these crucial biological systems. For example we are synthesising new antagonists (e.g. GZ-B1) that will, when irradiated with a UV light, covalently attach to the receptor completely blocking the active site. We can then observe how the cell recovers its receptor activity - affording new insights in to the ‘life cycle’ of receptors on the cells surface.

New approaches to photochemically manipulate peptides and proteins. We are investigating carrying out photochemical reactions on pre-activated peptides and proteins, which enable unprecedented modes of controlling the bioactivity of these biomolecules. This allows, for example, the activation or a peptide in a biological medium by simply irradiating the sample with light (and thus a highly controlled external stimulus).

New methods photochemistry 130%

Select publications in this area

[1] In situ Reduction in Photocycloadditions: A Method to Prevent Secondary Photoreactions, L. M. Tedaldi, J. R. Baker, Org. Lett., 2009, 11, 811-814. doi:10.1021/ol8026494

[2] 2+2 Photocycloadditions of thiomaleimides, L. M. Tedaldi, A. E. Aliev, J. R. Baker, Chem. Commun., 2012, 48, 4725-4727. doi:10.1039/c2cc31673k

[3] Synthesis and evaluation of highly potent GABA(A) receptor antagonists based on gabazine (SR-95531), F. Iqbal, R. Ellwood, M. Mortensen, T. G. Smart, J. R. Baker, Bioorg. Med. Chem. Lett., 2011, 21, 4252-4254. doi:10.1016/j.bmcl.2011.05.067.

[4] Diverse products accessible via 2+2 photocycloadditions of 3-aminocyclopentenones, A. J. A. Roupany, J. R. Baker, RSC Advances, 2013, 3, 10650-10653. doi:10.1039/C3RA42106F

[5] Photo-antagonism of the GABA(A) receptor, M. Mortensen, F. Iqbal, A. P. Pandurangan, S. Hannan, R. Huckvale, M. Topf, J. R. Baker, T. G. Smart, Nature Communications, 2014, 5. doi:10.1038/ncomms5454

JB_Thiologics heading

Thiologics is a UCL Business-owned company spun-out of the Department of Chemistry, UCL, in June 2011. The company aims to commercialise new bioconjugation technologies developed through collaboration between our group and Prof Steve Caddick’s. ThioLogics is particularly focused on delivering technology that will enable the construction of homogeneous antibody drug conjugate therapeutics (ADCs) (www.thiologics.com).

Thiologics scheme