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Dr James Redman  -  MA (Oxon) PhD


 

  • Protein engineering using phage display
  • Development of synthetic small molecule ligands for folded nucleic acids
  • Design of assays for probing interactions of ligands with nucleic acids
  • Computer assisted mass spectrometric structure determination of combinatorial library products
  • Application of solid phase chemistry for preparation of topologically diverse compounds

An understanding of the forces between molecules enables us to design synthetic compounds that interact with biological targets and to redesign natural biomolecules to achieve new functions. One of our research interests concerns the engineering of small molecule binding sites within proteins and in this area we are using phage display techniques to select for allosteric drug binding sites in zinc-finger transcription factor proteins.

Engineering an allosteric binding site into a zinc-finger transcription factor

Nucleic acids, and especially RNA, can adopt complex folded structures comparable to proteins and we are involved with development of small molecule ligands against these macromolecular targets. In order to realize our designs we need to call upon the skills of synthetic organic chemistry for preparation and assembly of molecular building blocks. We are currently synthesising a range of amino acids with guanidine side chains as building blocks for nucleic acid binding peptides.

Guanidine amino acids as building blocks for nucleic acid binding peptides

One of our goals is to increase the efficiency with which we discover new ligands through a combination of miniaturized parallel synthesis and analysis to verify the identity of reaction products. We have a particular interest in the application of tandem mass spectrometry and computer assisted structure determination of peptides with unnatural topologies, including cyclic, branched and cross linked molecules. We are developing software for structure determination of these compounds using an automated analysis of fragmentation patterns. These classes of compound are amenable to parallel synthesis, and through a judicious choice of building blocks we can tune them to exhibit a desired biological activity such as selective recognition of a nucleic acid fold.

Collision induced dissociation mass spectrum of a cyclic hexapeptide, calculated using our software, and the corresponding experimental spectrum.