Research interests: All aspects of organic reaction mechanism in (especially aqueous) solution, in the general context of mechanism and efficiency in enzyme catalysis. The approach is firmly based in Chemistry, and aimed at a sound understanding based on results from systems simple enough to understand in detail (and to synthesise without too much trouble). Enzymes do ordinary chemistry in extraordinary environments, using familiar mechanisms and taking advantage of textbook stereoelectronic effects.1 They work typically by binding and thus selectively stabilising transition states for the reactions they catalyse, so the general objective is to define both the structure of a given transition state (the mechanism) and how it is bound (efficiency). 2 We can only be confident that we really understand enzymes when we can reproduce their properties - especially their efficiency - in artificial catalysts.
We know that functional groups (FG's) are brought together in the enzyme substrate complex, so we start by bringing together the same groups, doing the same reactions, under controlled conditions: usually on the same molecule3 though occasionally in the binding site of an antibody or a synthetic host system. In this way we can learn how the mechanism and efficiency of catalysis depend on the way FG's are brought together. 4,5 We can apply this knowledge in the design and synthesis (now definitely non-trivial!) of molecules containing two or even three FG's to see how far these can reproduce both the high rates and the stereospecificity of enzyme reactions. We have developed the world's most efficient systems for various sorts of intramolecular catalysis - an example is a phosphate diester (think how stable DNA has to be) with a half-life of milliseconds - and are currently putting some of them together in the same molecule to create what we hope will be a new generation of super-efficient enzyme models. We have also investigated different ways of developing artificial catalysts, 2,6 which are potentially relevant to anything from academic theory to gene therapy. Recently we have been devising new systems7 which facilitate transfection - the transport of genes into the cell nucleus - a crucial step in gene therapy - as one aspect of the general problem of drug delivery (see ENGEMS). And are involved with former members of another European Network (ENDEVAN) in developing artificial nucleases - (relatively!) simple systems which will catalyse the sequence-specific cleavage of RNA and DNA.
Prof. Kirby formally retired from his Chair of Bioorganic Chemistry on 30 September 2002. He will take no more research students or postdoctoral researchers in Cambridge.
Research activities continue, through several valuable one-to-one collaborations: especially with Dr. Florian Hollfelder in Cambridge (Department of Biochemistry) and Prof. Faruk Nome in Brazil (Universidade Federal de Santa Catarina, in Florianópolis).
- Oxford Chemistry Primer, OUP, 1996
- From Enzyme Models to Model Enzymes, With Florian Hollfelder. RSC, Cambridge 2009
- Adv. Phys. Org. Chem. , 1980, 17, 183-279.
- Nature (London) , 1996, 383, 60-63; Bioorg. Med. Chem. , 2006, 14, 6189-6196.
- J. Am. Chem. Soc. , 2005, 127, 7033-7040; 2006, 128, 16944-16952.
- J. Am. Chem. Soc. , 2000, 122, 1022-9: Org. Lett. , 2000, 2, 127-30. J. Org. Chem. 2001, 66, 5866-5874.
- Angew. Chem., Intl. Ed. Engl. , 2003, 42, 1448-1457.