Purine nucleoside phosphorylase design

The review articles by Schramm (1998, 2003) provide a number of examples of the successful application of this protocol to the design of enzyme-specific transition state-like inhibitors. Among these, the transition state inhibitors of human purine nucleoside phosphorylase (PNP) are particularly interesting from a medicinal chemistry perspective, as examples of these compounds have entered human clinical trials for the treatment of T-cell cancers and autoimmune disorders. 

A. Secrist, III, Application of crystallographic and modelling methods in the design of purine nucleoside phosphorylase inhibitors, Proc. Natl. Acad. Sci. USA 88 11540 (1991). 

Secrist, S. Y. Babu, C. E. Bugg, W. C. Guida, and S. E. Ealick, Structure-based design of inhibitors of purine nucleoside phosphorylase, 3,9-arylmethyl derivatives of a 9-deazaguanine substituted on the methylene group, J. Med. Chem. 36 3771 (1993). 

This rational approach to drug design has been adopted in developing a specific inhibitor of the human cellular enzyme, purine nucleoside phosphorylase (PNP). PNP functions in the purine salvage pathway, catalysing the reversible reaction shown below ... 

Figure 2.5. Diagramatic representation of the goal of rational drug design (a) illustrates the normal catalytic activity exhibited by purine nucleoside phosphorylase (PNP) (b) represents an effective inhibitor of PNP, which hts well into the active site thereby blocking its normal enzymatic activity...

Montgomery JA, Niwas S, Rose JD, Secrist JA 3d., Babu YS, Bugg CE, Erion MD, Guida WC, Ealick SE. Structure-based design of inhibitors of purine nucleoside phosphorylase. 1. 9-(arylmethyl) derivatives of 9-deazaguinine. J Med Chem 1993 36 55-69. 

PURINE NUCLEOSIDE PHOSPHORYLASE - MULTIPLE KIEs STUDY AND TS ANALOGUES DESIGN... 

The purine nucleoside phosphorylases (PNPs) are N-ribosyltransferases (Figure 7-7) where transition state analogue design on the basis of kinetic isotope effects analysis has had success. The inhibition of phosphorylation catalyzed by human... 

Purine nucleoside phosphorylase (PNP) catalyses the phosphorolysis of purine ribonucleosides and 2 -deoxyribo-nucleosides to the purine base and ribose- or 2-deoxyribose-a-1-phosphate. PNP is a key enzyme in the T-cell-mediated immune response. As such, it is an attractive target in a number of therapeutic areas, such as organ transplantation, T-cell-mediated autoimmune disorders and T-cell proliferative diseases. PNP has been the subject of a thorough and successful structure-based drug design study, of which the following gives only a flavour. 

The ability to accurately compute kinetic isotope effects (KIEs) for chemical reactions in solution and in enzymes is important because the measured KIEs provide the most direct probe to the nature of the transition state and the computational results can help rationalize experimental findings. This is illustrated by the work of Schramm and co-workers, who have used the experimental KIEs to develop transition state models for the enzymatic process catalyzed by purine nucleoside phosphorylase (PNP), which in turn were used to design picomolar inhibitors. In principle, Schramm s approach can be applied to other enzymes however, in order to establish a useful transition state model for enzymatic reactions, it is often necessary to use sophisticated computational methods to model the structure of the transition state and to match the computed KIEs with experiments. The challenge to theory is the difficulty in accurately determining the small difference in free energy of activation due to isotope replacements, especially for secondary and heavy isotope effects. Furthermore, unlike studies of reactions in the gas phase, one has to consider... 

Full details have also been given of the synthesis of 207, designed as an inhibitor of purine nucleoside phosphorylase, from D-fructose.277... 

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