Synthesis and evaluation of TAC-based inhibitors of papain as mimics of cystatin B.


An approach for mimicking protein-protein interactions by using a discontinuous epitope to construct a mimic that is about one tenth of the size of a natural inhibitor of papain, namely, cystatin B, is described. The discontinuous epitope of cystatin B, which is involved in the interaction with papain, was mimicked by synthesis of a tripodal molecular construct by using the triazacyclophane (TAC) scaffold. The mimic contains three peptide arms: one that mimics the N terminus, one that mimics the C terminus, and one that mimics the beta-hairpin loop structure of cystatin B. These peptide sequences were assembled on the TAC scaffold. The resulting cystatin mimic, CysTACtin 9, showed excellent inhibition of papain with a K(i) of 12 nM, which approaches the inhibitory potency of cystatin B (K(i)=0.12 nM). Experiments with molecular constructs that contained one or two arms or a mixture of the nonscaffolded peptides showed that both scaffolding and the presence of the three peptide arms are crucial for a successful mimic.

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@article{Zoelen2007SynthesisAE, title={Synthesis and evaluation of TAC-based inhibitors of papain as mimics of cystatin B.}, author={Dirk-Jan van Zoelen and Maarten R. Egmond and Roland J Pieters and Rob M. J. Liskamp}, journal={Chembiochem : a European journal of chemical biology}, year={2007}, volume={8 16}, pages={1950-6} }