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

van Zoelen, D.-J., Egmond, M.R., Pieters, R.J. and Liskamp, R.M.J. (2007) Synthesis and evaluation of TAC-based inhibitors of papain as mimics of cystatin B. ChemBioChem, 8(16), pp. 1950-1956. (doi: 10.1002/cbic.200700243)

Abstract

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 β-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 Ki of 12 nm, which approaches the inhibitory potency of cystatin B (Ki=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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Liskamp, Professor Robert
• Authors: van Zoelen, D.-J., Egmond, M.R., Pieters, R.J., and Liskamp, R.M.J.
• College/School: College of Science and Engineering > School of Chemistry
• Journal Name: ChemBioChem
• ISSN: 1439-4227
• ISSN (Online): 1439-7633