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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.

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