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

Chembiochem : a European Journal of Chemical Biology
Dirk-Jan van ZoelenRob M J Liskamp


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.


May 14, 1992·Nature·T J MolinaA Veillette
Jul 22, 1991·FEBS Letters·V Turk, W Bode
Apr 5, 1985·Biochimica Et Biophysica Acta·S ZuckerA J Barrett
Jun 1, 1974·The Biochemical Journal·R Eisenthal, A Cornish-Bowden
Sep 29, 1999·Proceedings of the National Academy of Sciences of the United States of America·P M SelzerJ H McKerrow
Dec 26, 2001·Chemical Reviews·M W Peczuh, Andrew D Hamilton
Mar 29, 2002·Chembiochem : a European Journal of Chemical Biology·Frank J DekkerRob M J Liskamp
Jun 5, 2002·Nature Reviews. Cancer·Harald zur Hausen
Aug 23, 2003·Trends in Biochemical Sciences·Phoebe Harjes, Erich E Wanker
Jun 24, 2004·Molecular Diversity·Rishi JainAndrew D Hamilton
Sep 30, 2004·Organic & Biomolecular Chemistry·Raimo FrankeJ Eichler
Jun 15, 2005·Angewandte Chemie·Hang Yin, Andrew D Hamilton


Jan 17, 2012·Journal of Medicinal Chemistry·Christopher J ArnuschYechiel Shai
Sep 1, 2012·Chemical Communications : Chem Comm·Gwenn E MulderRob M J Liskamp
Oct 22, 2008·Current Opinion in Chemical Biology·Jutta Eichler

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