Synlett 2015; 26(01): 1-5
DOI: 10.1055/s-0034-1379425
synpacts
© Georg Thieme Verlag Stuttgart · New York

Constraining Peptide Conformations with the Help of Ring-Closing Metathesis

Adrian Glas
a  Technical University Dortmund, Department of Chemistry and Chemical Biology, Otto-Hahn-Straße 6, 44227 Dortmund, Germany
b  Chemical Genomics Centre of the Max Planck Society, Otto-Hahn-Straße 15, 44227 Dortmund, Germany   Fax: +49(231)97426479   Email: tom.grossmann@cgc.mpg.de
,
Tom N. Grossmann*
a  Technical University Dortmund, Department of Chemistry and Chemical Biology, Otto-Hahn-Straße 6, 44227 Dortmund, Germany
b  Chemical Genomics Centre of the Max Planck Society, Otto-Hahn-Straße 15, 44227 Dortmund, Germany   Fax: +49(231)97426479   Email: tom.grossmann@cgc.mpg.de
› Author Affiliations
Further Information

Publication History

Received: 12 August 2014

Accepted after revision: 14 October 2014

Publication Date:
18 November 2014 (eFirst)

Abstract

Chemical modifications are used to stabilize bioactive conformations of peptides thereby increasing their target affinity and selectivity. Such modified peptides proved particularly useful as inhibitors of protein–protein interactions. Most of these strategies aim at the stabilization of α-helices and β-sheets. The use of peptides with irregular secondary structure is hampered by a lack of appropriate stabilization approaches. Herein, we highlight a recent contribution from our group that uses ring-closing metathesis for the macrocyclization of peptides with irregular secondary structure. The peptide precursors are cyclized on solid support to provide cross-linked architectures that bind the ­human protein 14-3-3 thereby inhibiting its interaction with virulence factor exoenzyme S from Pseudomonas aeruginosa.

 
  • References

  • 1 Berman HM, Westbrook J, Feng Z, Gilliland G, Bhat TN, Weissig H, Shindyalov IN, Bourne PE. Nucleic Acids Res. 2000; 28: 235
  • 2 Brauckhoff N, Hahne G, Yeh JT, Grossmann TN. Angew. Chem. Int. Ed. 2014; 53: 4337
  • 3 Glas A, Bier D, Hahne G, Rademacher C, Ottmann C, Grossmann TN. Angew. Chem. Int. Ed. 2014; 53: 2489
  • 4 Spiegel J, Cromm PM, Itzen A, Goody RS, Grossmann TN, Waldmann H. Angew. Chem. Int. Ed. 2014; 53: 2498
  • 5 Thiel P, Kaiser M, Ottmann C. Angew. Chem. Int. Ed. 2012; 51: 2012
    • 6a Milroy LG, Grossmann TN, Hennig S, Brunsveld L, Ottmann C. Chem. Rev. 2014; 114: 4695
    • 6b Hahne G, Grossmann TN. Bioorg. Med. Chem. 2013; 21: 4020
  • 7 Wilson AJ. Chem. Soc. Rev. 2009; 38: 3289
  • 8 London N, Raveh B, Movshovitz-Attias D, Schueler-Furman O. Proteins Struct. Funct. Bioinf. 2010; 78: 3140
  • 9 Verdine GL, Walensky LD. Clin. Cancer Res. 2007; 13: 7264
  • 10 Houk KN, Leach AG, Kim SP, Zhang XY. Angew. Chem. Int. Ed. 2003; 42: 4872
  • 11 Kessler H. Angew. Chem., Int. Ed. Engl. 1982; 21: 512
  • 12 Bracken C, Gulyas J, Taylor JW, Baum J. J. Am. Chem. Soc. 1994; 116: 6431
  • 13 Jackson DY, King DS, Chmielewski J, Singh S, Schultz PG. J. Am. Chem. Soc. 1991; 113: 9391
  • 14 Blackwell HE, Grubbs RH. Angew. Chem. Int. Ed. 1998; 37: 3281
    • 15a Grossmann TN, Yeh JT, Bowman BR, Chu Q, Moellering RE, Verdine GL. Proc. Natl. Acad. Sci. U.S.A. 2012; 109: 17942
    • 15b Patgiri A, Jochim AL, Arora PS. Acc. Chem. Res. 2008; 41: 1289
  • 16 Schafmeister CE, Po J, Verdine GL. J. Am. Chem. Soc. 2000; 122: 5891
  • 17 Miller SJ, Blackwell HE, Grubbs RH. J. Am. Chem. Soc. 1996; 118: 9606
  • 18 Fasan R, Dias RL, Moehle K, Zerbe O, Obrecht D, Mittl PR, Grutter MG, Robinson JA. ChemBioChem 2006; 7: 515
  • 19 Guharoy M, Chakrabarti P. Bioinformatics 2007; 23: 1909
  • 20 Ottmann C, Yasmin L, Weyand M, Veesenmeyer JL, Diaz MH, Palmer RH, Francis MS, Hauser AR, Wittinghofer A, Hallberg B. EMBO J. 2007; 26: 902
  • 21 Kim YW, Grossmann TN, Verdine GL. Nat. Protoc. 2011; 6: 761
  • 22 Kim YW, Kutchukian PS, Verdine GL. Org. Lett. 2010; 12: 3046