2. Academic Validation
  3. De novo macrocyclic peptides that specifically modulate Lys48-linked ubiquitin chains

De novo macrocyclic peptides that specifically modulate Lys48-linked ubiquitin chains

  • Nat Chem. 2019 Jul;11(7):644-652. doi: 10.1038/s41557-019-0278-x.
Mickal Nawatha 1,  Joseph M Rogers 2,  Steven M Bonn 3,  Ido Livneh 4,  Betsegaw Lemma 3,  Sachitanand M Mali 1,  Ganga B Vamisetti 1,  Hao Sun 1,  Beatrice Bercovich 4,  Yichao Huang 2,  Aaron Ciechanover 4,  David Fushman 3,  Hiroaki Suga 5,  Ashraf Brik 6
Affiliations

Affiliations

  • 1 Schulich Faculty of Chemistry, Technion-Israel Institute of Technology, Haifa, Israel.
  • 2 Department of Chemistry, Graduate School of Science, The University of Tokyo, Bunkyo-ku, Tokyo, Japan.
  • 3 Department of Chemistry and Biochemistry, Center for Biomolecular Structure and Organization, University of Maryland, College Park, MD, USA.
  • 4 The Rappaport Faculty of Medicine and Research Institute, Technion-Israel Institute of Technology, Haifa, Israel.
  • 5 Department of Chemistry, Graduate School of Science, The University of Tokyo, Bunkyo-ku, Tokyo, Japan. hsuga@chem.s.u-tokyo.ac.jp.
  • 6 Schulich Faculty of Chemistry, Technion-Israel Institute of Technology, Haifa, Israel. abrik@technion.ac.il.
PMID: 31182821 DOI: 10.1038/s41557-019-0278-x
Abstract

A promising approach in Cancer therapy is to find ligands that directly bind ubiquitin (Ub) chains. However, finding molecules capable of tightly and specifically binding Ub chains is challenging given the range of Ub polymer lengths and linkages and their subtle structural differences. Here, we use total chemical synthesis of proteins to generate highly homogeneous Ub chains for screening against trillion-member macrocyclic peptide libraries (RaPID system). De novo cyclic Peptides were found that can bind tightly and specifically to K48-linked Ub chains, confirmed by NMR studies. These cyclic Peptides protected K48-linked Ub chains from deubiquitinating Enzymes and prevented proteasomal degradation of Ub-tagged proteins. The cyclic Peptides could enter cells, inhibit growth and induce programmed cell death, opening new opportunities for therapeutic intervention. This highly synthetic approach, with both protein target generation and cyclic peptide discovery performed in vitro, will make other elaborate post-translationally modified targets accessible for drug discovery.

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