Total Synthesis of Covalent Cysteine Protease Inhibitor N-Desmethyl Thalassospiramide C and Crystallographic Evidence for Its Mode of Action

Org Lett. 2019 Jan 18;21(2):508-512. doi: 10.1021/acs.orglett.8b03821. Epub 2019 Jan 10.


A total synthesis of N-desmethyl thalassospiramide C, a unique strained macrocyclic proteobacterial depsipeptide, enabled a detailed crystallographic study of its covalent complex with cathepsin K, a member of a medicinally important family of cysteine proteases. The study provides support for the mechanism of action, and the insight gained can be used for structure-based drug design targeting these calpain proteases.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Cathepsin K / chemistry*
  • Cysteine / chemistry*
  • Cysteine Proteinase Inhibitors / chemical synthesis*
  • Cysteine Proteinase Inhibitors / chemistry
  • Molecular Structure
  • Serine Endopeptidases / chemistry*


  • Cysteine Proteinase Inhibitors
  • Serine Endopeptidases
  • protease C
  • Cathepsin K
  • Cysteine