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

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

Author information

1
Department of Chemistry and Biochemistry , University of California , Santa Barbara , California 93111 , United States.
2
Blade Therapeutics , 442 Littlefield Avenue , South San Francisco , California 94080 , United States.
3
Bayside Pharma , 2600 Hilltop Drive , Richmond , California 94806 , United States.
4
ChemPartner , 280 Utah Avenue Suite 100 , South San Francisco , California 94080 , United States.
5
Proteros Biostructures GmbH , Bunsenstra├če 7 a , 82152 Planegg-Martinsried , Germany.

Abstract

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.

PMID:
30628449
DOI:
10.1021/acs.orglett.8b03821
[Indexed for MEDLINE]

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