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Stojkovska Docevska et al. Rare Dis Orphan Drugs J 2023;2:14 Rare Disease and
DOI: 10.20517/rdodj.2023.09
Orphan Drugs Journal

Review Open Access

Cathepsin C: structure, function, and pharmacological
targeting

Milena Stojkovska Docevska, Marko Novinec
Department of Chemistry and Biochemistry, Faculty of Chemistry and Chemical Technology, University of Ljubljana, Ljubljana
SI-1000, Slovenia.
Correspondence to: Dr. Marko Novinec, Department of Chemistry and Biochemistry, Faculty of Chemistry and Chemical
Technology, University of Ljubljana, Vecna pot 113, Ljubljana SI-1000, Slovenia. E-mail: marko.novinec@fkkt.uni-lj.si
How to cite this article: Stojkovska Docevska M, Novinec M. Cathepsin C: structure, function, and pharmacological targeting.
Rare Dis Orphan Drugs J 2023;2:14. https://dx.doi.org/10.20517/rdodj.2023.09

Received: 16 Mar 2023 First Decision: 29 Jun 2023 Revised: 14 Jul 2023 Accepted: 20 Jul 2023 Published: 27 Jul 2023
Academic Editors: Daniel Scherman, Bridget Bax Copy Editor: Dan Zhang Production Editor: Dan Zhang

Abstract
Cathepsin C is a papain-like cysteine peptidase known primarily for its involvement in the activation of serine
peptidases in neutrophils and other immune cells. Its critical role in this process qualifies cathepsin C as a target for
the treatment of inflammatory diseases, and its most advanced inhibitor, brensocatib (Insmed), is currently in
phase 3 clinical trials for the treatment of non-cystic fibrosis bronchiectasis. Beyond neutrophils, its importance is
highlighted by loss-of-function mutations that cause the recessively inherited Papillon-Lefèvre syndrome. At the
molecular level, cathepsin C has several structural and functional features that set it apart from other members of
the family and enable its selective targeting. It possesses dipeptidyl-peptidase activity (its other common name is
dipeptidyl-peptidase I) due to the presence of an additional exclusion domain that also controls its stepwise
tetramerization during maturation. In this review article, we summarize the current state of the art regarding the
biochemical properties of cathepsin C, its physiological and pathological roles in neutrophils and beyond, and
recent advances in the development and evaluation of cathepsin C inhibitors.

Keywords: Dipeptidyl-peptidase I, DPPI, cysteine cathepsin, bronchiectasis, brensocatib

INTRODUCTION
Cathepsin C (also known as dipeptidyl-peptidase I, EC 3.4.14.1) was among the first peptidases identified in

© The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0
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