Cysteine Cathepsins and Drug Discovery: Knowns and Unknowns

---

Andrey A. Zamyatnin, Jr.^1,2,3,a*

¹Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, 119234 Moscow, Russia

²Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119992 Moscow, Russia

³Department of Biological Chemistry, Sechenov First Moscow State Medical University, 119991 Moscow, Russia

^* To whom correspondence should be addressed.

Received: July 15, 2025; Revised: September 10, 2025; Accepted: September 11, 2025

---

Cysteine cathepsins are a group of closely related proteolytic enzymes active at low pH. The most well-studied function of these enzymes is protein degradation within lysosomes. However, accumulating evidence suggests that cysteine cathepsins also function at physiological pH levels in other cellular compartments outside lysosomes, as well as in the extracellular space. Many of these extra-lysosomal functions of cysteine cathepsins are typically associated with pathological processes, contributing to conditions such as oncogenesis and metastasis, neurodegenerative diseases, cardiovascular disorders, and autoimmune and inflammatory processes. Consequently, cysteine cathepsins have been proposed as diagnostic and prognostic molecular markers, as well as pharmacological targets. Notably, the pathological processes involving these enzymes often operate independently of their classical lysosomal functions. This work aims to outline key questions, the answers to which could enhance our understanding of the fundamental mechanisms governing the extra-lysosomal functions of cysteine cathepsins. Addressing these questions is also critical for developing novel therapeutic strategies to treat diseases in which cysteine cathepsins play a pathogenic role.

---

KEY WORDS: cysteine cathepsins, papain-like cysteine proteases, pharmacological targets, drug development, enzyme inhibitors

DOI: 10.1134/S0006297925602205

Publisher’s Note. Pleiades Publishing remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

---