Modulators of calpain activity: inhibitors and activators as potential drugs

ABSTRACT

Introduction: Calpains are intracellular Ca²⁺-dependent cysteine proteases with 15 known members in the enzyme family. They act as regulatory enzymes, their cleavage modifying the function of their substrates. As their substrates have important roles in many physiological processes, adequate function of calpains is mandatory for normal cellular functions. The adverse operation of them is often related to diseases (e.g. neurodegenerative disorders, cancer, type 2 diabetes mellitus, or limb-girdle muscular dystrophy type 2A).

Areas covered: Herein, the authors give an overview of calpains, their structure as well as their physiological and pathological functions. The authors further consider the challenges in calpain inhibitor and activator drug discovery and summarize examples of good candidates. New and applicable strategies are also discussed.

Expert opinion: Calpain enzymes are attractive targets for inhibitor or activator design and development. The authors believe this area of research is of high potential, although it has many challenges. For one, the selective and targeted inhibition or activation of calpains is needed. Furthermore, uncontrolled calpain activation may cause more serious side effects and so caution is needed when designing novel therapeutics.

KEYWORDS:

• Calpain
• cysteine proteases
• calpastatin
• calpain inhibitor
• calpain activator
• structure-activity-relationship (SAR)

Article Highlights

• Calpains are intracellular cysteine proteases with very diverse physiological roles. Aberrant activity of calpains; whether it be over- or under activation; is often associated with pathological functions and thus with diseases.

• Specific and effective inhibitors therefore may be potent candidates to treat these diseases.

• Peptide and peptidomimetic inhibitors have been developed to increase the specificity and potency through the use of different drug discovery strategies.

• Activators can also be used in the treatment of diseases with low calpain activity.

• In the case of both inhibitors and activators, targeted activity and high selectivity are desired.

This box summarizes key points contained in the article.

Acknowledgments

We thank Dr. Katalin Uray for language editing.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was completed in the ELTE Institutional Excellence Program (NKFIH-1157-8/2019-DT) supported by the National Research, Development and Innovation Office. M Yousef received Stipendium Hungaricum Scholarship from the Tempus Public Foundation.