Therapeutic cysteine protease inhibitors: a patent review (2018–present)

ABSTRACT

Introduction

Cysteine proteases are involved in a broad range of biological functions, ranging from extracellular matrix turnover to immunity. Playing an important role in the onset and progression of several diseases, including cancer, immune-related and neurodegenerative disease, viral and parasitic infections, cysteine proteases represent an attractive drug target for the development of therapeutic tools.

Areas covered

Recent scientific and patent literature focusing on the design and study of cysteine protease inhibitors with potential therapeutic application has been reviewed.

Expert opinion

The discovery of a number of effective structurally diverse cysteine protease inhibitors opened up new challenges and opportunities for the development of therapeutic tools. Mechanistic studies and the availability of X-ray crystal structures of some proteases, alone and in complex with inhibitors, provide crucial information for the rational design and development of efficient and selective cysteine protease inhibitors as preclinical candidates for the treatment of different diseases.

KEYWORDS:

• Cathepsins
• ubiquitin-specific-proteases
• main protease
• papain-like protease
• coronavirus
• SARS-CoV-2
• small molecules
• drugs

Article highlights

• Cysteine proteases play a number of pivotal biological roles.

• The dysregulation of Cysteine proteases functioning can occur at different levels and may contribute to the onset and progression of different pathologies.

• Targeting cysteine proteases represents an attractive approach to develop novel therapeutics tools for the treatment of viral infections, neurodegenerative disorders, and cancer.

• Recent-years researches and patents mainly focused on the inhibition of viral cysteine proteases like PL^pro and M^pro, Cathepsins (Cats) and Ubiquitin Specific Proteases (USPs) for the treatment of viral infections, cancer and inflammatory diseases.

• Different medicinal chemistry approaches were used to develop new molecules as potential drugs, ranging from drug repurposing to the most recent library screening techniques including HTS, including also the research on natural molecules.

• Mechanistic investigations and X-ray studies provide crucial information for the rational design and development of efficient and selective cysteine protease inhibitors.

• Reported small-molecule inhibitors include, among the others, Michael acceptors, nitriles, thioketones, α-ketoamides, chloromethyl ketones, disulfides, dithiocarbamtes, and organoselenium compounds.

• Small-molecule inhibitors of SARS-CoV-2 cysteine proteases (PL^pro and M^pro), cathepsins (Cats), and Ubiquitin Specific Proteases (USPs) are discussed in the context of their potential therapeutic application.

Declaration of interests

The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

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

Additional information

Funding

This paper was not funded.