Inhibitors of type II transmembrane serine proteases in the treatment of diseases of the respiratory tract – A review of patent literature

ABSTRACT

Introduction

Type II transmembrane serine proteases (TTSPs) of the human respiratory tract generate high interest owing to their ability, among other roles, to cleave surface proteins of respiratory viruses. This step is critical in the viral invasion of coronaviruses, including SARS-CoV-2 responsible for COVID-19, but also influenza viruses and reoviruses. Accordingly, these cell surface enzymes constitute appealing therapeutic targets to develop host-based therapeutics against respiratory viral diseases. Additionally, their deregulated levels or activity has been described in non-viral diseases such as fibrosis, cancer, and osteoarthritis, making them potential targets in these indications

Areas covered

Areas covered: This review includes WIPO-listed patents reporting small molecules and peptide-based inhibitors of type II transmembrane serine proteases of the respiratory tract.

Expert opinion

Expert opinion: Several TTSPs of the respiratory tract represent attractive pharmacological targets in the treatment of respiratory infectious diseases (notably COVID-19 and influenza), but also against idiopathic pulmonary fibrosis and lung cancer.

The current emphasis is primarily on TMPRSS2, matriptase, and hepsin, yet other TTSPs await validation. Compounds listed herein are predominantly peptidomimetic inhibitors, some with covalent reversible mechanisms of action and high potencies. Their selectivity profile, however, are often only partially characterized.

Preclinical data are promising and warrant further advancement in the above diseases.

KEYWORDS:

• Type II transmembrane serine proteases
• TTSP
• TMPRSS2
• TMPRSS4
• ST14 (matriptase)
• TMPRSS11d (HAT
• human airway trypsin)
• TMPRSS11e (DESC1)
• HPN (hepsin)

Article highlights

• TTSPs are proteases expressed at the extracellular surface of epithelial cells of various origins making them accessible and appealing therapeutic targets.

• TTSPs expressed in the human respiratory tract are involved in influenza and coronaviruses cell entry and penetration.

• TTSPs of the human respiratory tract, especially TMPRSS2, represent potential pharmacological targets for the treatment of COVID-19 and influenza.

• This review covers patents of the last 15 years describing compounds (peptidomimetics and small molecules) targeting TTSPs.

• Patents include sub-nanomolar selective inhibitors representing potential therapeutic candidates of interest for the aforementioned indications.

This box summarizes the key points contained in the article.

Acknowledgments

S.P.D. is a recipient of a Frederick Banting and Charles Best Canada Graduate Scholarships Doctoral Award.

The Genotype-Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. The data used for the analyses described in this manuscript were obtained from the GTEx Portal on 03/10/20.

Declaration of interest

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.

Supplementary material

Supplemental data for this article can be accessed here.

Additional information

Funding

Funding from the Canadian Institutes for Health Research and Neomed is gratefully acknowledged.