A patent review on HMGB1 inhibitors for the treatment of liver diseases

ABSTRACT

Introduction

HMGB1 is a non-histone chromatin protein released or secreted in response to tissue damage or infection. Extracellular HMGB1, as a crucial immunomodulatory factor, binds with several different receptors to innate inflammatory responses that aggravate acute and chronic liver diseases. The increased levels of HMGB1 have been reported in various liver diseases, highlighting that it represents a potential biomarker and druggable target for therapeutic development.

Areas covered

This review summarizes the current knowledge on the structure, function, and interacting receptors of HMGB1 and its significance in multiple liver diseases. The latest patented and preclinical studies of HMGB1 inhibitors (antibodies, peptides, and small molecules) for liver diseases are summarized by using the keywords ‘HMGB1,’ ‘HMGB1 antagonist, HMGB1-inhibitor,’ ‘liver disease’ in Web of Science, Google Scholar, Google Patents, and PubMed databases in the year from 2017 to 2023.

Expert opinions

In recent years, extensive research on HMGB1-dependent inflammatory signaling has discovered potent inhibitors of HMGB1 to reduce the severity of liver injury. Despite significant progress in the development of HMGB1 antagonists, few of them are approved for clinical treatment of liver-related diseases. Developing safe and effective specific inhibitors for different HMGB1 isoforms and their interaction with receptors is the focus of future research.

KEYWORDS:

• HMGB1 antagonists
• liver diseases
• small-molecule inhibitors
• immune response
• protein–protein interactions

Article highlights

• The review comprehensively examined the HMGB1 protein’s structure domain, activation, release, and receptors that bind in multiple liver diseases.

• The patents on HMGB1 antagonists, including antibodies, peptides, and small-molecule inhibitors, and their application in the preclinical and clinical treatments for inflammatory diseases are presented.

• We comprehensively reviewed the inhibitors based on different mechanisms of action, specificity, and binding affinity with the target protein HMGB1 from the published literature.

• The interactions between HMGB1 and TLR4/RAGE/CXCL12 receptor, possible intervention strategies, and corresponding antagonists were also discussed.

• Additionally, fwe have also discussed the future possibility of employing target engagement techniques that mimic cryptic binding and hotspot pockets between the targeted proteins.

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

One peer reviewer on this manuscript received an honorarium from Expert Opinion on Drug Safety for their review work but has no other relevant financial relationships to disclose.

Author contribution statement

Richa Raj conducted the literature search and wrote the manuscript. Pingping Shen created and edited the figures and revised a manuscript. Jian Zhang conceptualized and proofread the manuscript.

Acknowledgments

This work was supported by the National Nature Science Foundation of China (NSFC NO. 21302052) and the “Program for New Century Excellent Talents in University” awarded to Prof. Jian Zhang (NECT-11-0739). Thanks also go to the Postgraduate Research & Practice Innovation Program of Jiangsu Province (SJKY19_0658) and Jiangsu Funding Program for Excellent Postdoctoral Talent. Thanks also give to the “Jiangsu Funding Program for Excellent Postdoctoral Talent” awarded to Pingping Shen.

Additional information

Funding

This paper was funded by the National Natural Science Foundation of China [NSFCNO. 21302052] and the “Program for New Century Excellent Talents in University” awarded to Prof. Jian Zhang [NECT-11-0739].