ABSTRACT
Introduction
Aberrant citrullination and excessive peptidylarginine deiminase (PAD) activity are detected in numerous challenging autoimmune diseases such as rheumatoid arthritis, inflammatory bowel diseases, systemic lupus erythematosus, multiple sclerosis, and type 1 diabetes. Because excessive PAD activity is a common denominator in these diseases, PADs are interesting potential therapeutic targets for future therapies.
Areas covered
This review summarizes the advances made in the design of PAD inhibitors, their utilization and therapeutic potential in preclinical mouse models of autoimmunity. Relevant literature encompasses studies from 1994 to 2021 that are available on PubMed.gov.
Expert opinion
Pan-PAD inhibition is a promising therapeutic strategy for autoimmune diseases. Drugs achieving pan-PAD inhibition were capable of ameliorating, reversing, and preventing clinical symptoms in preclinical mouse models. However, the implications for PADs in key biological processes potentially present a high risk for clinical complications and could hamper the translation of PAD inhibitors to the clinic. We envisage that PAD isozyme-specific inhibitors will improve the understanding the role of PAD isozymes in disease pathology, reduce the risk of side-effects and enhance prospects for future clinical translation.
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
One reviewer is a consultant for several companies who are developing PAD inhibitors for human use. Peer reviewers on this manuscript have no other relevant financial or other relationships to disclose
Article highlights
Autoimmune diseases are complex and heterogeneous, with current treatment often focused on symptom alleviation and immune suppression rather than on causal or preventative interventions/measures.
Aberrant citrullination and peptidylarginine deiminase (PAD) activity are common denominators in disease onset and progression in rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), inflammatory bowel diseases (IBD), multiple sclerosis (MS) and type 1 diabetes (T1D).
PADs are potent therapeutic targets in autoimmune diseases by repressing, reversing and preventing clinical symptoms, as evidenced by murine models.
Pan-PAD inhibition is effective in autoimmune diseases due to various immunomodulatory and tissue-specific effects.
The generation of isozyme-specific inhibitors will aid our understanding of the isozyme-specific role in normal physiology and disease pathology. These inhibitors may also reduce the risk of unwanted side effects expected with pan-PAD inhibitors.
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