Cyclophilin inhibition as a potential treatment for nonalcoholic steatohepatitis (NASH)

ABSTRACT

Introduction: Cyclophilins are a family of diverse regulatory enzymes that have been studied for over 30 years; they participate in many pathophysiological processes. Genetic deletion or pharmacologic inhibition of cyclophilins has shown therapeutic effects in a wide spectrum of disease models, including liver disorders, and hence may be beneficial in treating nonalcoholic steatohepatitis (NASH).

Areas Covered: This articles briefly describes cyclophilin isomerases and the main classes of cyclophilin antagonists; it then summarizes data showing cyclophilin participation in the major pathophysiological activities that occur in NASH.

Expert Opinion: Optimization of therapeutic outcomes in the treatment of NASH may be best realized by targeting multiple pathologic pathways, especially when treating advanced stages of the disease. A preferred approach for achieving this goal is to use compounds such as cyclophilin inhibitors that simultaneously target multiple disease processes. The pleiotropic benefits of this drug class derive from the extraordinary functionality of prolyl isomerization as a regulatory mechanism and its evolutionary diversification into many biochemical pathways. Nonimmunosuppressive analogs of cyclosporine A are the most thoroughly characterized cyclophilin inhibitors and show significant potential to attenuate several of the major pathophysiological events in NASH – mitochondrial dysfunction, cellular injury and death, inflammation, and in particular, fibrosis.

KEYWORDS:

• Cyclophilin
• cyclosporine
• mitochondria
• inflammation
• fibrosis
• CRV431
• NASH
• liver
• hepatic
• disease
• necrosis
• collagen

Article Highlights

• Cyclophilin isomerases are evolutionarily diverse enzymes that regulate a vast number of biochemical processes by controlling the conformation of proline peptide bonds and in turn protein structure and function.

• Cyclosporine A (CsA) and nonimmunosuppressive CsA analogs are the best characterized cyclophilin antagonists and potently inhibit multiple cyclophilin isoforms due to highly conserved active sites.

• The most studied cyclophilin isoforms, A, B, and D, participate in many if not all of the major pathophysiologic processes that are active in NASH and other chronic liver diseases.

• Genetic knockout or pharmacologic inhibition of cyclophilins preserves mitochondrial function and decreases cell death, inflammation, and fibrosis in well over 30 disease models including NASH-related disease.

• Cyclophilin inhibitors have been pharmaceutically optimized by 35 years of study and hold considerable potential to safely and effectively treat NASH by directly targeting multiple pathologic mechanisms.

This box summarizes key points contained in the article.

Declaration of interest

The authors are employed by Hepion Pharmaceuticals Inc who are working on cyclophin inhibitors for the treatment of liver diseases. 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

One peer reviewer is an author on a patent for inhibitors of extracellular cyclophilins. Peer reviewers on this manuscript have no other relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.