Inhibitors of Cyclophilin A: Current and Anticipated Pharmaceutical Agents for Inflammatory Diseases and Cancers

Abstract

Cyclophilin A, a widely prevalent cellular protein, exhibits peptidyl-prolyl cis-trans isomerase activity. This protein is predominantly located in the cytosol; additionally, it can be secreted by the cells in response to inflammatory stimuli. Cyclophilin A has been identified to be a key player in many of the biological events and is therefore involved in several diseases, including vascular and inflammatory diseases, immune disorders, aging, and cancers. It represents an attractive target for therapeutic intervention with small molecule inhibitors such as cyclosporin A. Recently, a number of novel inhibitors of cyclophilin A have emerged. However, it remains elusive whether and how many cyclophilin A inhibitors function in the inflammatory diseases and cancers. In this review, we discuss current available data about cyclophilin A inhibitors, including cyclosporin A and its derivatives, quinoxaline derivatives, and peptide analogues, and outline the most recent advances in clinical trials of these agents. Inhibitors of cyclophilin A are poised to enhance our comprehension of the molecular mechanisms that underpin inflammatory diseases and cancers associated with cyclophilin A. This advancement will aid in the development of innovative pharmaceutical treatments in the future.

Keywords: cancer; cyclophilin A; cyclophilin inhibitor; cyclosporin A; inflammatory diseases; peptidyl-prolyl isomerase.

Figure 1

The cyclophilin A–CsA complex. Cyclophilin A binding site (using PDB structure 1CWA). β-sheets in light blue, α-helices in red in cyclophilin A structure. CsA is indicated in black and gray. The 19 residues of cyclophilin A bind in CsA are dark blue.

Figure 2

Chemical structure of the major compounds as inhibitors of cyclophilin A.

Figure 2

Chemical structure of the major compounds as inhibitors of cyclophilin A.

Figure 3

Chemical structure of aryl 1-indanylketones (C29) and their derivatives. (A): The nucleus of biaryl indenyl methanone, where R¹-R⁶ can be substituted by different groups to generate C29A1-4. (B): The nucleus of aryl indenyl methanone, where R¹-R³ can be substituted by different groups to generate C29B1-2.

Figure 4

Chemical structure of the compounds C51 and C52 based on their ground or transition states.