Cyclophilins are a highly conserved family of peptidyl-prolyl cis-trans isomerases (PPIases) that play essential roles in protein folding, trafficking, and cellular stress adaptation across all domains of life. While extensively studied in humans, cyclophilins from pathogenic microorganisms have garnered growing interest due to their involvement in virulence, immune evasion, and antimicrobial resistance. Unlike bacteria, which typically encode only one or two isoforms, many protozoan parasites possess expanded cyclophilin repertoires, raising important questions about whether these proteins perform redundant functions or have evolved distinct roles in pathogenesis. Despite their biological relevance, detailed structural and mechanistic studies of microbial cyclophilins remain limited. This review focuses on the structural variability and kinetic diversity of pathogen-derived cyclophilins, emphasizing how differences in three-dimensional architecture, enzymatic kinetics, and ligand-binding properties distinguish these enzymes from their host homologues. It also provides an overview of the therapeutic landscape, highlighting natural product-based pan-selective inhibitors such as cyclosporin A and sanglifehrin A, their nonimmunosuppressive analogues, and the recent development of more selective synthetic scaffolds with improved drug-like properties. Deciphering the structural features, enzymatic behavior, and druggability of microbial cyclophilins is key to unlocking their full therapeutic potential.
Favretto et al. (Wed,) studied this question.