Cyclosporin (CsA) has antiparasite activity against the human pathogen Toxoplasma gondii. We characterized the functional and structural properties of two cyclophilins from T. gondii, TgCyp23 and TgCyp18.4.

TgCyp23 is a highly active cis−trans-prolyl isomerase (PPIase) and binds CsA with nanomolar affinity. However, TgCyp18.4 shows low PPIase activity and is significantly less sensitive to CsA inhibition. The crystal structure of the TgCyp23:CsA complex was solved at 1.1 Å resolution showing the molecular details of CsA recognition by the protein, and revealing relevant differences at the CsA-binding site compared to TgCyp18.4. The biochemical and structural data presented herein represents a relevant step toward understanding the molecular mechanisms of the anti-Toxoplasma action of CsA and may be instrumental in the rational design of new therapeutic drugs modulating TgCyp activity. 

ACS Infectious Diseases (2023) (doi: 10.1021/acsinfecdis.2c00566)