Table 3.

Overall characteristics of some cyclophilins encoded in the genomes of parasites invading humans

Parasite	Species (disease)	Cyclophilin	Acc. No.	Observations	Ref.	CsA and its derivatives PPIase activity inhibition	Ref.	CsA and its derivatives Parasiticidal effect	Ref.	Probable CsA mechanism of action
Apicomplexa	Plasmodium falciparum (Malaria)	PfCyP19A	XP_001351290	CyP highly expressed in intra-erythocytic parasites. Mature protein isolated	[124]	CsA K d = 13 nM, K i = 6.9 nM similar K d/K i with 11 CsA-analogs	[124]	[val2]CsA inhibited parasites. PSC-833 EC50 = 0.032 mM CsA = 0.32 mM	[124, 125]	P- glycoprotein as target molecule PfCyP19/CsA can bind to calcineurin
		PfCyP22	XP_001351841	Ibid. ER signal peptide. Mature protein isolated	[126]	CsA IC50 = 10 nM	[126]
		PfCyP24	XP_001349469	CyP highly expressed at the late-ring parasite stage	[127]			Trophozoites more sensitive to CsA due to a high level of PfCyP24 expression	[127]
	Toxoplasma gondii (Toxoplasmosis)	TgCyP18	AAA17997	Mature protein isolated. Secreted. CyP binds to CCR5 receptor. Induces IL-12. Inhibits HIV infectivity by co-receptor antagonism	[128, 129]	CsA IC50 = 32 nM	[128]	T. gondii less susceptible than Plasmodium parasites. SDZ 215-918 EC50 = 0.45 mg/ml with low affinity for T. gondii CyPs	[123]	P- glycoprotein is likely the molecular target
		TgCyP20	XP_002367801	Mature protein isolated. N-terminal sequence with identity to calcineurin	[128]	CsA IC50 = 5 nM	[128]
		TgFCBP57.3	AAX51680	Dual immunophilin, N-terminal FKBP and C-terminal CLD Essential for parasite survival.	[130]	FK506 IC50 = 70 nM CsA IC50 = 750 nM	[130]
Trypanosomatids	Leishmania major (Cutaneous Leishmaniasis)	LmCyP19	CAA73904	Cyps of 18, 19, 22 and 40 kDa were CsA affinity isolated. LmCyP19, the most expressed. No affinity for calcineurin	[131, 133]	CsA K i = 5.2 nM	[131]	Extracellular L. major growth inhibition. Relatively insensitive to CsA	[134]	A single AA mutation in LmCyP19 fails to interact with calcineurin
	Leishmania donovani (Visceral Leishmaniasis)	LdCyP	AAD46565	CyP of the endoplasmic reticulum. Secreted to culture medium under oxidative stress	[132]	CsA K d = 135 nM	[135]		[135]	Low expression of LdCyP in the cytosol Insensitivity to CsA
	Trypanosoma brucei (Sleeping sickness)	TbCyP19	AAB07896	Expressed and differentially transcribed Secreted protein. Cytosolic and flagellum localized	[136]	CsA binds TbCyP19 No inhibition experiments	[136]
	Trypanosoma cruzi (Chagas´ disease)	TcCyP19	AAF05985	TcCyP19, TcCyP22, TcCyP28 and TcCyP40 isolated by CsA affinity. TcCyP19 major cytosolic isoform, present in all parasite stages. Mitochondrial TcCyP21was identified.	[9]	CsA IC50 = 14 nM and H-7-94 analog IC50 = 12 nM	[137, 138]	Trypanocidal activity in vitro and in vivo. H-7-94 CsA analog is the most effective: TcCyP19 IC50 = 12.5 nM, T. cruzi EC50 = 0.8 mM, NIM811 is not effective	[137]	Besides TcCyPs also P-glycoprotein could be a molecular target
Amebae	Entamoeba histolytica (Enteric diseases)	EhCyp	AAB86601	60 to 70% sequence identity with the other cyclophilins. Transcribed and expressed.	[139]	PPIase Inhibition with CsA at nM concentration	[139]	CsA EC50 at 1–10 mg/ml on thophozoites	[139, 140]	Interference the activity of calcineurin and P-gP
Flagellates	Giardia intestinalis (Enteric diseases)	GiCyP1	XP_001707838	Found as a single gene. Similar to EhCyP and hCyP18	[141]	Total PPIase Inhibition with 500 nM CsA	[141]
Coccidia	Cryptosporidium parvum (Cryptosporidiosis)							CsA EC50 at 1.5 mM and IC50 of 1 mM for PSC-833 derivative	[142]	CsA inhibits CnA PSC-833 binds to P-glycoprotein
For comparison	Homo sapiens	hCyPA	CAA37039	Cyclophilin like domain characteristics in the text.		CsA IC50 = 20 nM, NIM811 K i = 2.1 nM, Debio-025 K i = 0.34 nM H-7-94 IC50 = 70 nM PSC-833 does not bind hCyPA	[8, 9, 137, 143]