Peptidyl-prolyl cis/trans isomerases (PPIases) are an enzyme family which catalyse the cis/trans isomerisation of proline peptide bonds to promote the folding and re-folding of peptides and proteins. Three subfamilies have been identified: cyclophilins, FK506-binding proteins and parvulins. Individual PPIases are overexpressed in a number of cancers [17], and family members have been targetted for immunosuppressant effects.

* Key recommended reading is highlighted with an asterisk

* Annett S, Moore G, Robson T. (2020) FK506 binding proteins and inflammation related signalling pathways; basic biology, current status and future prospects for pharmacological intervention. Pharmacol Ther, 215: 107623. [PMID:32622856]

* Bukrinsky M. (2015) Extracellular cyclophilins in health and disease. Biochim Biophys Acta, 1850 (10): 2087-95. [PMID:25445705]

* Kang CB, Hong Y, Dhe-Paganon S, Yoon HS. (2008) FKBP family proteins: immunophilins with versatile biological functions. Neurosignals, 16 (4): 318-25. [PMID:18635947]

* Schiene-Fischer C. (2015) Multidomain Peptidyl Prolyl cis/trans Isomerases. Biochim Biophys Acta, 1850 (10): 2005-16. [PMID:25445709]

* Schmidpeter PA, Koch JR, Schmid FX. (2015) Control of protein function by prolyl isomerization. Biochim Biophys Acta, 1850 (10): 1973-82. [PMID:25542300]

* Wang T, Donahoe PK. (2004) The immunophilin FKBP12: a molecular guardian of the TGF-beta family type I receptors. Front Biosci, 9: 619-31. [PMID:14766396]

1. Annett S, Moore G, Short A, Marshall A, McCrudden C, Yakkundi A, Das S, McCluggage WG, Nelson L, Harley I et al.. (2020) FKBPL-based peptide, ALM201, targets angiogenesis and cancer stem cells in ovarian cancer. Br J Cancer, 122 (3): 361-371. [PMID:31772325]

2. Edlich F, Weiwad M, Wildemann D, Jarczowski F, Kilka S, Moutty MC, Jahreis G, Lücke C, Schmidt W, Striggow F et al.. (2006) The specific FKBP38 inhibitor N-(N',N'-dimethylcarboxamidomethyl)cycloheximide has potent neuroprotective and neurotrophic properties in brain ischemia. J Biol Chem, 281 (21): 14961-70. [PMID:16547004]

3. Esnault S, Shen ZJ, Malter JS. (2008) Pinning down signaling in the immune system: the role of the peptidyl-prolyl isomerase Pin1 in immune cell function. Crit Rev Immunol, 28 (1): 45-60. [PMID:18298383]

4. Fruman DA, Klee CB, Bierer BE, Burakoff SJ. (1992) Calcineurin phosphatase activity in T lymphocytes is inhibited by FK 506 and cyclosporin A. Proc Natl Acad Sci USA, 89 (9): 3686-90. [PMID:1373887]

5. Gaali S, Kirschner A, Cuboni S, Hartmann J, Kozany C, Balsevich G, Namendorf C, Fernandez-Vizarra P, Sippel C, Zannas AS et al.. (2015) Selective inhibitors of the FK506-binding protein 51 by induced fit. Nat Chem Biol, 11 (1): 33-7. [PMID:25436518]

6. Garcia-Touchard A, Burke SE, Toner JL, Cromack K, Schwartz RS. (2006) Zotarolimus-eluting stents reduce experimental coronary artery neointimal hyperplasia after 4 weeks. Eur Heart J, 27 (8): 988-93. [PMID:16449248]

7. Gopalakrishnan R, Kozany C, Wang Y, Schneider S, Hoogeland B, Bracher A, Hausch F. (2012) Exploration of pipecolate sulfonamides as binders of the FK506-binding proteins 51 and 52. J Med Chem, 55 (9): 4123-31. [PMID:22455398]

8. Guo C, Hou X, Dong L, Marakovits J, Greasley S, Dagostino E, Ferre R, Johnson MC, Humphries PS, Li H et al.. (2014) Structure-based design of novel human Pin1 inhibitors (III): optimizing affinity beyond the phosphate recognition pocket. Bioorg Med Chem Lett, 24 (17): 4187-91. [PMID:25091930]

9. Hamilton GS, Steiner JP. (1998) Immunophilins: beyond immunosuppression. J Med Chem, 41 (26): 5119-43. [PMID:9857082]

10. Hultsch T, Müller KD, Meingassner JG, Grassberger M, Schopf RE, Knop J. (1998) Ascomycin macrolactam derivative SDZ ASM 981 inhibits the release of granule-associated mediators and of newly synthesized cytokines in RBL 2H3 mast cells in an immunophilin-dependent manner. Arch Dermatol Res, 290 (9): 501-7. [PMID:9808344]

11. Kuglstatter A, Mueller F, Kusznir E, Gsell B, Stihle M, Thoma R, Benz J, Aspeslet L, Freitag D, Hennig M. (2011) Structural basis for the cyclophilin A binding affinity and immunosuppressive potency of E-ISA247 (voclosporin). Acta Crystallogr D Biol Crystallogr, 67 (Pt 2): 119-23. [PMID:21245533]

12. Kuo J, Bobardt M, Chatterji U, Mayo PR, Trepanier DJ, Foster RT, Gallay P, Ure DR. (2019) A Pan-Cyclophilin Inhibitor, CRV431, Decreases Fibrosis and Tumor Development in Chronic Liver Disease Models. J Pharmacol Exp Ther, 371 (2): 231-241. [PMID:31406003]

13. McClements L, Annett S, Yakkundi A, O'Rourke M, Valentine A, Moustafa N, Alqudah A, Simões BM, Furlong F, Short A et al.. (2019) FKBPL and its peptide derivatives inhibit endocrine therapy resistant cancer stem cells and breast cancer metastasis by downregulating DLL4 and Notch4. BMC Cancer, 19 (1): 351. [PMID:30975104]

14. McClements L, Yakkundi A, Papaspyropoulos A, Harrison H, Ablett MP, Jithesh PV, McKeen HD, Bennett R, Donley C, Kissenpfennig A et al.. (2013) Targeting treatment-resistant breast cancer stem cells with FKBPL and its peptide derivative, AD-01, via the CD44 pathway. Clin Cancer Res, 19 (14): 3881-93. [PMID:23741069]

15. Pinch BJ, Doctor ZM, Nabet B, Browne CM, Seo HS, Mohardt ML, Kozono S, Lian X, Manz TD, Chun Y et al.. (2020) Identification of a potent and selective covalent Pin1 inhibitor. Nat Chem Biol, 16 (9): 979-987. [PMID:32483379]

16. Porter Jr GA, Beutner G. (2018) Cyclophilin D, Somehow a Master Regulator of Mitochondrial Function. Biomolecules, 8 (4). [PMID:30558250]

17. Rippmann JF, Hobbie S, Daiber C, Guilliard B, Bauer M, Birk J, Nar H, Garin-Chesa P, Rettig WJ, Schnapp A. (2000) Phosphorylation-dependent proline isomerization catalyzed by Pin1 is essential for tumor cell survival and entry into mitosis. Cell Growth Differ, 11 (7): 409-16. [PMID:10939594]

18. Valentine A, O'Rourke M, Yakkundi A, Worthington J, Hookham M, Bicknell R, McCarthy HO, McClelland K, McCallum L, Dyer H et al.. (2011) FKBPL and peptide derivatives: novel biological agents that inhibit angiogenesis by a CD44-dependent mechanism. Clin Cancer Res, 17 (5): 1044-56. [PMID:21364036]

Stephanie Annett School of Pharmacy and Biomolecular Sciences 1st Floor Ardilaun House Block B 111 St Stephen's Green Dublin 2, D02 YN77 Ireland Tracy Robson School of Pharmacy and Biomolecular Sciences 1st Floor Ardilaun House Block B 111 St Stephen's Green Dublin 2, D02 YN77 Ireland