Some science

Cyclophilins belong to the family of peptidyl-prolyl isomerases (PPIases), a well conserved class of enzymes found throughout nature in microorganisms, plants and animals. PPIases catalyze the interconversion of cis- and trans- peptidyl-proline bonds in proteins thereby changing the local 3D structures of their client proteins and maintaining local conformational fluidity. Because localised 3D structures in a protein determine interactions with other proteins, PPIases consequently are master regulators of protein-protein interactions.

The cis-trans interconversion and consequences for the local 3D structure are shown below. Whereas the overall shape of the peptide sequence is conserved in both conformers, the spatial disposition of the amino acid sidechain preceding proline-7 is different.

Cyclophilins were initially identified as binding proteins of the immunosuppressant drug cyclosporin (Sandimmun™, Neoral™). However, the existence of cyclosporin analogues (e.g. NIM-811) that retained inhibitory potency to cyclophilin but completely lacked immunosuppression demonstrated (1) the existence of non-immunosuppressive cyclophilin inhibitors, (2) that the biology exhibited by these compounds differed substantially from that of cyclosporin and (3) that cyclophilins are a target class that is amenable to inhibition by small molecules. As the wider role of cyclophilins in disease has become better understood, the therapeutic potential of cyclophilin inhibitors has become clearer. Cyclophilins are used as virulence factors by many viruses (HIV, HCV, coronaviruses, others) and non-immunosuppressive cyclophilin inhibitors have been evaluated in clinical studies for the treatment of infection by HCV and HIV (Alisporivir, SCY-635).

Of all the human cyclophilins, cyclophilins A and D are by far the most intensely investigated proteins. Cyclophilin A is predominantly an intracellular protein but can in certain circumstances be released into circulation where, through interaction with CD147 and other membrane receptors, it acts as a powerful pro-inflammatory mediator1. Secretion of cyclophilin A from many cell types is triggered by LPS, ROS, or various forms of necrotic cell death. In fact, circulating cyclophilin A has been proposed as a biomarker for necrotic cell death2. Cyclophilin D is a component of the mitochondrial permeability transition pore (MPTP) which plays a key role in cell death by regulating the threshold of MPTP opening3; absence or pharmacological inhibition of cyclophilin D makes the pore more resistant to opening stimuli, which in the widest sense include any factor that stresses the cell, including toxins, infection, hypoxia, reactive oxygen species (ROS), UV radiation, or Ca2+ overload (i.e. excessive physiological signals). MPTP-mediated cell death can occur by many mechanisms that can be broadly categorised into apoptotic (non-inflammatory) or necrotic (inflammatory) pathways. Thus, inhibition of cyclophilin D by increasing the threshold to MPTP opening protects cells from both apoptotic and necrotic death and is therefore expected to slow/halt chronic degenerative diseases as well as inflammatory conditions caused by necrotic cell death or infection4. Dual inhibitors of cyclophilins A and D can therefore be viewed as damage control agents that provide some protection against stress-induced death of cells as well as the associated inflammatory processes at the same time. Such situations occur e.g. in trauma-induced sepsis, where patients often survive the early period after trauma but suffer morbidity and complications during the subsequent treatment phase, or in acute pancreatitis where diet-induced necrosis of the acinar cells triggers a violent inflammation that in severe cases can lead to acute respiratory distress syndrome and multiple organ failure4.

 

References

  1. Yurchenko, V. et al. (2010), “Cyclophilin-CD147 interactions: a new target for anti-inflammatory therapeutics”, Clin. Exp. Immunol. 160: 305-17Christofferson & Yuan (2010), “Cyclophilin A release as a biomarker of necrotic cell death”, Cell Death Different. 17(12): 1942-43
  2. Giorgio V et al. (2010) “Cyclophilin D in mitochondrial pathophysiology”, Biochim. Biophys. Acta 1797(6-7): 1113-18
  3. Fliri, H. (2016), Drug Target Review, “Neurodegenerative diseases: The potential of cyclophilin inhibition”, Jan 21
  4. Jin H et al., (2014) “Prediction of sepsis in trauma patients”, Burns Trauma 2(3):106-113

Read the white paper, Prolyl Isomerases as Therapeutic Targets, co-written by Selcia and Cypralis scientists.
 

 

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