Peptidyl-prolyl isomerases

Peptidyl-prolyl isomerases (PPIases) are a well conserved class of enzymes found throughout nature in microorganisms, plants and animals. They are characterized by their ability to catalyze the conversion of cis- and trans- peptidyl-proline bonds in proteins and consequently are able to exert control over target protein structure and function.

PPIases are widely expressed across cell types with isoforms demonstrating subcellular specificity and trafficking between compartments. Certain PPIases may be secreted and it is now recognized that, in addition to being chaperones that control the spatial-temporal function of target proteins, they may also be able to act as secreted cytokines acting at cell surface receptors.

PPIases also interact with other post-translational control mechanisms, elegantly exemplified by the PPIase Pin1. It recognises target proteins containing a phosphoSer/Thr-Pro motif and its activity is therefore able to control events governed by proline-directed phosphorylation and dephosphorylation. As a result, Pin1 has become a focus of attention for oncology and Alzheimer’s disease research.

Original studies on the immunosuppressive properties of cyclosporine identified the cyclophilin subfamily of PPIases as molecules important in controlling inflammatory responses, either intracellularly or via interaction with cell surface receptors such as CD147 and probably others. A large body of work has focused on the immunomodulatory activity of cyclophilin and FKBP inhibitors and their use in transplantation has formed the basis of their commercial exploitation.

As the wider role of PPIases has become better understood, additional uses have arisen. In particular, several cyclophilin inhibitors are in clinical development for the treatment of viral infections as the host cell cyclophilin A is an important co-factor in the replication of certain viruses such as HCV and HIV.

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

Sub-type selective cyclophilin inhibitors

The cyclophilin inhibitors on the market or in development are non-selective between the four common cyclophilin isoforms A, B, C and D. Knockout animals have been used to identify roles specific to the individual isoforms and highlight their use as targets for treating diseases. This has elevated the interest in obtaining drugs selective for particular isoforms, in particular cyclophilin D for degenerative diseases involving mitochondrial dysfunction.

Cyclophilin D has been recognized as an excellent molecular target for several years [1] but until recently, achieving sub-type selectivity has been elusive. Cypralis is at the forefront of developing sub-type selective cyclophilin inhibitors.

A 2015 publication [2] describes a critical role for cyclophilin D in regulating the MPTP in pancreatic acinar cells subject to toxic insults known to be causative for acute pancreatitis.  Further, genetic deletion or pharmacological inhibition of cyclophilin D were both found to attenuate the severity of experimental acute pancreatitis in murine models.  A role for cyclophilin D in modulating MPTP in models of Alzheimer’s disease was indicated when the learning deficiency of mutant amyloid precursor protein (mAPP) mice was rescued by crossing these mAPP animals with a cyclophilin D knockout [3]. 

Publications

Neurodegenerative diseases: The potential of cyclophilin inhibition
Drug Target Review, 21 January 2016


1. Halestrap AP (2010) A pore way to die: the role of mitochondria in reperfusion injury and cardioprotection. Biochem Soc Trans 38:841-860

2. Sutton R, Mukherjee R, et al. (2015) Mechanism of mitochondrial permeability transition pore induction and damage in the pancreas: inhibition prevents acute pancreatitis by protecting production of ATP. Gut. 65(8):1333-46.

3. Du H, Guo L, Fang F, Chen D, Sosunov AA, et al. (2008) Cyclophilin D deficiency attenuates mitochondrial and neuronal perturbation and ameliorates learning and memory in Alzheimer’s disease. Nat Med 14:1097-1105 | Download PDF

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