Cyclophilin function in Cancer; lessons from virus replication

Abstract

Cyclophilins belong to a group of proteins that possess peptidyl prolyl isomerase activity and catalyse the cis-trans conversion of proline peptide bonds. Cyclophilin members play important roles in protein folding and as molecular chaperones, in addition to a wellestablished role as host factors required for completion of the virus life cycle. Members of the cyclophilin family are overexpressed in a range of human malignancies including hepatocellular cancer, pancreatic cancer, non-small cell lung cancer, gastric cancer, colorectal cancer and glioblastoma multiforme, however, their precise role in tumourigenesis remains unclear. In recent years, mounting evidence supports a role for prolyl isomerisation during mammalian cell division; a process with striking similarity to plasma membrane remodelling during virus replication. Here we will summarise our current understanding of the role of cyclophilins in cancer. We will review the function of cyclophilins during mammalian cell division and during HIV-1 infection, and highlight common processes involving members of the ESCRT and Rab GTPase families. IntroductionThe interconversion of protein backbone between cis and trans, catalysed by peptidyl prolyl isomerases (PPIases), is an important event that alters protein structure and activity and regulates a wide spectrum of cellular functions in normal physiological processes. For example, isomerisation mediates the spatiotemporal control of fundamental processes including cell cycle progression, cell proliferation and cell death [1][2][3][4]. In recent years, mounting evidence implicates deregulated isomerase activity in a range of age-related pathologies including neurodegeneration, cardiovascular disease and cancer [5]. As a result, isomerases have gained significant interest as therapeutic targets in the treatment of these diseases.

A Pan-Cyclophilin Inhibitor, CRV431, Decreases Fibrosis and Tumor Development in Chronic Liver Disease Models

“…CRV431 inhibited the isomerase activity of cyclophilins A, B, D, and G. However, CRV431 probably also blocks several other isoforms based on conservation of the active sites and by the observation that CsA binds to at least 11 of the 18 reported isoforms (Davis et al, 2010; Lavin and McGee, 2015). The pan-inhibitory activity is proposed to be advantageous because a single drug could simultaneously target multiple pathologic activities and minimize the risk, complications, and expense of combining multiple, single-pathway drugs.…”

“…Cyp A is also known as peptidyl prolyl isomerase A (PPIA) because its primary biochemical activity is catalytic regulation of cis-trans isomerization of X-proline peptide bonds (where X represents any amino acid), which are important for protein folding and function. Eighteen human proteins with cyclophilin isomerase domains exist and occupy many cellular compartments (Davis et al, 2010; Lavin and McGee, 2015). The best described isoforms include Cyp A (PPIA; cytosol), cyclophilin B (Cyp B; peptidyl prolyl isomerase B; endoplasmic reticulum), and cyclophilin D (Cyp D; peptidyl prolyl isomerase F; mitochondria).…”

“…Cyp A has been evolutionarily recruited into the life cycles of many viruses such as hepatitis B and C viruses (Dawar et al, 2017a). Overexpression of cyclophilins has been observed in many types of cancer, which appears to facilitate adaptation to hypoxia and elevated anabolic demands (Lavin and McGee, 2015). Extracellular Cyp A released from injured or dying cells can be proinflammatory through its binding to CD147.…”

A computationally designed binding mode flip leads to a novel class of potent tri-vector cyclophilin inhibitors

“…Besides neurodegenerative disorders, CypD inhibition is protective in animal models of acute kidney injury, a condition that accounts for a fifth of emergency hospitalizations in the USA 5. Other related cyclophilin isoforms CypA and CypB are overexpressed in malignant cancers,6 and CypA inhibition has potent antiviral and anti-inflammatory effects 7. Cyp inhibition may also protect the liver from fibrosis subsequent to non-alcoholic steatohepatitis (NASH), a common indication for liver transplantation after chronic hepatitis C 8…”

Pushing The Limits Of Detection Of Weak Binding Using Fragment Based Drug Discovery: Identification Of New Cyclophilin Binders

“…Because of their diverse biological roles Cyps are recognized as potential biological targets for the treatment of HCV [19][20][21], HIV [22][23][24], cancer [25][26][27] and neurodegenerative diseases such as Parkinson's and Alzheimer's [28][29][30]. Originally, efforts for the identification of cyclophilin inhibitors were focused on cyclic peptides, analogues of CsA [20,21,31,32].…”