Dunsmore CJ et al. (2011) Chembiochem "Design and synthesis of conformationally constrained cyclophilin inhibitors showing a cyclosporin-A phenotype in C. elegans."

Bailey KR, Page AP, Turner NJ, Shiran S, Barran PE, Dunsmore CJ, Wear MA, Florance H, Walkinshaw MD, Malone KJ

[Chembiochem, 2011]

Cyclophilin A (CypA) is a member of the immunophilin family of proteins and receptor for the immunosuppressant drug cyclosporin A (CsA). Here we describe the design and synthesis of a new class of small-molecule inhibitors for CypA that are based upon a dimedone template. Electrospray mass spectrometry is utilised as an initial screen to quantify the protein affinity of the ligands. Active inhibitors and fluorescently labelled derivatives are then used as chemical probes for investigating the biological role of cyclophilins in the nematode Caenorhabditis elegans.

Jang M et al. (2020) Antioxidants (Basel) "Antioxidant Capacity of Thistle (Cirsium japonicum) in Various Drying Methods and their Protection Effect on Neuronal PC12 Cells and Caenorhabditis elegans."

Kim GH, Jang M, Kim KH

[Antioxidants (Basel), 2020]

The aim of this study was, firstly, to evaluate the phenol profile of thistle (<i>Cirsium japonicum</i>, CJ) by High performance liquid chromatography-electrospray ionization-mass spectrometry (HPLC-ESI-MS), dried by different methods (90 C hot-air, 70 C hot-air, shade-, and freeze-drying). Secondly, we aimed to evaluate the relationship between phenolic compounds content and antioxidant properties. CJ contained chlorogenic acid, linarin, and pectolinarin. Total phenolic contents of CJ significantly decreased under hot-air-drying condition, especially chlorogenic acid contents in CJ have been reduced by 85% and 60% for 90 C and 70 C hot-air-drying, respectively. We evaluated the protective effect on adrenal pheochromocytoma (PC12) cells and <i>Caenorhabditis elegans</i> using shade-dried CJ, which has the largest phenolic contents and the strongest antioxidant property. CJ-treated PC 12 cells dose-dependently exhibited the protective effects against reactive oxygen species (ROS), while cell viability increases, lactate dehydrogenase release decreases, and ROS formation decreases. Furthermore, CJ has also shown protection against ROS in <i>C. elegans.</i> Consequently, CJ contributed to lifespan extension under ROS stress without influencing the physiological growth.

Yang Y et al. (2007) Biochem Biophys Res Commun "Structure-based discovery of a family of synthetic cyclophilin inhibitors showing a cyclosporin-A phenotype in Caenorhabditis elegans."

Dunsmore CJ, Yang Y, Moir E, Kontopidis G, Malone K, Taylor P, Walkinshaw MD, Page AP, Turner NJ, Wear MA

[Biochem Biophys Res Commun, 2007]

Cyclophilins, which are found in all cellular compartments and with diverse biological roles, are now drug targets for a number of diseases including HIV infection, malaria and ischaemia. We used the database-mining program LIDAEUS and in silico screening to discover the dimedone family of inhibitors which show a conserved ''ball and socket'' binding mode with a dimethyl group in the hydrophobic binding pocket of human cyclophilin A (CypA) mimicking a key interaction of the natural inhibitor cyclosporin A (CsA). The most potent derivative binds CypA with a K(d) of 11.2+/-9.2muM and an IC(50) for activity against Caenorhabditis elegans (C. elegans) of 190muM compared to 28muM for CsA. These dimedone analogues provide a new scaffold for the synthesis of families of peptidomimetic molecules with potential activity against HIV, malaria, and helminth parasite infections.