CPN reg Inhibitors

Chemical inhibitors of CPN reg can disrupt its function through various mechanisms, each targeting different aspects of cellular processes that CPN reg is involved in. Alsterpaullone, by targeting cyclin-dependent kinases, can inhibit CPN reg by interfering with cell cycle regulation and, consequently, the protein folding requirements that are heightened during cell division. Tunicamycin, on the other hand, hinders N-linked glycosylation, leading to an accumulation of misfolded glycoproteins within the endoplasmic reticulum (ER). This accumulation creates a burden that CPN reg, despite its chaperoning capabilities, cannot efficiently manage due to the increased volume and complexity of the misfolded proteins.

Thapsigargin and Cyclopiazonic Acid both disrupt calcium homeostasis within the ER by inhibiting the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) pump. Given that CPN reg's activity is sensitive to calcium levels, the disruption caused by these chemicals can impair its ability to assist in proper protein folding. In a similar vein, Salubrinal and Guanabenz extend the phosphorylation state of eukaryotic translation initiation factor 2 alpha (eIF2α), which can lead to an exaggerated stress response in the cell. The overload of stress responses can overwhelm CPN reg's functional capacity, leading to its inhibition. Eeyarestatin I disrupts the ER-associated degradation (ERAD) pathway by inhibiting the p97 ATPase and associated deubiquitinating enzymes. Since CPN reg is associated with the ERAD pathway for the processing of misfolded proteins, the inhibition from Eeyarestatin I can lead to an excess of proteins that require refolding, thereby straining CPN reg's capabilities. Furthermore, Bortezomib and MG-132, both proteasome inhibitors, prevent the degradation of ubiquitinated proteins, leading to their accumulation within the cell. This build-up of proteins earmarked for degradation increases the demand on CPN reg for protein folding assistance, which can lead to its inhibition due to the sheer volume of proteins needing attention. Finally, Pifithrin-μ and Geldanamycin inhibit molecular chaperones HSP70 and HSP90, respectively. As these chaperones work in conjunction with CPN reg to manage protein folding, their inhibition indirectly impairs CPN reg's ability to maintain cellular proteostasis by increasing the pool of misfolded proteins that CPN reg would otherwise help to manage.