Diacylglycerol kinases are lipid kinases that phosphorylate DAG to generate phosphatidic acid (PA). In mammals, there are ten isoforms of DGKs. R 59-022 is a diacylglycerol kinase inhibitor (IC50=2.8 μM). In addition, R 59-022 potentiates thrombin-induced diacylglycerol production in platelets and inhibits phosphatidic acid production in neutrophils. In intact platelets, R 59-022 inhibits the phosphorylation of OAG to 1-oleoyl-2-acetylglyceryl-3-phosphoric acid (OAPA) (IC50: 3.8 μM).
Meanwhile, it activates protein kinase C (PKC).
When in platelets inositol lipid turnover is accelerated by thrombin, further addition of R 59-022 results in a marked elevation of diacylglycerol levels, a decreased formation of phosphatidic acid and an increased protein kinase C activity as compared with the controls. In addition, R59022 (10 microM) potentiates secretion and aggregation responses in human platelets challenged with sub-maximal concentrations of thrombin. R 59-022 is also a 5-HTR antagonist. In the intact platelet, R 59-022 is able to interrupt thrombin-induced inositol lipid cycling at the level of diacylglycerol and leads to an elevation of protein kinase C activity. Moreover, R59022 (10 μM) has no significant effect on the dose-response curve for the mobilization of intracellular Ca2+ by thrombin in either the presence or the absence of extracellular Ca2+.
In addition, R 59-022 is an inhibitor of filovirus entry. R 59-022 prevents the macropinocytosis uptake of filoviral particles. Moreover, it inhibits entry mediated by multiple filovirus GPs, and blocks replicative EBOV growth. Furthermore, R 59-022 blocks the entry of EBOV pseudotypes in a concentration-dependent manner (IC50: ~5 µM). It dose-dependent decreases in entry by the VLPs harboring the EBOV GP (IC50: ~2 µM). R 59-022 can inhibit EBOV GP-mediated entry in multiple cell types. Besides, R 59-022 blocks macropinocytosis in Vero cells.
In summary, R 59-022 is a diacylglycerol kinase inhibitor and is a 5-HTR antagonist, and it activates PKC.
Nunn DL, et al. Biochem J. 1987 May 1;243(3):809-13.;