title: Phosphonate-phospholipid analogues inhibit human phospholipase A2.
abstract: A phosphonate-containing phospholipid (PL) analogue (Compound 1) designed as a transition-state inhibitor competively inhibits non-human extracellular PLA2 at a mole fraction of 0.003 in the kinetic "scooting mode" (Jain et al., Biochem 28:4135 (1989]. To further profile the activity of Compound 1, we examined its activity with purified human enzyme and in whole cell systems. Compound 1 effectively inhibited a 14 kDa human PLA2 purified from joint synovial fluid of patients with rheumatoid arthritis using 3H-AA labeled E. coli as substrate (IC50 = 1.7 microM) and a high MW PLA2 (110 kDa) isolated from the cytosol of a human monocytic cell line, U-937, which selectively hydrolyzes AA-containing PL (IC50 = 165 microM). It failed to reduce A23187-induced PGE2 or LTC4 production by human adherent monocytes or LTB4 release from human neutrophils which may be due, in part, to poor membrane partitioning.
authors.affiliation: SmithKline Beecham Pharmaceuticals, King of Prussia, PA 19406-0939.
authors.forename: L A
authors.initials: LA
authors.lastname: Marshall
authors.forename: B
authors.initials: B
authors.lastname: Bolognese
authors.forename: W
authors.initials: W
authors.lastname: Yuan
authors.forename: M
authors.initials: M
authors.lastname: Gelb
mesh_terms: D001172:Arthritis, Rheumatoid / Q000201:enzymology; D000001:Calcimycin / Q000494:pharmacology; D002460:Cell Line; D015232:Dinoprostone / Q000096:biosynthesis; D015777:Eicosanoids / Q000378:metabolism; D004926:Escherichia coli / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism; D009504:Neutrophils / Q000378:metabolism; D063065:Organophosphonates / Q000494:pharmacology*; D010741:Phospholipases A / Q000037:antagonists & inhibitors*; D054467:Phospholipases A2; D010743:Phospholipids / Q000494:pharmacology*; D013189:SRS-A / Q000096:biosynthesis; D013582:Synovial Fluid / Q000201:enzymology
chemical_list: D015777:Eicosanoids; D063065:Organophosphonates; D010743:Phospholipids; D013189:SRS-A; D000001:Calcimycin; D010741:Phospholipases A; D054467:Phospholipases A2; D015232:Dinoprostone