Chemically modified non-antimicrobial tetracyclines inhibit activity of phospholipases A2

Objective. Tetracyclines have been recognized as useful agents for therapy of inflammatory arthritides. However, prolonged use of tetracyclines is limited by their detrimental antimicrobial properties. Recently. a group of chemically modified tetracyclines (CMT) devoid of antimicrobial properties has been synthesized. Some CMT were found to inhibit various matrix metalloproteinases (MMP). We reported previously that antimicrobial tetracyclines inhibit the activity of proinflammatory secretory group II phospholipase A 2 (sPLA 2 ). The objective of this study was to detect whether non-antimicrobial CMT also inhibit sPLA 2 and other phospholipases A 2 . Methods. Ten synthetic CMT were tested for inhibition of sPLA 2 human and porcine PLA 2 , and Naja naja PLA 2 , PLA. activity was assessed by radiolabeled Escherichia coli assay using standard and high calcium concentrations. Results. Six of 10 CMT inhibited sPLA2 activity at concentrations close to or lower than 50 μg/ml. All 6 CMT had identical C 1-3 and C 10-12a positions in the 4-ringed nucleus of the tetracycline molecule. Calcium concentrations up to 20 mM did not eliminate the inhibitory activity of CMT. Inhibition of other PLA 2 was induced by some CMT, all but one (CMT-9) belonging to the group of strong inhibitors of sPLA 2 . Thus, inhibition of PLA 2 different from sPLA 2 , does not necessarily require identical C 1-3 /C 10-12a residues. Conclusion. Since CMT, which inhibit proinflammatory sPLA 2 , are also inhibitors of some MMP, they may be useful for therapy of inflammatory diseases in which both MMP and sPLA 2 are overexpressed.