INHIBITION OF GPI PHOSPHOLIPASE-C FROM TRYPANOSOMA-BRUCEI BY FLUORO-INOSITOL DODECYLPHOSPHONATES

Glycosyl phosphatidylinositol phospholipase C (GPI-PLC) of Trypanosoma brucei is inhibited by myoinositol(Ins)-1-O-dodecylphosphonate (VP-60 2L). Several novel fluoro-substituted analogs of 2-deoxy-myo-Ins-1-O-d odecylphosphonate, among which 2-deoxy-2-fluoro-scyllo-Ins-1-O-dodecyl phosphonate (VP-616L) was the most powerful, were shown to be competit ive inhibitors of GPI-PLC, VP-616L was 14-fold more active than VP-602 L. 2-Deoxy-2-fluoro-myo-Ins-1-O-dodecylphosphonate and -deoxy-2,2-difl uoro-myo-Ins-1-O-dodecylphosphonate were 1.55- and 4.67-fold, respecti vely, more potent than VP-602L. Methyl -deoxy-2,2-difluoro-myo-Ins-1-O -dodecylphosphonate did not inhibit GPI-PLC. These observations provid e several insights into how GPI-PLC might interact with its substrate at the active site. We surmise that (i) the 2-OH of Ins is probably di spensable for substrate recognition; (ii) an equatorially oriented act ive site residue might interact with substituents at the 2-position of Ins, and (iii) the negative charge on the phosphoryl at the 1-OH posi tion of Ins might be important for substrate recognition. (C) 1998 Aca demic Press.