Replacing the pyrophosphate group of HMB-PP by a diphosphonate function abrogates Its potential to activate human γδ T cells but does not lead to competitive antagonism

Stimulation of Vγ9/Vδ2 T-lymphocyte proliferation by the isoprenoid precursor, (E)-1-hydroxy-2-methyl-but-2-enyl 4-diphosphate

“…Thus, the monophosphate 11 is 1700 times less efficient as a stimulator than the diphosphate 5. The replacement of the bridging oxygen atom of the phosphoanhydride motif of 5 by a methylene group affording 13 is accompanied by a 79,000-fold loss in efficacy which is in perfect agreement with earlier studies (Reichenberg et al, 2003). Most 6); &, dimethylallyl diphosphate (DMAPP, 7); K, (E)-1-hydroxy-2-methylbut-2-enyl 4-diphosphate (5), J, (E)-1-hydroxy-3-methyl-but-2-enyl 4-phosphate (11); , (E)-2-methyl-but-2-ene-1,4-diol (12); , (E)-1-hydroxy-2-methyl-but-2-enyl 4-(methylene-diphosphonate) (13); m, (E)-3-formyl-but-2-enyl 1-diphosphate (14).…”

Isoprenoid biosynthesis in bacterial pathogens

“…The stimulatory capacity of several MEP pathway mutants in E. coli was analysed and a significant difference was observed between a DgcpE mutant which exhibited a reduced capacity to elicit an immune response in contrast to the highly immunostimulatory DlytB mutant. Analysis of DlytB mutant extracts identified HMB-PP as the most potent stimulator of Vc9/Vd2 T cells, with a 10 000-fold increase in the stimulatory capacity of this compound compared with IPP (Altincicek et al, 2001;Eberl et al, 2002;Hecht et al, 2001;Reichenberg et al, 2003). These findings made it clear that the inability of the pathogenic bacteria Staphlococcus, Streptococcus and Borrelia to stimulate Vc9/Vd2 T cells was due to the lack of an MEP pathway and the absence of HMB-PP (Jomaa et al, 1999a).…”

“…These findings made it clear that the inability of the pathogenic bacteria Staphlococcus, Streptococcus and Borrelia to stimulate Vc9/Vd2 T cells was due to the lack of an MEP pathway and the absence of HMB-PP (Jomaa et al, 1999a). The ability of isoprenoid biosynthetic pathways to produce non-peptidic compounds and stimulate Vc9/Vd2 T cells has been reviewed elsewhere (Eberl et al, 2003;Bonneville & Scotet, 2006 (Begley et al, 2008). The precise mechanism underpinning the stimulation of Vc9/Vd2 T cells by HMB-PP is unclear.…”

Synthesis of Analogues of (E)-1-Hydroxy-2-methylbut-2-enyl 4-Diphosphate, an Isoprenoid Precursor and Human γδ T Cell Activator

“…It was demonstrated that only very minor modifications of this group such as in (E)-4-hydroxy-3-methyl-but-2-enylmethylenediphosphonate (HMB-PCP), which represents the bis-phosphonate analogue of HMBPP, results in 10,000-fold reduced activity in the V9V2 T cell activation assay. 27 A QSAR study by Gossman and Oldfield revealed four essential components arranged in the appropriate relative geometry are critical for  T cell activation: an H-bond donor (e.g., the OH group of HMBPP (7)), a hydrophobic feature (e.g., the methyl group of HMBPP) and two negative ionisable groups (e.g., the two pyrophosphate phosphate groups of HMBPP). 28 While all analogues investigated contain the former two pharmacophore features, our data suggest that the polar diphosphate mimetics investigated are unable to bioisosterically replace the pyrophosphate moiety of HMBPP, despite the fact that a NH group flanked by a carbonyl and a sulphonamide as in 31-36 and 41-44 will be deprotonated at physiological pH.…”