Synthesis of prenyl pyrophosphonates as new potent phosphoantigens inducing selective activation of human Vgamma9Vdelta2 T lymphocytes.
Gamma9delta2T cells represent the most abundant population of human blood gammadeltaT lymphocytes. They produce and promote strong cytotoxic activity against many pathogens that are implicated in several human infectious diseases. Their activation requires their exposure to small phosphorus-containing antigens in the family of prenyl pyrophosphates and their related biosynthetic precursors such as isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP), which are naturally occurring metabolites in mycobacteria and several other microbial pathogens. The broad specificity in the recognition of these molecules by the T-lymphocyte population expressing a Vgamma9Vdelta2 cell receptor might facilitate their manipulation by designing small potent synthetic agonist ligands. In this paper, we describe the synthesis and the biological evaluation of new pyrophosphonate compounds as new isosteric analogues of natural prenyl pyrophosphates. Several prenyl and alkenyl pyrophosphonate with different chain lengths and degrees of insaturation (24-28, 48-50, and 64-66) were tested as well as the alkoxymethylpyrophosphonic analogue of IPP (compound 76) as its closest isostere. Several of them appeared to be better activators of Vgamma9Vdelta2 T cell proliferation than IPP. These results open the perspective of a potential use of isoprenoides pyrophosphonates as specific immunoregulatory molecules.
Zgani
Ibrahim
I
LCBM, UMR 5032, Université Montpellier II, CNRS, MAYOLY-SPINDLER, 8 Rue de l'Ecole Normale, 34296 Montpellier, France.
Menut
Chantal
C
Seman
Michel
M
Gallois
Valerie
V
Laffont
Virginie
V
Liautard
Jeanine
J
Liautard
Jean-Pierre
JP
Criton
Marc
M
Montero
Jean-Louis
JL
D000941:Antigens / Q000737:chemistry* / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D015195:Drug Design; D045782:Hemiterpenes; D006801:Humans; D008024:Ligands; D008213:Lymphocyte Activation / Q000187:drug effects*; D009943:Organophosphorus Compounds / Q000138:chemical synthesis* / Q000276:immunology / Q000494:pharmacology*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000032:analysis; D013329:Structure-Activity Relationship; D016176:T-Lymphocyte Subsets / Q000187:drug effects*
D000941:Antigens; D045782:Hemiterpenes; D008024:Ligands; D009943:Organophosphorus Compounds; D016692:Receptors, Antigen, T-Cell, gamma-delta; C004809:isopentenyl pyrophosphate