Abstract:
: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.
journal_name
J Med Chemjournal_title
Journal of medicinal chemistryauthors
Zgani I,Menut C,Seman M,Gallois V,Laffont V,Liautard J,Liautard JP,Criton M,Montero JLdoi
10.1021/jm049861zkeywords:
subject
Has Abstractpub_date
2004-08-26 00:00:00pages
4600-12issue
18eissn
0022-2623issn
1520-4804journal_volume
47pub_type
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