Thiopyrophosphoantigens: solid-phase synthesis and in vitro characterization of a new class of Vgamma9 Vdelta2 T cells activators.
The Vgamma9 Vdelta2 T cells mediate rapid, innate-like immune responses to pathogens and are important in several key immunoregulatory pathways, including those involved in infections and tumor development. Vgamma9 Vdelta2 T cells respond to low molecular weight isoprenoid phosphoantigens; the prototypic stimulatory compound is isopentenylpyrophosphate (IPP), an alkylphosphate intermediate of mevalonate metabolism that elicits proliferative, cytotoxic, and cytokine secretion responses. We studied the replacement of the pyrophosphate moiety with the thiopyrophosphate bioisostere, synthesizing thioanalogues of IPP and 4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP, the most potent natural antigen known to date). Once their in vitro efficacy and stability had been demonstrated, we synthesized a small library of compounds through the development of an innovative solid-phase strategy. Biological results confirmed thioHMBPP to be the best compound of this first series. Future aims are (i) the exploitation of the parallel solid-phase strategy to further explore structure-activity relationships of this new class of synthetic antigens and (ii) the determination of the PK/PD profile of thioHMBPP.
Breccia
Perla
P
Colosseum Combinatorial Chemistry Centre for Technology (C4T SCarl), Via della Ricerca Scientifica snc, I-00173 Rome, Italy.
Angeli
Francesca
F
Cerbara
Ilaria
I
Topai
Alessandra
A
Auricchio
Giovanni
G
Martino
Angelo
A
Colizzi
Vittorio
V
Poccia
Fabrizio
F
D045782:Hemiterpenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000276:immunology; D015394:Molecular Structure; D008970:Molecular Weight; D009943:Organophosphorus Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000187:drug effects* / Q000276:immunology; D054852:Small Molecule Libraries; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology*
D045782:Hemiterpenes; D009943:Organophosphorus Compounds; D016692:Receptors, Antigen, T-Cell, gamma-delta; D054852:Small Molecule Libraries; D013438:Sulfhydryl Compounds; C004809:isopentenyl pyrophosphate