Phosphonamidate Prodrugs of a Butyrophilin Ligand Display Plasma Stability and Potent Vγ9 Vδ2 T Cell Stimulation

  • J Med Chem. 2018 Oct 11;61(19):8658-8669. doi: 10.1021/acs.jmedchem.8b00655.
Nicholas A Lentini  1 ,  Benjamin J Foust  1 ,  Chia-Hung Christine Hsiao  2 ,  Andrew J Wiemer  2  3 ,  David F Wiemer  1  4
Affiliations
  • 1. Department of Chemistry , University of Iowa , Iowa City , Iowa 52242-1294 , United States.
  • 2. Department of Pharmaceutical Sciences , University of Connecticut , Storrs , Connecticut 06269-3092 , United States.
  • 3. Institute for Systems Genomics , University of Connecticut , Storrs , Connecticut 06269-3092 , United States.
  • 4. Department of Pharmacology , University of Iowa , Iowa City , Iowa 52242-1109 , United States.
PMID: 30199251 DOI: 10.1021/acs.jmedchem.8b00655
Abstract

Small organophosphorus compounds stimulate Vγ9 Vδ2 T cells if they serve as ligands of butyrophilin 3A1. Because the most potent natural ligand is ( E)-4-hydroxy-3-methyl-but-2-enyl diphosphate (HMBPP), which is the last intermediate in Bacterial biosynthesis of isoprenoids that is not found in mammalian metabolism, activation of these T cells represents an important component of the immune response to Bacterial infections. To identify butyrophilin ligands that may have greater plasma stability, and clinical potential, we have prepared a set of aryl phosphonamidate derivatives (9a-i) of the natural ligand. Testing of these new compounds in assays of T cell response has revealed that this strategy can provide compounds with high potency for expansion of Vγ9 Vδ2 T cells (9f, EC50 = 340 pM) and interferon γ production in response to loaded K562 cells (9e, EC50 = 62 nM). Importantly, all compounds of this class display extended plasma stability ( t1/2 > 24 h). These findings increase our understanding of metabolism of butyrophilin ligands and the structure-activity relationships of phosphonamidate prodrugs.