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HMBP_Kadri_Preprint_F.pdf (1.99 MB)

Aryloxy Triester Phosphonamidates of Phosphoantigens Exhibit Favorable Stability and Potent Activation of Vγ9/Vδ2 T‐Cells

preprint
submitted on 06.07.2018 and posted on 06.07.2018 by Hachemi Kadri, Taher E. Taher, Qin Xu, Richard T. Bryan, Benjamin E. Willcox, Youcef Mehellou
We previously reported the application of the aryloxy triester phosphoramidate prodrug technology to the phosphoantigen (E)-4-hydroxybut-2-enyl phosphate (HMBP). Although these prodrugs exhibited potent activation of Vγ9/Vδ2 T‐cell immune responses, their stability was low due to the rapid cleavage of the -O-P- bond. To address this, we herein report the application of the same prodrug strategy to two HMBP phosphonates, which have stable -CH2-P- or -CF2-P- bonds. These HMBP phosphonate prodrugs, phosphonamidates, exhibited excellent serum stability and potent activation of Vgama9/Vdelta2 T‐cells making them attractive compounds for further development as potential immunotherapeutics.

Funding

Wellcome Trust: grant codes: 514079, 099266/Z/12/Z, and 200983/Z/16/Z.

History

Email Address of Submitting Author

MehellouY1@cardiff.ac.uk

Institution

Cardiff University

Country

United Kingdom

ORCID For Submitting Author

0000-0001-5720-8513

Declaration of Conflict of Interest

The authors declare no competing financial interest.

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