Diprovocims: A New and Exceptionally Potent Class of Toll-like Receptor Agonists

Matthew D. Morin, Ying Wang, Brian T. Jones, Yuto Mifune, Lijing Su, He-Xin Shi, Eva Marie Y. Moresco, Hong Zhang, Bruce A Beutler, Dale L. Boger

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

A screen conducted with nearly 100000 compounds and a surrogate functional assay for stimulation of an immune response that measured the release of TNF-α from treated human THP-1 myeloid cells differentiated along the macrophage line led to the discovery of the diprovocims. Unique to these efforts and of special interest, the screening leads for this new class of activators of an immune response came from a compound library designed to promote cell-surface receptor dimerization. Subsequent comprehensive structure-activity relationship studies improved the potency 800-fold over that of the screening leads, providing diprovocim-1 and diprovocim-2. The diprovocims act by inducing cell-surface toll-like receptor (TLR)-2 dimerization and activation with TLR1 (TLR1/TLR2 agonist), bear no structural similarity to any known natural or synthetic TLR agonist, and are easy to prepare and synthetically modify, and selected members are active in both human and murine systems. The most potent diprovocim (3, diprovocim-1) elicits full agonist activity at extraordinarily low concentrations (EC50 = 110 pM) in human THP-1 cells, being more potent than the naturally derived TLR1/TLR2 agonist Pam3CSK4 or any other known small molecule TLR agonist.

Original languageEnglish (US)
JournalJournal of the American Chemical Society
DOIs
StateAccepted/In press - Jan 1 2018

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ASJC Scopus subject areas

  • Catalysis
  • Chemistry(all)
  • Biochemistry
  • Colloid and Surface Chemistry

Cite this

Morin, M. D., Wang, Y., Jones, B. T., Mifune, Y., Su, L., Shi, H-X., Moresco, E. M. Y., Zhang, H., Beutler, B. A., & Boger, D. L. (Accepted/In press). Diprovocims: A New and Exceptionally Potent Class of Toll-like Receptor Agonists. Journal of the American Chemical Society. https://doi.org/10.1021/jacs.8b09223