Next-Generation Diprovocims with Potent Human and Murine TLR1/TLR2 Agonist Activity That Activate the Innate and Adaptive Immune Response

Ming Hsiu Yang, Jamie L. Russell, Yuto Mifune, Ying Wang, Hexin Shi, Eva Marie Y. Moresco, Daniel J. Siegwart, Bruce Beutler, Dale L. Boger

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

The diprovocims, a new class of toll-like receptor (TLR) agonists, bear no similarity to prior TLR agonists, act through a well-defined mechanism (TLR1/TLR2 agonist), exhibit exquisite structure-activity relationships, and display in vivo adjuvant activity. They possess potent and efficacious agonist activity toward human TLR1/TLR2 but modest agonism toward the murine receptor. A manner by which diprovocims can be functionalized without impacting hTLR1/TLR2 activity is detailed, permitting future linkage to antigenic, targeting, or delivery moieties. Improvements in both potency and its low efficacy in the murine system were also achieved, permitting more effective use in animal models while maintaining the hTLR1/TLR2 activity. The prototypical member diprovocim-X exhibits the excellent potency/efficacy of diprovocim-1 in human cells, displays substantially improved potency/efficacy in mouse macrophages, and serves as an adjuvant in mice when coadministered with a nonimmunogenic antigen, indicating stimulation of the adaptive as well as innate immune response.

Original languageEnglish (US)
Pages (from-to)9230-9252
Number of pages23
JournalJournal of Medicinal Chemistry
Volume65
Issue number13
DOIs
StatePublished - Jul 14 2022

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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