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

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.