The Development of a Highly Potent and Selective Human Toll-like Receptor 2 Agonist: Synthesis and Biological Evaluation of CaLGL‑1 and Its Derivatives

Toll-like receptor 2 (TLR2) plays a crucial role in detecting
microbial
pathogen-associated molecular patterns, offering potential applications
as an adjuvant for vaccines and antitumor therapies. Here, we present
the gram-scale synthesis of CaLGL-1 and its derivatives, natural products
known for activating mouse TLR2 (EC50 = 3.2 μM).
This synthesis involves a streamlined six-step reaction sequence utilizing
oxidant-promoted acetalization, effectively preserving the acid-sensitive
glycosidic bond for maintaining the compounds’ functional integrity.
Our structure–activity relationship studies identified R-7d as a potent human TLR2 activator. It demonstrated subnanomolar
activity (EC50 = 116 pM) in human THP-1 cells, comparable
to that of diprovocim (EC50 = 110 pM). Experiments revealed
that R-7d enhances NF-kB promoter activation through
TLR2/TLR1 heterodimers rather than TLR2/TLR6. The discovery of R-7d as a robust human TLR2 agonist opens up new possibilities
for combination therapies.