Call for Papers: Medicinal Chemistry of Next Generation Vaccine Adjuvants

Salunke, Deepak B.; Lindsley, Craig W.

doi:10.1021/acs.jmedchem.3c01248

Cited by 3 publications

(1 citation statement)

References 38 publications

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“…TLR agonists, given their capacity to bridge innate and adaptive immune responses, are frequently employed as adjuvants in vaccines designed to combat severe and complex diseases such as cancer, HIV, herpes simplex virus, and COVID-19. − While many aspects of the immune system’s structure and function are conserved across species, it is critical to note that there are substantial and significant differences in elements like TLRs and STING among various receptors. These differences necessitate meticulous consideration when developing specific agonists. , …”

Section: Introductionmentioning

confidence: 99%

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

Jia,

Luo,

Jing

et al. 2024

J. Med. Chem.

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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 (EC 50 = 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 (EC 50 = 116 pM) in human THP-1 cells, comparable to that of diprovocim (EC 50 = 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.

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