Stereoisomeric Pam 2 CS based TLR2 agonists: synthesis, structural modelling and activity as vaccine adjuvants.
Arshpreet KaurSakshi PiplaniDeepender KaushikJohnson FungIsaac G SakalaYoshikazu Honda-OkuboSurinder Kumar MehtaNikolai PetrovskySurinder K MehtaPublished in: RSC medicinal chemistry (2022)
Lipopeptides including diacylated Pam 2 CSK 4 as well as triacylated Pam 3 CSK 4 act as ligands of toll-like receptor (TLR)-2, a promising target for the development of vaccine adjuvants. The highly investigated Pam 2 CSK 4 and Pam 3 CSK 4 , despite their aqueous solubility have not performed well as vaccine adjuvants which may be attributable to potential denaturation of protein antigens by these cationic surfactant-like lipopeptides. In the present investigation, we synthesized ( R ), ( S ) and racemic Pam 2 CS(OMe) analogs and their N -acetyl derivatives without the tetralysine component to systematically investigate the effect of stereochemistry at the thio-glycerol lipopeptide core of these lipopeptide based TLR2 agonists. The resulting compounds were compared using TLR2 reporter cell-based assays and the ability of the synthesized lipopeptides to stimulate cytokine production (IL-6, IL-10 and TNF-α) by freshly collected human PBMCs and CD40 and CD86 expressions by mouse spleen cells was also investigated. Notably, few synthesized lipopeptides were found to be potent TLR2/6 agonists, inducing cytokine production and upregulating CD40 and CD86 expressions. The TLR2/6 agonistic lipopeptides were further assessed for vaccine adjuvant effects in mice. The results confirmed that the R -stereochemistry at the thio-glycerol lipopeptide core was preferred for maximal TLR2/6 activity, as reflected in Th1 immune deviation, higher antibody levels and enhanced vaccine protection against a lethal influenza challenge.
Keyphrases
- toll like receptor
- inflammatory response
- nuclear factor
- immune response
- nk cells
- rheumatoid arthritis
- endothelial cells
- adipose tissue
- type diabetes
- stem cells
- high throughput
- signaling pathway
- crispr cas
- single cell
- cell therapy
- insulin resistance
- cell proliferation
- atomic force microscopy
- molecular docking
- resistance training
- molecular dynamics simulations
- metabolic syndrome
- high speed
- high fat diet induced