Design synthesis and self assembly of TLR2 agonistic lipopeptides

Abstract

The idea of the present investigation originated in the admiration of a crucial role of Toll-Like Receptors (TLRs) to link innate and adaptive immune system which further halts the infection. The work was initiated with an aim to target TLR2 with lipopeptides and explore the influence of physical properties of surfactant-like lipopeptides on the bioactivity. Initially, an efficient and scalable 20 step synthesis of Pam2CSK4 in good yield (all steps gt 60%) was carried out and further Pam2CS(OMe) analogues were synthesized without the tetralysine component. Out of the various analogues, Nacetylated derivative with R-stereochemistry outperformed in TLR2 agonistic activity and demonstrated potent adjuvant activity against influenza and hepatitis. Additionally, a watersoluble analogue was synthesized via coupling with 3- (dimethylamino)-1-propylamine. Additionally, a conjugate of TLR2 agonistic lipopeptide with TLR7 agonistic imidazoquinoline was also synthesized to simultaneously activate TLR2 and TLR7 that demonstrated Th1 and Th2 biased immune responses similar to a parent N-AcPam2CS(OMe). Moreover, the co-encapsulation of TLR2 agonistic lipopeptide and TLR7 agonist in Nanostructured Lipid Carriers (NLCs) and poly(lactic-co-glycolic acid) (PLGA) nanoparticles was investigated to enhance water solubility and modulate antibody responses. Overall, these findings demonstrated that the synthesized TLR2 agonistic lipopeptides and nanoparticulate systems can be successfully employed and novel vaccine adjuvants. newline