Hydroxyapatite nanoparticles drive the potency of Toll-like receptor 9 agonist for amplified innate and adaptive immune response

The potency of Toll-like receptor 9(TLR9)agonist to drive innate immune response was limited due to immune suppression or tolerance during TLR9 signaling activation in immune cells.Herein we addressed this problem by introducing hydroxyapatite nanoparticles(HANPs)to CpG ODN(CpG),a TLR9 agonist.The study revealed that HANPs concentration and durationdependently reprogramed the immune response by enhancing the secretion of immunostimulatory cytokines(tumor necrosis factorα(TNFα)or IL-6)while reducing the production of immunosuppressive cytokine(IL-10)in macrophages in response to CpG.Next,the enhanced immune response benefited from increased intracellular Ca2+in macrophage by the addition of HANPs.Further,we found exposure to HANPs impacted the mitochondrial function of macrophages in support of the synthesis of adenosine triphosphate(ATP),the production of nicotinamide adenine dinucleotide(NAD),and reactive oxygen species(ROS)in the presence or absence of CpG.In vaccinated mice model,only one vaccination with a mixture of CpG,HANPs,and OVA,a model antigen,allowed the development of a long-lasting balanced humoral immunity in mice without any histopathological change in the local injection site.Therefore,this study revealed that HANPs could modulate the intracellular calcium level,mitochondrial function,and immune response in immune cells,and suggested a potential combination adjuvant of HANPs and TLR9 agonist for vaccine development.

Chemical and chemoenzymatic stereoselectivesynthesis of β-nucleosides and their analogues

β-Nucleosides are fundamental building blocks of biological systems and are widely used as therapeuticagents for the treatment of cancer and viral infections, among others. In the last two years, nucleosideanalogues have been investigated with renewed urgency in the search for agents that are effective againstSARS-CoV-2, the cause of the ongoing global pandemic of COVID-19. This has resulted in an explosionof activities in the field of β-nucleoside synthesis. This review summarizes the historical perspective andthe recent advances in the stereoselective synthesis of β-nucleosides and their analogues. The syntheticstrategies to obtain β-nucleosides can be divided into three categories: (1) N-glycosylation;(2) intramolecular sugar ring formation;and (3) enzymatic transglycosylation.