ABSTRACT
The obstacles to the development of therapeutic aptamers for systemic inflammatory diseases, such as nuclease degradation and renal clearance, have not been fully overcome. Here, we report a novel PEGylation method, sbC-PEGylation, which improves the pharmacokinetic properties of RNA aptamers that act against interleukin-17A (IL-17A) in mice and monkeys. sbC-PEGylated aptamers were synthesized by coupling the symmetrical branching molecule 2-cyanoethyl-N,N-diisopropyl phosphoroamidite to the 5' end of the aptamer, before conjugating two polyethylene glycol (PEG) molecules to the aptamer. Pharmacokinetic studies showed that compared with conventionally PEGylated aptamers, the sbC-PEGylated aptamer exhibited excellent stability in the blood circulation of mice and monkeys. In addition, one of the sbC-PEGylated aptamers, 17M-382, inhibited the interleukin-6 (IL-6) production induced by IL-17A in NIH3T3 cells in a concentration-dependent manner, and the half-maximal inhibitory concentration of sbC-PEGylated 17M-382 was two times lower than that of non-PEGylated 17M-382. Furthermore, the intraperitoneal administration of sbC-PEGylated 17M-382 significantly inhibited the IL-6 production induced by IL-17A in a mouse air pouch model. Our findings suggest that the novel PEGylation method described in this study, sbC-PEGylation, could be used to develop anti-IL-17A aptamers as a therapeutic option for systemic inflammatory disease.
Subject(s)
Aptamers, Nucleotide/chemistry , Aptamers, Nucleotide/pharmacokinetics , Interleukin-17/antagonists & inhibitors , Polyethylene Glycols/chemistry , Animals , Blood Chemical Analysis , Humans , Inhibitory Concentration 50 , Injections, Intraperitoneal , Interleukin-17/genetics , Interleukin-6/antagonists & inhibitors , Macaca fascicularis , Male , Mice , Mice, Inbred C57BL , NIH 3T3 CellsABSTRACT
A novel compound (1) and a known one (2) were isolated from Makomotake, Zizania latifolia infected with Ustilago esculenta, as osteoclast-forming suppressive substances.
