Glycosylated human interleukin-1alpha, neoglyco IL-1alpha, coupled with N-acetylneuraminic acid exhibits selective activities in vivo and altered tissue distribution.
In order to study the effect of glycosylation on its biological activities and to develop IL-1 with less deleterious effects, N-acetylneuraminic acid (NeuAc) with C9 spacer was chemically coupled to human recombinant IL-1alpha. NeuAc-coupled IL-1alpha (NeuAc-IL-1alpha) exhibited reduced activities in vitro and receptor-binding affinities by about ten times compared to IL-1alpha. In this study, we examined a variety of IL-1 activities in vivo. NeuAc-IL-1alpha exhibited a marked reduction in the activity to up-regulate serum IL-6, moderate reduction in the activities to up-regulate serum amyloid A and NOx. However, it exhibited comparable activities as IL-1alpha to down-regulate serum glucose and to improve the recovery of peripheral white blood cells from myelosuppression in 5-fluorouracil-treated mice. In addition, tissue level of NeuAc-IL-1alpha was high compared to IL-1alpha. These results indicate that coupling with NeuAc enabled us to develop neo-IL-1 with selective activities in vivo and enhanced tissue level.
Sasayama
S
S
Department of Hygienic Chemistry, Faculty of Pharmaceutical Sciences, Nagoya City University, Mizuho, Japan.
Moriya
K
K
Chiba
T
T
Matsumura
T
T
Hayashi
H
H
Hayashi
A
A
Onozaki
K
K
D000818:Animals; D001053:Apolipoproteins / Q000097:blood; D001786:Blood Glucose / Q000378:metabolism; D001853:Bone Marrow / Q000187:drug effects; D005260:Female; D005472:Fluorouracil / Q000633:toxicity; D006023:Glycoproteins / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D006031:Glycosylation; D006801:Humans; D007375:Interleukin-1 / Q000737:chemistry / Q000493:pharmacokinetics* / Q000494:pharmacology*; D015850:Interleukin-6 / Q000097:blood; D051379:Mice; D008813:Mice, Inbred ICR; D019158:N-Acetylneuraminic Acid / Q000737:chemistry; D009569:Nitric Oxide / Q000097:blood; D011994:Recombinant Proteins / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000685:Serum Amyloid A Protein; D014018:Tissue Distribution
D001053:Apolipoproteins; D001786:Blood Glucose; D006023:Glycoproteins; D007375:Interleukin-1; D015850:Interleukin-6; D011994:Recombinant Proteins; D000685:Serum Amyloid A Protein; D009569:Nitric Oxide; D019158:N-Acetylneuraminic Acid; D005472:Fluorouracil