AF 12198 是一种有效、选择性和特异性的肽拮抗剂，作用于人类 I 型白细胞介素-1 受体 (IL1-R1) (IC50\u003d8 nM)，而不是人类 II 型受体 (IC50\u003d6.7 μM) 或鼠 I 型受体 ( IC50\u003e200 μM)。
IC50: 25 nM for IL-1-induced IL-8 production
Interleukin-1 (IL-1) -α and -β are potent regulators of inflammatory responses. Naturally occurring interleukin-1 receptor antagonist (IL-1ra) is effective in vitro and in vivo in modulating biological responses to IL-1. AF 12198 is a novel low molecular weight antagonist of IL-1.
In vitro: AF 12198 binds the human type I IL-1 receptor selectively but not the human type II receptor or the murine type I receptor. AF12198 also inhibits IL-1-induced IL-8 formation by human dermal fibroblasts with a half-maximal inhibition concentration or IC50 of 25 nM and IL-1-induced intercellular adhesion molecule-1 (ICAM-1) expression by endothelial cells with an IC50 of 9 nM [2].
In vivo: When given as an intravenous infusion to cynomolgus monkeys, AF 12198 blocks ex vivo IL-1 induction of IL-6 and down modulates in vivo induction of IL-6. This is the first small molecule to show IL-1 receptor antagonist activity in vivo [3].
Clinical trial: Up to now, AF 12198 is still in the preclinical development stage.
Reference:
[1] Akeson AL, Woods CW, Hsieh LC, Bohnke RA, Ackermann BL, Chan KY, Robinson JL, Yanofsky SD, Jacobs JW, Barrett RW, Bowlin TL.? AF12198, a novel low molecular weight antagonist, selectively binds the human type I interleukin (IL)-1 receptor and blocks in vivo responses to IL-1. J Biol Chem. 1996 Nov 29;271(48):30517-23.
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