RU.521 (RU320521) is a potent and selective cyclic GMP-AMP synthase (cGAS) inhibitor that binds to the catalytic domain of cGAS, thereby inhibiting the activation of cGAS by dsDNA. The IC50 value of RU.521 in inhibiting cGAS-mediated signal transduction is 700nM[1].
RU.521 (10μM) can inhibit the replication of human metapneumovirus (hMPV) in 16HBE cells, and exogenous addition of interleukin 1 beta (IL-1β) in the presence of RU.521 does not affect hMPV replication (IL-1β can promote hMPV replication) [2]. RU.521 (700nM) can reverse the damage of HUVEC cells caused by neutrophil extracellular traps (NETs) by inhibiting the cGAS/STING pathway[3].
RU.521 (5mg/kg) can inhibit the cGAS-STING pathway and reduce endoplasmic reticulum stress (ERS), thereby alleviating lung injury and promoting pulmonary ventilation function in rats with pulmonary ischemia/reperfusion (I/R)[4]. Intracisternary infusion of RU.521 (0.4mg/kg) in hypertensive mice reduced the expression of cGAS and STING in the paraventricular nucleus (PVN) of mice, and also reduced the LC3II/I ratio and p62 expression level[5].
References:
[1] Vincent J, Adura C, Gao P, Luz A, Lama L, Asano Y, Okamoto R, Imaeda T, Aida J, Rothamel K, Gogakos T, Steinberg J, Reasoner S, Aso K, Tuschl T, Patel DJ, Glickman JF, Ascano M. Small molecule inhibition of cGAS reduces interferon expression in primary macrophages from autoimmune mice. Nat Commun. 2017 Sep 29;8(1):750. doi: 10.1038/s41467-017-00833-9. Erratum in: Nat Commun. 2017 Nov 23;8(1):1827.
[2] Wu G, Zhang Y, Niu L, Hu Y, Yang Y, Zhao Y. Interleukin-1β promotes human metapneumovirus replication via activating the cGAS-STING pathway. Virus Res. 2024 May;343:199344.
[3] Zhang B, Fang Z, Lin Y, et al. RU. 521 protects against neutrophil extracellular traps-induced vascular endothelial injury by inhibiting cGAS/STING pathway[J]. ||| Bangladesh Journal of Pharmacology|||, 2024, 19(2): 59-64.
[4] Vincent J, Adura C, Gao P, Luz A, Lama L, Asano Y, Okamoto R, Imaeda T, Aida J, Rothamel K, Gogakos T, Steinberg J, Reasoner S, Aso K, Tuschl T, Patel DJ, Glickman JF, Ascano M. Small molecule inhibition of cGAS reduces interferon expression in primary macrophages from autoimmune mice. Nat Commun. 2017 Sep 29;8(1):750.
[5] Han C, Qian X, Ren X, Zhang S, Hu L, Li J, Huang Y, Huang R, Ooi K, Lin H, Xia C. Inhibition of cGAS in Paraventricular Nucleus Attenuates Hypertensive Heart Injury Via Regulating Microglial Autophagy. Mol Neurobiol. 2022 Nov;59(11):7006-7024.
RU.521 （RU320521）是一种有效的选择性环状GMP-AMP合酶 （cGAS）抑制剂，可与cGAS 的催化结构域结合，从而抑制dsDNA对cGAS的激活，RU.521抑制cGAS介导的信号传导的IC50值为700nM[1]。
RU.521（10μM ）可抑制16HBE细胞中的人偏肺病毒（hMPV）的复制，并且在RU.521存在下外源添加白细胞介素1 β（IL-1β）不会影响hMPV复制（IL-1β可促进hMPV复制）[2] 。RU.521（700nM）可通过抑制cGAS/STING通路，逆转中性粒细胞胞外陷阱（NETs）导致的HUVEC细胞的损伤[3] 。
RU.521（5mg/kg）可抑制cGAS-STING通路减弱内质网应激（ERS），从而减轻肺缺血/再灌注（I/R）大鼠的肺损伤并促进肺通气功能[4] 。在高血压小鼠脑池内输注RU.521（0.4mg/kg）降低了小鼠室旁核（PVN）中cGAS和STING的表达，也降低了LC3II/I比率和p62表达水平[5]。