Retro-2 is a potent ebolavirus (EBOV) infection inhibitor with an EC50 value of 12.2μM [1]. Retro-2 protects cells against ricin and Shiga toxin by blocking retrograde toxin transport at the early endosomes-TGN interface [2]. Retro-2 has been widely used to inhibit the replication of SARS-CoV-2 and to modify the Golgi structure[3].
In vitro, Retro-2 pretreatment at 20μM for 4 hours protected RAW264.7 cells from death caused by ricin toxin and restored protein synthesis function[4]. After 24 hours of treatment with 10μM Retro-2, the subcellular localization of Syntaxin 5 protein in HeLa cells was altered, and the abundance of Syntaxin 5 localized in the Golgi apparatus was decreased[5]. Treatment with 5μM Retro-2 for 4 hours induced autophagy in HeLa cells expressing GFP-LC3, accompanied by a significant increase in the number of large vesicles[6].
In vivo, Retro-2 (2.5μl; 20μM) was injected into the dentate gyrus of mice at a single dosage for 6 hours increased the generation activity of Aβ42 in the brain tissue of mice[7]. Retro-2 treatment via intraperitoneal injection at a single dose of 200mg/kg protected mice against intoxication by ricin and prolonged the survival of the mice[8].
References:
[1] Shtanko O, Sakurai Y, Reyes A N, et al. Retro-2 and its dihydroquinazolinone derivatives inhibit filovirus infection[J]. Antiviral research, 2018, 149: 154-163.
[2] Gupta N, Pons V, Noel R, et al. (S)-N-methyldihydroquinazolinones are the active enantiomers of Retro-2 derived compounds against toxins[J]. ACS medicinal chemistry letters, 2014, 5(1): 94-97.
[3] Yue X, Gim B, Zhu L, et al. Retro-2 alters Golgi structure[J]. Scientific Reports, 2022, 12(1): 14975.
[4] Jiao Z, Ke Y, Li S, et al. Pretreatment with retro‐2 protects cells from death caused by ricin toxin by retaining the capacity of protein synthesis[J]. Journal of Applied Toxicology, 2020, 40(10): 1440-1450.
[5] Morgens D W, Chan C, Kane A J, et al. Retro-2 protects cells from ricin toxicity by inhibiting ASNA1-mediated ER targeting and insertion of tail-anchored proteins[J]. Elife, 2019, 8: e48434.
[6] Nicolas V, Lievin-Le Moal V. Small trafficking inhibitor retro-2 disrupts the microtubule-dependent trafficking of autophagic vacuoles[J]. Frontiers in Cell and Developmental Biology, 2020, 8: 464.
[7] Kanatsu K, Hori Y, Ebinuma I, et al. Retrograde transport of γ‐secretase from endosomes to the trans‐Golgi network regulates Aβ42 production[J]. Journal of neurochemistry, 2018, 147(1): 110-123.
[8] Stechmann B, Bai S K, Gobbo E, et al. Inhibition of retrograde transport protects mice from lethal ricin challenge[J]. Cell, 2010, 141(2): 231-242.
Retro-2是一种强效埃博拉病毒（EBOV）感染抑制剂，EC50值为12.2μM[1]。Retro-2通过阻断早期内体与高尔基体反面网络界面之间的毒素逆行转运，保护细胞免受蓖麻毒素和志贺毒素的侵害[2]。Retro-2已被广泛用于抑制SARS-CoV-2的复制以及修饰高尔基体结构[3]。
在体外，使用20μM的Retro-2预处理4小时，保护了RAW264.7细胞免受蓖麻毒素引起的死亡，并恢复了蛋白质合成功能[4]。使用10μM的Retro-2处理24小时后，HeLa细胞中Syntaxin 5蛋白的亚细胞定位发生改变，定位于高尔基体的Syntaxin 5蛋白丰度降低[5]。使用5μM的Retro-2处理4小时，诱导了表达GFP-LC3的HeLa细胞发生自噬，并伴有大型囊泡数量的显著增加[6]。
在体内，向小鼠齿状回单次注射Retro-2（2.5μl；20μM）6小时，可增加小鼠脑组织中Aβ42的生成活性[7]。通过腹腔注射单次给予200mg/kg剂量的Retro-2，保护小鼠免受蓖麻毒素中毒，并延长了小鼠的存活时间[8]。