Department of Experimental Pharmacology, Mossakowski Medical Research Institute, Polish Academy of Sciences, Pawinskiego 5, 02-106 Warsaw, Poland.
Chair and Department of Medical Microbiology, Medical University of Warsaw, 02-091 Warsaw, Poland.
Int J Mol Sci. 2021 Feb 18;22(4):2020. doi: 10.3390/ijms22042020.
Adenovirus infections tend to be mild, but they may pose a serious threat for young and immunocompromised individuals. The treatment is complicated because there are no approved safe and specific drugs for adenovirus infections. Here, we present evidence that 17-(Allylamino)-17-demethoxygeldanamycin (17-AAG), an inhibitor of Hsp90 chaperone, decreases the rate of human adenovirus 5 (HAdV-5) replication in cell cultures by 95%. 17-AAG inhibited the transcription of early and late genes of HAdV-5, replication of viral DNA, and expression of viral proteins. 6 h after infection, Hsp90 inhibition results in a 6.3-fold reduction of the newly synthesized E1A protein level without a decrease in the E1A mRNA level. However, the Hsp90 inhibition does not increase the decay rate of the E1A protein that was constitutively expressed in the cell before exposure to the inhibitor. The co-immunoprecipitation proved that E1A protein interacted with Hsp90. Altogether, the presented results show, for the first time. that Hsp90 chaperones newly synthesized, but not mature, E1A protein. Because E1A serves as a transcriptional co-activator of adenovirus early genes, the anti-adenoviral activity of the Hsp90 inhibitor might be explained by the decreased E1A level.
腺病毒感染通常较为轻微，但对儿童和免疫功能低下者可能构成严重威胁。由于目前尚无针对腺病毒感染的安全有效的特效药物，因此治疗较为复杂。在此，我们提供的证据表明，Hsp90 伴侣抑制剂 17-（丙烯胺基）-17-脱甲氧基格尔德霉素（17-AAG）可将人腺病毒 5（HAdV-5）在细胞培养物中的复制率降低 95%。17-AAG 抑制 HAdV-5 的早期和晚期基因转录、病毒 DNA 复制和病毒蛋白表达。感染后 6 小时，Hsp90 抑制导致新合成的 E1A 蛋白水平降低 6.3 倍，而 E1A mRNA 水平没有降低。然而，Hsp90 抑制不会增加在接触抑制剂之前细胞中持续表达的 E1A 蛋白的降解率。共免疫沉淀证明 E1A 蛋白与 Hsp90 相互作用。总的来说，这些结果首次表明 Hsp90 伴侣蛋白新合成而非成熟的 E1A 蛋白。由于 E1A 作为腺病毒早期基因的转录共激活因子，Hsp90 抑制剂的抗腺病毒活性可能与 E1A 水平降低有关。
