Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", 47014 Meldola, Italy.
Medicinal Chemistry and Pharmaceutical Technology Section, Department of Drug Sciences, University of Pavia, 27100 Pavia, Italy.
Molecules. 2022 Jul 6;27(14):4327. doi: 10.3390/molecules27144327.
Different pathological conditions, including viral infections and cancer, can have a massive impact on the endoplasmic reticulum (ER), causing severe damage to the cell and exacerbating the disease. In particular, coronavirus infections, including SARS coronavirus-2 (SARS-CoV-2), responsible for COVID-19, cause ER stress as a consequence of the enormous amounts of viral glycoproteins synthesized, the perturbation of ER homeostasis and the modification of ER membranes. Therefore, ER has a central role in the viral life cycle, thus representing one of the Achilles' heels on which to focus therapeutic intervention. On the other hand, prolonged ER stress has been demonstrated to promote many pro-tumoral attributes in cancer cells, having a key role in tumor growth, metastasis and response to therapies. In this report, adopting a repurposing approach of approved drugs, we identified the antiplatelet agent ticlopidine as an interferent of the unfolded protein response (UPR) via sigma receptors (SRs) modulation. The promising results obtained suggest the potential use of ticlopidine to counteract ER stress induced by viral infections, such as COVID-19, and cancer.
不同的病理状况，包括病毒感染和癌症，都会对内质网（endoplasmic reticulum，ER）造成巨大影响，导致细胞严重损伤并使疾病恶化。特别是冠状病毒感染，包括导致 COVID-19 的 SARS 冠状病毒-2（SARS-CoV-2），会大量合成病毒糖蛋白，破坏内质网的内稳态并改变内质网膜，从而导致内质网应激。因此，内质网在病毒生命周期中起着核心作用，因此成为治疗干预的重点之一。另一方面，研究表明，长期的内质网应激会促进癌细胞中许多促进肿瘤的特性，在肿瘤生长、转移和对治疗的反应中起着关键作用。在本报告中，我们采用已批准药物的再利用方法，通过调节 sigma 受体（SRs）发现抗血小板药物噻氯匹定是未折叠蛋白反应（unfolded protein response，UPR）的干扰剂。有前途的结果表明，噻氯匹定可能被用于对抗由病毒感染（如 COVID-19）和癌症引起的内质网应激。
