Photoresponsive G-quadruplex Ligands as Antivirals to Combat COVID-19

鉴于最近的COVID-19大流行，迫切需要开发针对SARS病毒（包括SARS-CoV-2）的新疗法。虽然使用现有的抗病毒药物开发了有限的治疗方法，但尚未开发出针对COVID-19的特异性抗病毒药物。G-四链体（G4）是由富含鸟嘌呤的序列形成的核酸二级结构，其中方形平面鸟嘌呤四联体堆叠以形成3D结构。G4的独特结构特征有助于靶向其他生物分子结构，提供潜在的治疗靶点。研究表明，SARS冠状病毒的必需蛋白Nsp 3通过其SARS独特结构域（SUD）与RNA G4结合，导致Nsp 3二聚化，这是病毒复制的关键。重要的是，G4稳定分子已被证明可以调节SARS-CoV-2中的G4折叠和病毒蛋白表达，这对于靶向SARS-CoV-2特异性G4序列的治疗药物的开发是有希望的。Galan小组正在进行的工作已经导致了可光切换的G4靶向小分子的开发，这些小分子允许在生理条件下对G4折叠进行可见光调节。这些分子显示出抗病原体活性，并且具有用作治疗剂的巨大潜力，特别是因为使用外部刺激来调节活性提供了更大的时空控制。该项目旨在发现和开发可光转换的G4配体，用作抗COVID-19的抗病毒药物。

In light of the recent COVID-19 pandemic, there is a pressing need to develop new therapeutics against SARS viruses including SARS-CoV-2. While limited treatments have been developed using existing antivirals, no specific antiviral drug has been developed against COVID-19. G-quadruplexes (G4s) are nucleic acid secondary structures formed from guanine rich sequences, with square planar guanine tetrads stacked to form a 3D structure. The unique structural features of G4s facilitate targeting over other biomolecular structures, providing a potential therapeutic target. The essential SARS Coronavirus protein, Nsp3, was shown to bind RNA G4 via its SARS Unique Domain (SUD), leading to Nsp3 dimerization which is key for viral replication. Importantly, G4- stabilising molecules have been shown to modulate both G4 folding and viral protein expression in SARS-CoV-2, which is promising for the development of therapeutics targeting SARS-CoV-2 specific G4 sequences. Ongoing work in the Galan group has led to the development of photoswitchable G4-targeting small molecules which allow visible light photoregulation of G4 folding under physiological conditions. These molecules show anti-pathogenic activity and have great potential for use as therapeutics, particularly as use of an external stimulus to modulate activity provides greater spatio-temporal control. This project aims to discover and develop photoswitchable G4 ligands for use as antivirals against COVID-19.