Abstract：
Human respiratory viruses have an enormous impact on national health systems, societies, and economy due to the rapid airborne transmission and epidemic spread of such pathogens, while effective specific antiviral drugs to counteract infections are still lacking. Here, we identified two Keggin-type polyoxometalates (POMs), [TiW11CoO40]8- (TiW11Co) and [Ti2PW10O40]7- (Ti2PW10), endowed with broad-spectrum activity against enveloped and non-enveloped human respiratory viruses, i.e., coronavirus (HCoV-OC43), rhinovirus (HRV-A1), respiratory syncytial virus (RSV-A2), and adenovirus (AdV-5). Ti2PW10 showed highly favorable selectivity indexes against all tested viruses (SIs >700), and its antiviral potential was further investigated against human coronaviruses and rhinoviruses. This POM was found to inhibit replication of multiple HCoV and HRV strains, in different cell systems. Ti2PW10 did not affect virus binding or intracellular viral replication, but selectively inhibited the viral entry. Serial passaging of virus in presence of the POM revealed a high barrier to development of Ti2PW10-resistant variants of HRV-A1 or HCoV-OC43. Moreover, Ti2PW10 was able to inhibit HRV-A1 production in a 3D model of the human nasal epithelium and, importantly, the antiviral treatment did not determine cytotoxicity or tissue damage. A mucoadhesive thermosensitive in situ hydrogel formulation for nasal delivery was also developed for Ti2PW10. Overall, good biocompatibility on cell lines and human nasal epithelia, broad-spectrum activity, and absence of antiviral resistance development reveal the potential of Ti2PW10 as an antiviral candidate for the development of a treatment of acute respiratory viral diseases, warranting further studies to identify the specific target/s of the polyanion and assess its clinical potential.
摘要：
人类呼吸道病毒对国家卫生系统产生巨大影响，社会,由于这种病原体的快速空气传播和流行传播，而有效的特异性抗病毒药物来对抗感染仍然缺乏。这里,我们确定了两种Keggin型多金属氧酸盐（POM），[TiW11CoO40]8-(TiW11Co)和[Ti2PW10O40]7-(Ti2PW10),具有针对有包膜和无包膜人类呼吸道病毒的广谱活性，即，冠状病毒（HCoV-OC43），鼻病毒（HRV-A1），呼吸道合胞病毒（RSV-A2），和腺病毒(AdV-5)。Ti2PW10对所有测试的病毒显示出非常有利的选择性指数（SI>700），并进一步研究了其针对人类冠状病毒和鼻病毒的抗病毒潜力。发现该POM抑制多种HCoV和HRV菌株的复制，在不同的细胞系统中。Ti2PW10不影响病毒结合或细胞内病毒复制，但选择性地抑制了病毒的进入。在POM存在下病毒的连续传代揭示了HRV-A1或HCoV-OC43的Ti2PW10抗性变体的发展的高度障碍。此外，Ti2PW10能够在人类鼻上皮的3D模型中抑制HRV-A1的产生，重要的是,抗病毒治疗未确定细胞毒性或组织损伤.还为Ti2PW10开发了用于鼻递送的粘膜粘附热敏原位水凝胶制剂。总的来说,对细胞系和人鼻上皮具有良好的生物相容性，广谱活动，和缺乏抗病毒抗性的发展揭示了Ti2PW10作为治疗急性呼吸道病毒性疾病发展的抗病毒候选物的潜力，保证进一步的研究，以确定聚阴离子的具体目标，并评估其临床潜力。
