由一种新型冠状病毒引起的新冠肺炎史无前例的大流行,SARS-CoV-2及其高度传播的变体,导致了巨大的人类痛苦,死亡,和全世界的经济破坏。最近,规避抗体的SARS-CoV-2亚变体,BQ和XBB,已被报道。因此,继续开发具有泛冠状病毒抑制作用的新药对于治疗和预防COVID-19感染以及任何可能出现的新流行病至关重要.我们报告了几种高效小分子抑制剂的发现。其中之一,NBCoV63对SARS-CoV-2显示出低nM效力(IC50:55nM),SARS-CoV-1(IC50:59nM),和MERS-CoV(IC50:75nM)在基于假病毒的检测中具有优异的选择性指数(SI>900),表明它的泛冠状病毒抑制作用。NBCoV63对SARS-CoV-2突变体(D614G)和一些关注的变体(VOCs),如B.1.617.2(Delta),表现出同样有效的抗病毒效力,B.1.1.29/BA.1和BA.4/BA.5(Omicron),和K417T/E484K/N501Y(伽马)。NBCoV63对地道的SARS-CoV-2(香港株)及其两种变体(Delta和Omicron)也显示出与Remdesivir相似的功效,SARS-CoV-1和MERS-CoV通过减少Calu-3细胞中的斑块。此外,我们显示NBCoV63以剂量依赖性方式抑制病毒介导的细胞与细胞融合。此外,吸收,分布,新陈代谢,NBCoV63的排泄(ADME)数据证明了药物样特性。
The unprecedented pandemic of COVID-19, caused by a novel coronavirus, SARS-CoV-2, and its highly transmissible variants, led to massive human suffering, death, and economic devastation worldwide. Recently, antibody-evasive SARS-CoV-2 subvariants, BQ and XBB, have been reported. Therefore, the continued development of novel drugs with pan-coronavirus inhibition is critical to treat and prevent infection of COVID-19 and any new pandemics that may emerge. We report the discovery of several highly potent small-molecule inhibitors. One of which, NBCoV63, showed low nM potency against SARS-CoV-2 (IC50: 55 nM), SARS-CoV-1 (IC50: 59 nM), and MERS-CoV (IC50: 75 nM) in pseudovirus-based assays with excellent selectivity indices (SI > 900), suggesting its pan-coronavirus inhibition. NBCoV63 showed equally effective antiviral potency against SARS-CoV-2 mutant (D614G) and several variants of concerns (VOCs) such as B.1.617.2 (Delta), B.1.1.529/BA.1 and BA.4/BA.5 (Omicron), and K417T/E484K/N501Y (Gamma). NBCoV63 also showed similar efficacy profiles to Remdesivir against authentic SARS-CoV-2 (Hong Kong strain) and two of its variants (Delta and Omicron), SARS-CoV-1, and MERS-CoV by plaque reduction in Calu-3 cells. Additionally, we show that NBCoV63 inhibits virus-mediated cell-to-cell fusion in a dose-dependent manner. Furthermore, the absorption, distribution, metabolism, and excretion (ADME) data of NBCoV63 demonstrated drug-like properties.