Laboratory of Molecular Modeling and Drug Design, Lindsey F. Kimball Research Institute, New York Blood Center, New York, NY 10065, USA.
SRI Biosciences (A Division of SRI International), 333 Ravenswood Avenue, Menlo Park, CA 94025, USA.
Viruses. 2023 Apr 19;15(4):1001. doi: 10.3390/v15041001.
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 (IC: 55 nM), SARS-CoV-1 (IC: 59 nM), and MERS-CoV (IC: 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.
由新型冠状病毒 SARS-CoV-2 及其高度传染性的变体引起的 COVID-19 疫情是前所未有的，给全球带来了巨大的人员痛苦、死亡和经济破坏。最近，已经报道了具有抗体逃逸能力的 SARS-CoV-2 亚变体 BQ 和 XBB。因此，继续开发具有泛冠状病毒抑制作用的新型药物对于治疗和预防 COVID-19 感染以及可能出现的任何新的大流行至关重要。我们报告了几种高活性小分子抑制剂的发现。其中，NBCoV63 在基于假病毒的测定中对 SARS-CoV-2（IC：55 nM）、SARS-CoV-1（IC：59 nM）和 MERS-CoV（IC：75 nM）具有低纳摩尔效力，具有出色的选择性指数（SI>900），表明其具有泛冠状病毒抑制作用。NBCoV63 对 SARS-CoV-2 突变体（D614G）和几种关注变体（VOC）如 B.1.617.2（Delta）、B.1.1.529/BA.1 和 BA.4/BA.5（Omicron）以及 K417T/E484K/N501Y（Gamma）同样具有有效的抗病毒效力。NBCoV63 对真实的 SARS-CoV-2（香港株）及其两种变体（Delta 和 Omicron）、SARS-CoV-1 和 MERS-CoV 的疗效与 Remdesivir 相似，通过 Calu-3 细胞中的蚀斑减少法测定。此外，我们表明 NBCoV63 以剂量依赖性方式抑制病毒介导的细胞间融合。此外，NBCoV63 的吸收、分布、代谢和排泄（ADME）数据表明其具有类药性。
