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Design and development of an oral remdesivir derivative VV116 against SARS-CoV-2

2021; Springer Nature; Volume: 31; Issue: 11 Linguagem: Inglês

10.1038/s41422-021-00570-1

1748-7838

Yuanchao Xie, Wanchao Yin, Yumin Zhang, Weijuan Shang, Zhen Wang, Xiaodong Luan, Guanghui Tian, Haji Akber Aisa, Yechun Xu, Gengfu Xiao, Jia Li, Hualiang Jiang, Shuyang Zhang, Leike Zhang, H. Eric Xu, Jingshan Shen,

PARP inhibition in cancer therapy

Since the declaration of COVID-19 as a global pandemic on March 11, 2020, this pandemic has been circulating for 17 months throughout the world, leading to more than 200 million infections and nearly 4.4 million deaths as of August 15, 2021.The pathogen of COVID-19 is a novel coronavirus named SARS-CoV-2, which shares ~79% genome sequence identity with SARS-CoV. 1 At the early stage of the COVID-19 outbreak, SARS-CoV-2 caused great panic in the hardest-hit areas due to its high transmissibility and pathogenicity.To fight the COVID-19 crisis, drug repurposing was immediately pursued in order to find potential therapeutics.Until now, though some treatment options are available, there still lack effective antiviral agents.Vaccination is considered as the best way to control this global pandemic, but the emerging SARS-CoV-2 variants pose a great challenge to the protective efficacy of the existing vaccines.Hence, in the long run, finding an effective antiviral medication against the SARS-CoV-2 infection is a pressing need.Great efforts have been put into the development of novel drugs against SARS-CoV-2 infection.Currently, remdesivir (RDV) (Fig. 1a), an intravenously administered nucleotide prodrug, is the only approved anti-SARS-CoV-2 drug.However, it displays limited therapeutic efficacy especially for severe COVID-19 cases. 2 Nucleoside analogs are an important class of antivirals acting by interfering with the viral polymerases that are highly conserved in the active center.Besides RDV, two oral nucleoside analogs, molnupiravir (EIDD-2801) 3 and AT-527, 4 have entered phase II/III clinical studies.Herein, we reported the discovery of an oral anti-SARS-CoV-2 nucleoside candidate, VV116, which displays favorable drug-like properties, and is going to be evaluated in clinical study for treating COVID-19.At the onset of the COVID-19 outbreak, we conducted a fast in vitro screening for anti-SARS-CoV-2 activity of various nucleoside/ nucleotide analogs (listed in Supplementary information, Table S1) in Vero E6 cells.Most of these compounds are known antiviral agents that show inhibitory activities against one or several viruses.Among them, we discovered that only RDV and its parent nucleoside (GS-441524) could remarkably inhibit the replication of SARS-CoV-2 at 5.0 µM.Determination of their EC 50 values indicated that GS-441524 with an EC 50 of 0.59 µM was a stronger viral replication inhibitor than RDV in Vero E6 cells (Fig. 1b).RDV is a phosphoramidate prodrug of GS-441524, originally designed for enhancing the antiviral activity against hepatitis C virus. 5 This kind of prodrug exhibits liver-targeting property, and may not be suitable for application in nucleoside-based antiviral therapy for COVID-19 since lungs are the most affected organs.Therefore, we chose GS-441524 as the parent structure for modifications to achieve improved druggability against SARS-CoV-2. 6 previous study showed that substituents at the 7-position (purine numbering) of the pyrrolotriazine base had a great