The antiviral activity of a small molecule drug targeting the NSP1-ribosome complex against Omicron, especially in elderly patients

Abstract

IntroductionWith the emergence of SARS-CoV-2 mutant strains, especially the epidemic of Omicron, it continues to evolve to strengthen immune evasion. Omicron BQ. 1 and XBB pose a serious threat to the current COVID-19 vaccine (including bivalent mRNA vaccine for mutant strains) and COVID-19-positive survivors, and all current therapeutic monoclonal antibodies are ineffective against them. Older people, those with multimorbidity, and those with specific underlying health conditions remain at increased risk of COVID-19 hospitalization and death after the initial vaccine booster. However, small-molecule drugs for conserved targets remain effective and urgently needed.MethodsThe non-structural protein of SARS-CoV-2 non-structural protein 1(Nsp1) can bind to the host 40S ribosomal subunit and activate the nuclease to hydrolyze the host RNA, while the viral RNA is unaffected, thus hijacking the host system. First, the present study analyzed mutations in the Nsp1 protein and then constructed a maximum-likelihood phylogenetic tree. A virtual drug screening method based on the Nsp1 structure (Protein Data Bank ID: 7K5I) was constructed, 7495 compounds from three databases were collected for molecular docking and virtual screening, and the binding free energy was calculated by the MM/GBSA method.ResultsOur study shows that Nsp1 is relatively conserved and can be used as a comparatively fixed drug target and that therapies against Nsp1 will target all of these variants. Golvatinib, Gliquidone, and Dihydroergotamine were superior to other compounds in the crystal structure of binding conformation and free energy. All effectively interfered with Nsp1 binding to 40S protein, confirming the potential inhibitory effect of these three compounds on SARS-CoV-2.DiscussionIn particular, Golwatinib provides a candidate for treatment and prophylaxis in elderly patients with Omicjon, suggesting further evaluation of the anti-SARS-CoV-2 activity of these compounds in cell culture. Further studies are needed to determine the utility of this finding through prospective clinical trials and identify other meaningful drug combinations.

Antiviral responses versus virus-induced cellular shutoff: a game of thrones between influenza A virus NS1 and SARS-CoV-2 Nsp1

“…A bioinformatics drug screening based on SARS-CoV-2 Nsp1 structure was performed and around 7,500 compounds from three databases were collected for molecular docking and in silico evaluation ( Shen et al., 2023 ). The data suggested that golvatinib, gliquidone, and dihydroergotamine were superior to other compounds in binding conformation and free energy ( Shen et al., 2023 ). These drugs could interfere with SARS-CoV-2 Nsp1 binding to 40S protein, resulting in inhibition of SARS-CoV-2 infection ( Shen et al., 2023 ).…”

“…The data suggested that golvatinib, gliquidone, and dihydroergotamine were superior to other compounds in binding conformation and free energy ( Shen et al., 2023 ). These drugs could interfere with SARS-CoV-2 Nsp1 binding to 40S protein, resulting in inhibition of SARS-CoV-2 infection ( Shen et al., 2023 ). However, studies to confirm the antiviral properties of these potential antiviral compounds against SARS-CoV-2 were not conducted in this study ( Shen et al., 2023 ).…”

“…These drugs could interfere with SARS-CoV-2 Nsp1 binding to 40S protein, resulting in inhibition of SARS-CoV-2 infection ( Shen et al., 2023 ). However, studies to confirm the antiviral properties of these potential antiviral compounds against SARS-CoV-2 were not conducted in this study ( Shen et al., 2023 ).…”

The brief overview, antivirus and anti-SARS-CoV-2 activity, quantitative methods, and pharmacokinetics of cepharanthine: a potential small-molecule drug against COVID-19

“…CEP was an inexpensive and well-established medication in Japan, authorized for more than 70 years. As early as 30 years ago, CEP was applied in the empirical treatment of pneumoconiosis in China, with good results ( Shen et al, 2023 ). Presently, no fewer than four pharmaceutical enterprises in China have been approved to manufacture and distribute CEP for the prevention and treatment of cancer patients with leukopenia endangered by radiotherapy and chemotherapy.…”

Broad-Spectrum Antivirals Derived from Natural Products

“…It has been reported that amontelukast sodium hydrate may be the potential inhibitor for SARS-CoV-2 Nsp1 [ 100 ]. Additionally, the researchers found that Golvatinib, Gliquidone, and Dihydroergotamine bind to Nsp1 and have a potential inhibitory effect against SARS-CoV-2 [ 101 ].…”