Transferrin Receptor Protein 1 Cooperates with mGluR2 To Mediate the Internalization of Rabies Virus and SARS-CoV-2.

Identification of bona fide functional receptors and elucidation of the mechanism of receptor-mediated virus entry are important to reveal targets for developing therapeutics against rabies virus (RABV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Our previous studies suggest that metabotropic glutamate receptor subtype 2 (mGluR2) functions as an entry receptor for RABV in vitro, and is an important internalization factor for SARS-CoV-2 in vitro and in vivo. Here, we demonstrate that mGluR2 facilitates RABV internalization in vitro and infection in vivo. We found that transferrin receptor 1 (TfR1) interacts with mGluR2 and internalizes with mGluR2 and RABV in the same clathrin-coated pit. Knockdown of TfR1 blocks agonist-triggered internalization of mGluR2. Importantly, TfR1 also interacts with the SARS-CoV-2 spike protein and is important for SARS-CoV-2 internalization. Our findings identify a novel axis (mGluR2-TfR1 axis) used by RABV and SARS-CoV-2 for entry, and reveal TfR1 as a potential target for therapeutics against RABV and SARS-CoV-2. IMPORTANCE We previously found that metabotropic glutamate receptor subtype 2 (mGluR2) is an entry receptor for RABV in vitro, and an important internalization factor for SARS-CoV-2 in vitro and in vivo. However, whether mGluR2 is required for RABV infection in vivo was unknown. In addition, how mGluR2 mediates the internalization of RABV and SARS-CoV-2 needed to be resolved. Here, we found that mGluR2 gene knockout mice survived a lethal challenge with RABV. To our knowledge, mGluR2 is the first host factor to be definitively shown to play an important role in RABV street virus infection in vivo. We further found that transferrin receptor protein 1 (TfR1) directly interacts and cooperates with mGluR2 to regulate the endocytosis of RABV and SARS-CoV-2. Our study identifies a novel axis (mGluR2-TfR1 axis) used by RABV and SARS-CoV-2 for entry and opens a new door for the development of therapeutics against RABV and SARS-CoV-2.

Transferrin Receptor Protein 1 Is an Entry Factor for Rabies Virus.

Rabies virus (RABV) is a prototypical neurotropic virus that causes rabies in human and animals with an almost 100% mortality rate. Once RABV enters the central nervous system, no treatment is proven to prevent death. RABV glycoprotein (G) interacts with cell surface receptors and then enters cells via clathrin-mediated endocytosis (CME); however, the key host factors involved remain largely unknown. Here, we identified transferrin receptor 1 (TfR1), a classic receptor that undergoes CME, as an entry factor for RABV. TfR1 interacts with RABV G and is involved in the endocytosis of RABV. An antibody against TfR1 or the TfR1 ectodomain soluble protein significantly blocked RABV infection in HEK293 cells, N2a cells, and mouse primary neuronal cells. We further found that the endocytosis of TfR1 is coupled with the endocytosis of RABV and that TfR1 and RABV are transported to early and late endosomes. Our results suggest that RABV hijacks the transport pathway of TfR1 for entry, thereby deepening our understanding of the entry mechanism of RABV. IMPORTANCE For most viruses, cell entry involves engagement with many distinct plasma membrane components, each of which is essential. After binding to its specific receptor(s), rabies virus (RABV) enters host cells through the process of clathrin-mediated endocytosis. However, whether the receptor-dependent clathrin-mediated endocytosis of RABV requires other plasma membrane components remain largely unknown. Here, we demonstrate that transferrin receptor 1 (TfR1) is a functional entry factor for RABV infection. The endocytosis of RABV is coupled with the endocytosis of TfR1. Our results indicate that RABV hijacks the transport pathway of TfR1 for entry, which deepens our understanding of the entry mechanism of RABV.

Diltiazem inhibits SARS-CoV-2 cell attachment and internalization and decreases the viral infection in mouse lung.

The continuous emergence of severe acute respiratory coronavirus 2 (SARS-CoV-2) variants and the increasing number of breakthrough infection cases among vaccinated people support the urgent need for research and development of antiviral drugs. Viral entry is an intriguing target for antiviral drug development. We found that diltiazem, a blocker of the L-type calcium channel Cav1.2 pore-forming subunit (Cav1.2 α1c) and an FDA-approved drug, inhibits the binding and internalization of SARS-CoV-2, and decreases SARS-CoV-2 infection in cells and mouse lung. Cav1.2 α1c interacts with SARS-CoV-2 spike protein and ACE2, and affects the attachment and internalization of SARS-CoV-2. Our finding suggests that diltiazem has potential as a drug against SARS-CoV-2 infection and that Cav1.2 α1c is a promising target for antiviral drug development for COVID-19.

The ATPase ATP6V1A facilitates rabies virus replication by promoting virion uncoating and interacting with the viral matrix protein.

Rabies virus (RABV) matrix protein (M) plays crucial roles in viral transcription, replication, assembly, and budding; however, its function during the early stage of virus replication remains unknown. Here, we mapped the protein interactome between RABV M and human host factors using a proteomic approach, finding a link to the V-type proton ATPase catalytic subunit A (ATP6V1A), which is located in the endosomes where RABV first enters. By downregulating or upregulating ATP6V1A expression in HEK293T cells, we found that ATP6V1A facilitated RABV replication. We further found that ATP6V1A was involved in the dissociation of incoming viral M proteins during viral uncoating. Coimmunoprecipitation demonstrated that M interacted with the full length or middle domain of ATP6V1A, which was dependent on the lysine residue at position 256 and the glutamic acid residue at position 279. RABV growth and uncoating in ATP6V1A-depleted cells was restored by trans-complementation with the full length or interaction domain of ATP6V1A. Moreover, stably overexpressed ATP6V1A enhanced RABV growth in Vero cells, which are used for the production of rabies vaccine. Our findings identify a new partner for RABV M proteins and establish a new role of ATP6V1A by promoting virion uncoating during RABV replication.

How the Dark Triad associated with internet gaming disorder? The serial mediation of basic psychological needs satisfaction and negative coping styles.

According to the I-PACE model, this study focused on the role of need satisfaction and negative coping styles in the relationship between the Dark Triad (i.e., Machiavellianism, psychopathy, and narcissism) and internet gaming disorder (IGD). In a sample of 749 emerging adult gamers, a multiple mediation model with Dark Triad as the distal variable, psychological need satisfaction and negative coping style as mediating variables, and IGD as the outcome variable was tested. Results indicated that Machiavellianism and psychopathy were found to be significant predictors of IGD when mediated by psychological need satisfaction and negative coping styles. Narcissism predicts IGD only through the indirect effect of negative coping styles. The findings enhanced our understanding that Machiavellianism and psychopathy are characterized by compensatory use of internet games, as well as added new perspectives to the understanding of addiction mechanisms in narcissists.

Integrin ß1 Promotes Peripheral Entry by Rabies Virus.

Rabies virus (RABV) is a widespread pathogen that causes fatal disease in humans and animals. It has been suggested that multiple host factors are involved in RABV host entry. Here, we showed that RABV uses integrin ß1 (ITGB1) for cellular entry. RABV infection was drastically decreased after ITGB1 short interfering RNA knockdown and moderately increased after ITGB1 overexpression in cells. ITGB1 directly interacts with RABV glycoprotein. Upon infection, ITGB1 is internalized into cells and transported to late endosomes together with RABV. The infectivity of cell-adapted RABV in cells and street RABV in mice was neutralized by ITGB1 ectodomain soluble protein. The role of ITGB1 in RABV infection depends on interaction with fibronectin in cells and mice. We found that Arg-Gly-Asp (RGD) peptide and antibody to ITGB1 significantly blocked RABV infection in cells in vitro and street RABV infection in mice via intramuscular inoculation but not the intracerebral route. ITGB1 also interacts with nicotinic acetylcholine receptor, which is the proposed receptor for peripheral RABV infection. Our findings suggest that ITGB1 is a key cellular factor for RABV peripheral entry and is a potential therapeutic target for postexposure treatment against rabies.IMPORTANCE Rabies is a severe zoonotic disease caused by rabies virus (RABV). However, the nature of RABV entry remains unclear, which has hindered the development of therapy for rabies. It is suggested that modulations of RABV glycoprotein and multiple host factors are responsible for RABV invasion. Here, we showed that integrin ß1 (ITGB1) directly interacts with RABV glycoprotein, and both proteins are internalized together into host cells. Differential expression of ITGB1 in mature muscle and cerebral cortex of mice led to A-4 (ITGB1-specific antibody), and RGD peptide (competitive inhibitor for interaction between ITGB1 and fibronectin) blocked street RABV infection via intramuscular but not intracerebral inoculation in mice, suggesting that ITGB1 plays a role in RABV peripheral entry. Our study revealed this distinct cellular factor in RABV infection, which may be an attractive target for therapeutic intervention.

Transcriptome analysis of differentially expressed genes in chrysanthemum MET1 RNA interference lines.

DNA methylation is the most important epigenetic modification involved in many essential biological processes. MET1 is one of DNA methyltransferases that affect the level of methylation in the entire genome. To explore the effect of MET1 gene silencing on gene expression profile of Chrysanthemum × morifolium 'Zijingling'. The stem section and leaves at the young stage were taken for transcriptome sequencing. MET1-RNAi leaves had 8 differentially expressed genes while 156 differentially expressed genes were observed in MET1-RNAi stem compared with control leaves and stem. These genes encode many key proteins in plant biological processes, such as transcription factors, signal transduction mechanisms, secondary metabolite synthesis, transport and catabolism and interaction. In general, 34.58% of the differentially expressed genes in leaves and stems were affected by the reduction of the MET1 gene. The differentially expressed genes in stem and leaves of transgenic plants went through significant changes. We found adequate amount of candidate genes associated with flowering, however, the number of genes with significant differences between transgenic and control lines was not too high. Several flowering related genes were screened out for gene expression verification and all of them were obseved as consistent with transcriptome data. These candidate genes may play important role in flowering variation of chrysanthemum. This study reveals the mechanism of CmMET1 interference on the growth and development of chrysanthemum at the transcriptional level, which provides the basis for further research on the epigenetic regulation mechanism in flower induction and development. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12298-021-01022-1.

Metabotropic glutamate receptor subtype 2 is a cellular receptor for rabies virus.

Rabies virus (RABV) invades the central nervous system and nearly always causes fatal disease in humans. How RABV interacts with host neuron membrane receptors to become internalized and cause rabid symptoms is not yet fully understood. Here, we identified a novel receptor of RABV, which RABV uses to infect neurons. We found that metabotropic glutamate receptor subtype 2 (mGluR2), a member of the G protein-coupled receptor family that is abundant in the central nervous system, directly interacts with RABV glycoprotein to mediate virus entry. RABV infection was drastically decreased after mGluR2 siRNA knock-down in cells. Antibodies to mGluR2 blocked RABV infection in cells in vitro. Moreover, mGluR2 ectodomain soluble protein neutralized the infectivity of RABV cell-adapted strains and a street strain in cells (in vitro) and in mice (in vivo). We further found that RABV and mGluR2 are internalized into cells and transported to early and late endosomes together. These results suggest that mGluR2 is a functional cellular entry receptor for RABV. Our findings may open a door to explore and understand the neuropathogenesis of rabies.

A quantitative spectral component analysis method based on maximum likelihood.

In spectroscopy, the compositional analysis of the spectrum is important, such as extracting information about the species of spectral objects contributing to spectral data from an emission spectrum of photon energy. A quantitative spectral component analysis method based on Maximum Likelihood Estimation using Expectation Maximization (MLEM) is developed, which could quantitatively decompose out the components of the measured spectrum of low counts and surpass conventional techniques which belong to classification or regression. Abundant experimental and simulated spectra data on gamma-ray spectrum of radionuclides are presented to demonstrate and evaluate this method, while the ingredient radionuclides in the mixed spectrum are identified accurately with high precision. It will be a powerful and alternative method recommended for the circumstances needing fast and quantitative spectral analysis, including radionuclide identification (gamma-ray spectra), biomass or mineral composition (near-infrared spectra), laser-induced breakdown spectra and other spectroscopy scenarios.

A Well-Established POM-based Single-Crystal Proton-Conducting Model Incorporating Multiple Weak Interactions.

Three new proton conductors with simple structures based on isolated olyoxometalate anions as well as protonated imidazole and benzimidazole, namely, NNU-6-8, have been successfully prepared by hydrothermal reaction. We could control the number of proton sources by selecting different types and changing the charges of POM anions. The single crystal sample of NNU-6 along a-axis shows a highest proton conductivity of 1.91×10-2  S cm-1 , which is two and three orders of magnitude higher than that of 2.42×10-4 and 8.90×10-5  S cm-1 along b- and c-axes, respectively, due to the more unobstructed H-bonding network and stronger π-π stacking between benzimidazole rings as proton-transferring pathway along a-axis than that along b and c axes. It is a straightforward model to understand the metaphysical proton-conducting process, and this is the first time to put forward the idea that π-π stacking could assist proton transfer and be in favor of proton conduction, which has been demonstrated by calculating potential energy surfaces of proton transfer between benzimidazole molecules.

[Analysis of Samples from Wastewater Treatment Plant and Receiving Waters Using EEM Fluorescence Spectroscopy].

The samples from several treatment units in wastewater treatment plant (WWTP) and different sample sites of receiving waters were characterized using excitation-emission matrix (EEM) fluorescence spectroscopy. After analyzed by parallel factor analysis (PARAFAC) method, the EEM fluorescence spectra of the principal components and fluorescence intensity scores matrix were acquired. Results showed that protein-like and fulvic-like substances were the main components of the samples from the WWTP and the receiving water body. The intensity of protein-like fluorescence in the influent samples was rather strong, and those of the following samples decreased significantly. The protein-like fluorescence intensity of the samples was relatively weak from the upstream of receiving water body, while those of the samples increased significantly from the water body near the urban area. The protein-like fluorescence intensity of upstream samples of the WWTP disposal outlet was stronger than that of downstream in the receiving waters. The fluorescence intensity scores of protein-like substance could be correlated with the COD concentration of the samples and the correlation curves were established. The correlation coefficient of the WWTP samples was 0. 930 and that of receiving water body samples was 0.913. The protein-like fluorescence could be used to evaluate the organic pollution of the samples. This study will provide a new method to investigate the operation status of WWTP and corresponding effect on the receiving water body.

Numerical thermal assessment and theoretical analysis of horizontal-hole interlock composite insulation blocks.

In this paper, the thermal performance of 54 horizontal-hole interlocking composite insulation blocks was numerically analyzed based on the steady-state heat transfer model, the regulations were found, and prediction models for the thermal parameters of the blocks were established based on the parallel network thermal resistance model. The influence of block types and block materials on the thermal performance was studied, and it was found that the thermal performance of H-shaped interlocking insulation blocks was better than that of crossed-shaped ones, and the lower the thermal conductivity of block materials, the better the thermal performance of blocks, among which the reduction of thermal conductivity of concrete materials improved the thermal performance of blocks the most. The simulated values of thermal conductivity of H-shaped interlocking insulation blocks and thermal conductivity under the parallel network thermal resistance model were highly linearly correlated with correlation coefficients as high as 0.998 and 0.999. This finding enables the prediction models of thermal parameters of H-shaped interlocking insulation blocks to be established with high accuracy and provides an effective guide for the energy-saving design of interlocking insulation blocks wall.

Mobile phone addiction and academic burnout: the mediating role of technology conflict and the protective role of mindfulness.

With the rapid development of Internet technology, more and more college students are facing the threat of mobile phone addiction. However, the relationship and underlying mechanism between mobile phone addiction and academic burnout haven't been explored in depth. This study proves the mediating role of technology conflict and the moderating role of mindfulness in the relation between mobile phone addiction and academic burnout. 752 college students were recruited to complete the questionnaire of mobile phone addiction, technology conflict, mindfulness and academic burnout. Results showed that mobile phone addiction was significantly and positively associated with academic burnout, and this relationship could be mediated by technology conflict. Besides, the direct effect of mobile phone addiction on academic burnout and the indirect effect of technology conflict in this link were moderated by mindfulness. Both these two effects are stronger for college students with lower level of mindfulness. Our findings enrich our understanding of how and when mobile phone addiction was related to academic burnout. Educational professionals and parents should take timely measure to the academic burnout of college students suffering from mobile phone addiction, particularly for those with lower level of mindfulness.

Moderating Effects of Mindfulness in the Relation between Bullying Victimization and Sleep Disturbance in Chinese Children: Sex Differences.

Bullying victimization is associated with sleep disturbance. The present study aimed to investigate the impact of bullying victimization on sleep disturbance, and the moderating effect of mindfulness on this association, also exploring differences across sex. A sample of 420 Chinese children (Mage = 9.60, SD age = 1.11, 48.10% girls) in grade 3 to grade 6 were recruited to complete the revised Bully/Victim Questionnaire, the Chinese version of Pittsburg Sleep Quality Index, the Child and Adolescent Mindfulness Measure, as well as the Family Affluence Scale. Results showed that bullying victimization was positively associated with sleep disturbance (ß = 0.20, p < 0.001). And the effect of bullying victimization on sleep disturbance was moderated by mindfulness (ß = -0.16, p < 0.001), and the effect was invalid for children with high mindfulness (ß = 0.04, p > 0.05). Subgroup analyses indicated the buffering effect of mindfulness only existed among boys (ß = -0.19, p < 0.01) but not girls (ß = -0.11, p > 0.05), suggesting that mindfulness may buffer this association, mainly for boys.

Family cohesion and adaptability reduces mobile phone addiction: the mediating and moderating roles of automatic thoughts and peer attachment.

With the popularity of mobile Internet devices, the incidence of mobile phone addiction has been increasing, which has aroused the concern of all sectors of society. Due to the difficulty of eliminating the risk factors of mobile phone addiction, it's significant for researchers to examine the function and underlying mechanisms of positive environmental factors in reducing individuals' mobile phone addiction. Thus, the current study aimed to examine the relationship between family cohesion and adaptability and mobile phone addiction among university students and analyzed the mediating role of automatic thoughts as well as the moderating role of peer attachment in this link. The sample consisted of 958 Chinese university students. Participants completed self-report questionnaires assessing family cohesion and adaptability, mobile phone addiction, automatic thoughts, and peer attachment. PROCESS model 8 was significant (the total effect model (F (5, 952) = 19.64, R2 = 0.09, p < 0.001)). Results indicated that family cohesion and adaptability could not only negatively predict mobile phone addiction directly, but also indirectly through the mediating effect of automatic thoughts. Moreover, both the direct association between family cohesion and adaptability and mobile phone addiction as well as the indirect effect of automatic thoughts were moderated by peer attachment. Findings emphasized the beneficial role of peer attachment on the effect of family cohesion and adaptability on automatic thoughts and mobile phone addiction.

Post-crotonylation oxidation by a monooxygenase promotes acetyl-CoA synthetase degradation in Streptomyces roseosporus.

Protein post-translational modifications (PTMs) with various acyl groups play central roles in Streptomyces. But whether these acyl groups can be further modified, and the influences of these potential modifications on bacterial physiology have not been addressed. Here in Streptomyces roseosporus with rich crotonylation, a luciferase monooxygenase LimB is identified to elaborately regulate the crotonylation level, morphological development and antibiotic production by oxidation on the crotonyl groups of an acetyl-CoA synthetase Acs. This chemical modification on crotonylation leads to Acs degradation via the protease ClpP1/2 pathway and lowered intracellular crotonyl-CoA pool. Thus, we show that acyl groups after PTMs can be further modified, herein named post-PTM modification (PPM), and LimB is a PTM modifier to control the substrate protein turnover for cell development of Streptomyces. These findings expand our understanding of the complexity of chemical modifications on proteins for physiological regulation, and also suggest that PPM would be widespread.

Development of Highly Potent Noncovalent Inhibitors of SARS-CoV-2 3CLpro.

The 3C-like protease (3CLpro) is an essential enzyme for the replication of SARS-CoV-2 and other coronaviruses and thus is a target for coronavirus drug discovery. Nearly all inhibitors of coronavirus 3CLpro reported so far are covalent inhibitors. Here, we report the development of specific, noncovalent inhibitors of 3CLpro. The most potent one, WU-04, effectively blocks SARS-CoV-2 replications in human cells with EC50 values in the 10-nM range. WU-04 also inhibits the 3CLpro of SARS-CoV and MERS-CoV with high potency, indicating that it is a pan-inhibitor of coronavirus 3CLpro. WU-04 showed anti-SARS-CoV-2 activity similar to that of PF-07321332 (Nirmatrelvir) in K18-hACE2 mice when the same dose was administered orally. Thus, WU-04 is a promising drug candidate for coronavirus treatment.

Alpha-Soluble NSF Attachment Protein Prevents the Cleavage of the SARS-CoV-2 Spike Protein by Functioning as an Interferon-Upregulated Furin Inhibitor.

Loss of the furin cleavage motif in the SARS-CoV-2 spike protein reduces the virulence and transmission of SARS-CoV-2, suggesting that furin is an attractive antiviral drug target. However, lack of understanding of the regulation of furin activity has largely limited the development of furin-based therapeutic strategies. Here, we find that alpha-soluble NSF attachment protein (α-SNAP), an indispensable component of vesicle trafficking machinery, inhibits the cleavage of SARS-CoV-2 spike protein and other furin-dependent virus glycoproteins. SARS-CoV-2 infection increases the expression of α-SNAP, and overexpression of α-SNAP reduces SARS-CoV-2 infection in cells. We further reveal that α-SNAP is an interferon-upregulated furin inhibitor that inhibits furin function by interacting with its P domain. Our study demonstrates that α-SNAP, in addition to its role in vesicle trafficking, plays an important role in the host defense against furin-dependent virus infection and therefore could be a target for the development of therapeutic options for COVID-19. IMPORTANCE Some key mutations of SARS-CoV-2 spike protein, such as D614G and P681R mutations, increase the transmission or pathogenicity by enhancing the cleavage efficacy of spike protein by furin. Loss of the furin cleavage motif of SARS-CoV-2 spike protein reduces the virulence and transmission, suggesting that furin is an attractive antiviral drug target. However, lack of understanding of the regulation of furin activity has largely limited the development of furin-based therapeutic strategies. Here, we found that in addition to its canonical role in vesicle trafficking, alpha-soluble NSF attachment protein (α-SNAP) plays an important role in the host defense against furin-dependent virus infection. we identified that α-SNAP is a novel interferon-upregulated furin inhibitor and inhibits the cleavage of SARS-CoV-2 spike protein and other furin-dependent virus glycoproteins by interacting with P domain of furin. Our study demonstrates that α-SNAP could be a target for the development of therapeutic options for COVID-19.

A hybrid coded-aperture and Compton camera based on cerium-doped Gd3Al2Ga3O12 scintillators coupled with multi-pixel photon counter arrays.

In this study, we propose a hybrid coded-aperture and Compton camera based on cerium-doped Gd3Al2Ga3O12 (GAGG:Ce) scintillator arrays coupled with Multi-Pixel Photon Counter (MPPC) arrays. The sensitive detector of the gamma camera consists of a single GAGG:Ce crystal coupled with a single-chip MPPC unit module. An impedance bridge circuit and a 64-channel data acquisition system were employed to record the code-aperture events and Compton coincidence events. After the calibration of position and energy, the total energy resolution for 662 keV gamma-rays from 137Cs was 6.6%. The hybrid camera had the characteristics of mechanical collimation and electronic collimation at the same time. In the code aperture mode, the reconstructed images were obtained by direct deconvolution and maximum likelihood expectation maximization (MLEM) methods. In the Compton imaging mode, the energy-dependent method was applied to order the sequence of Compton scatter events. The simple back-projection algorithm and list-mode MLEM algorithm were adopted for image reconstruction. Practical performances demonstrated that the angular resolutions in two modes were measured as 5.2° and 11.4°, respectively. In addition, the hybrid camera had a desirable imaging capability in a wide energy range (32 keV-2.6 MeV) and a wide field of view (∼210° in the horizontal direction). As for the sensitivity, the camera had a commercially available sensitivity level of localizing a 137Cs point source, producing ∼0.026 µSv/h in 5 min. Furthermore, the function of distinction for different radiation sources was preliminarily realized.

Gossypol Broadly Inhibits Coronaviruses by Targeting RNA-Dependent RNA Polymerases.

Outbreaks of coronaviruses (CoVs), especially severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), have posed serious threats to humans and animals, which urgently calls for effective broad-spectrum antivirals. RNA-dependent RNA polymerase (RdRp) plays an essential role in viral RNA synthesis and is an ideal pan-coronaviral therapeutic target. Herein, based on cryo-electron microscopy and biochemical approaches, gossypol (GOS) is identified from 881 natural products to directly block SARS-CoV-2 RdRp, thus inhibiting SARS-CoV-2 replication in both cellular and mouse infection models. GOS also acts as a potent inhibitor against the SARS-CoV-2 variant of concern (VOC) and exerts same inhibitory effects toward mutated RdRps of VOCs as the RdRp of the original SARS-CoV-2. Moreover, that the RdRp inhibitor GOS has broad-spectrum anti-coronavirus activity against alphacoronaviruses (porcine epidemic diarrhea virus and swine acute diarrhea syndrome coronavirus), betacoronaviruses (SARS-CoV-2), gammacoronaviruses (avian infectious bronchitis virus), and deltacoronaviruses (porcine deltacoronavirus) is showed. The findings demonstrate that GOS may serve as a promising lead compound for combating the ongoing COVID-19 pandemic and other coronavirus outbreaks.