目的评价原型株SARS-CoV-2灭活疫苗免疫BALB/c小鼠后对Delta株病毒的体液及细胞免疫效果,为现有疫苗对变异株的保护效果评价以及研发更加安全有效的疫苗提供参考。方法将SARS-CoV-2灭活疫苗经腹腔免疫雌性BALB/c小鼠2次,间隔14 d,以免疫...目的评价原型株SARS-CoV-2灭活疫苗免疫BALB/c小鼠后对Delta株病毒的体液及细胞免疫效果,为现有疫苗对变异株的保护效果评价以及研发更加安全有效的疫苗提供参考。方法将SARS-CoV-2灭活疫苗经腹腔免疫雌性BALB/c小鼠2次,间隔14 d,以免疫PBS作为对照,每组10只。初次免疫后第7、14、21、28、35和42天采集血清,间接ELISA法检测血清中针对Delta株病毒S和N蛋白的结合抗体效价,微量中和试验检测针对Delta株病毒的中和抗体效价。初次免疫后第42天,取小鼠脾脏,进行Elispot检测,评价细胞免疫水平。结果初次免疫后第7天即可检测到S蛋白结合抗体,加强免疫后抗体效价进一步升高,至第21天抗体几何平均滴度(geometric mean titer,GMT)为89144;而初次免疫后N蛋白结合抗体水平较低,加强免疫后迅速升高,与S蛋白抗体水平相当。初次免疫后第7、14天小鼠中和抗体阳转数为4/10和8/10,加强免疫后全部小鼠抗体阳转,中和抗体GMT达391。初次免疫后第42天,疫苗组IFNγ和IL-2平均斑点数均显著高于对照组(t分别为8.094和13.08,P均<0.0001)。结论SARS-CoV-2灭活疫苗2次免疫能够有效刺激小鼠产生针对Delta株病毒的体液免疫和细胞免疫。展开更多
Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)enters host cells via the angiotensin-converting enzyme 2(ACE2)receptor.Mounting evidence has indicated the presence of hepatic SARS-CoV-2 infection and liver...Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)enters host cells via the angiotensin-converting enzyme 2(ACE2)receptor.Mounting evidence has indicated the presence of hepatic SARS-CoV-2 infection and liver injury in pa-tients with coronavirus disease 2019(COVID-19).Understanding the mechanisms of hepatic SARS-CoV-2 infection is crucial for addressing COVID-19–related liver pathology and developing targeted therapies.This editorial discusses the signi-ficance of ACE2 in hepatic SARS-CoV-2 infection,drawing on the research by Jacobs et al.Their findings indicate that hepatic ACE2 expression,frequency of hepatic SARS-CoV-2 infection,and severity of liver injury are elevated in patients with pre-existing chronic liver diseases.These data suggest that hepatic ACE2 could be a promising therapeutic target for COVID-19.展开更多
Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)mutations are influenced by random and uncontrollable factors,and the risk of the next widespread epidemic remains.Dual-target drugs that synergistically act ...Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)mutations are influenced by random and uncontrollable factors,and the risk of the next widespread epidemic remains.Dual-target drugs that synergistically act on two targets exhibit strong therapeutic effects and advantages against mutations.In this study,a novel computational workflow was developed to design dual-target SARS-CoV-2 candidate inhibitors with the Envelope protein and Main protease selected as the two target proteins.The drug-like molecules of our self-constructed 3D scaffold database were used as high-throughput molecular docking probes for feature extraction of two target protein pockets.A multi-layer perceptron(MLP)was employed to embed the binding affinities into a latent space as conditional vectors to control conditional distribution.Utilizing a conditional generative neural network,cG-SchNet,with 3D Euclidean group(E3)symmetries,the conditional probability distributions of molecular 3D structures were acquired and a set of novel SARS-CoV-2 dual-target candidate inhibitors were generated.The 1D probability,2D joint probability,and 2D cumulative probability distribution results indicate that the generated sets are significantly enhanced compared to the training set in the high binding affinity area.Among the 201 generated molecules,42 molecules exhibited a sum binding affinity exceeding 17.0 kcal/mol while 9 of them having a sum binding affinity exceeding 19.0 kcal/mol,demonstrating structure diversity along with strong dual-target affinities,good absorption,distribution,metabolism,excretion,and toxicity(ADMET)properties,and ease of synthesis.Dual-target drugs are rare and difficult to find,and our“high-throughput docking-multi-conditional generation”workflow offers a wide range of options for designing or optimizing potent dual-target SARS-CoV-2 inhibitors.展开更多
文摘目的评价原型株SARS-CoV-2灭活疫苗免疫BALB/c小鼠后对Delta株病毒的体液及细胞免疫效果,为现有疫苗对变异株的保护效果评价以及研发更加安全有效的疫苗提供参考。方法将SARS-CoV-2灭活疫苗经腹腔免疫雌性BALB/c小鼠2次,间隔14 d,以免疫PBS作为对照,每组10只。初次免疫后第7、14、21、28、35和42天采集血清,间接ELISA法检测血清中针对Delta株病毒S和N蛋白的结合抗体效价,微量中和试验检测针对Delta株病毒的中和抗体效价。初次免疫后第42天,取小鼠脾脏,进行Elispot检测,评价细胞免疫水平。结果初次免疫后第7天即可检测到S蛋白结合抗体,加强免疫后抗体效价进一步升高,至第21天抗体几何平均滴度(geometric mean titer,GMT)为89144;而初次免疫后N蛋白结合抗体水平较低,加强免疫后迅速升高,与S蛋白抗体水平相当。初次免疫后第7、14天小鼠中和抗体阳转数为4/10和8/10,加强免疫后全部小鼠抗体阳转,中和抗体GMT达391。初次免疫后第42天,疫苗组IFNγ和IL-2平均斑点数均显著高于对照组(t分别为8.094和13.08,P均<0.0001)。结论SARS-CoV-2灭活疫苗2次免疫能够有效刺激小鼠产生针对Delta株病毒的体液免疫和细胞免疫。
基金Supported by National Natural Science Foundation of China,No.82172915,No.81972648,and No.81773011Chongqing Medical University Program for Youth Innovation in Future Medicine,No.W0084+1 种基金Science and Technology Innovation Project of Chongqing Medical Universityand Chongqing Postdoctoral Science Foundation,No.CSTB2023NSCQ-BHX0134.
文摘Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)enters host cells via the angiotensin-converting enzyme 2(ACE2)receptor.Mounting evidence has indicated the presence of hepatic SARS-CoV-2 infection and liver injury in pa-tients with coronavirus disease 2019(COVID-19).Understanding the mechanisms of hepatic SARS-CoV-2 infection is crucial for addressing COVID-19–related liver pathology and developing targeted therapies.This editorial discusses the signi-ficance of ACE2 in hepatic SARS-CoV-2 infection,drawing on the research by Jacobs et al.Their findings indicate that hepatic ACE2 expression,frequency of hepatic SARS-CoV-2 infection,and severity of liver injury are elevated in patients with pre-existing chronic liver diseases.These data suggest that hepatic ACE2 could be a promising therapeutic target for COVID-19.
基金supported by Interdisciplinary Innova-tion Project of“Bioarchaeology Laboratory”of Jilin University,China,and“MedicineþX”Interdisciplinary Innovation Team of Norman Bethune Health Science Center of Jilin University,China(Grant No.:2022JBGS05).
文摘Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)mutations are influenced by random and uncontrollable factors,and the risk of the next widespread epidemic remains.Dual-target drugs that synergistically act on two targets exhibit strong therapeutic effects and advantages against mutations.In this study,a novel computational workflow was developed to design dual-target SARS-CoV-2 candidate inhibitors with the Envelope protein and Main protease selected as the two target proteins.The drug-like molecules of our self-constructed 3D scaffold database were used as high-throughput molecular docking probes for feature extraction of two target protein pockets.A multi-layer perceptron(MLP)was employed to embed the binding affinities into a latent space as conditional vectors to control conditional distribution.Utilizing a conditional generative neural network,cG-SchNet,with 3D Euclidean group(E3)symmetries,the conditional probability distributions of molecular 3D structures were acquired and a set of novel SARS-CoV-2 dual-target candidate inhibitors were generated.The 1D probability,2D joint probability,and 2D cumulative probability distribution results indicate that the generated sets are significantly enhanced compared to the training set in the high binding affinity area.Among the 201 generated molecules,42 molecules exhibited a sum binding affinity exceeding 17.0 kcal/mol while 9 of them having a sum binding affinity exceeding 19.0 kcal/mol,demonstrating structure diversity along with strong dual-target affinities,good absorption,distribution,metabolism,excretion,and toxicity(ADMET)properties,and ease of synthesis.Dual-target drugs are rare and difficult to find,and our“high-throughput docking-multi-conditional generation”workflow offers a wide range of options for designing or optimizing potent dual-target SARS-CoV-2 inhibitors.
