Currently,human health due to corona virus disease 2019(COVID-19)pandemic has been seriously threatened.The coronavirus severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)spike(S)protein plays a crucial role i...Currently,human health due to corona virus disease 2019(COVID-19)pandemic has been seriously threatened.The coronavirus severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)spike(S)protein plays a crucial role in virus transmission and several S-based therapeutic approaches have been approved for the treatment of COVID-19.However,the efficacy is compromised by the SARS-CoV-2 evolvement and mutation.Here we report the SARS-CoV-2 S protein receptor-binding domain(RBD)inhibitor licorice-saponin A3(A3)could widely inhibit RBD of SARS-CoV-2 variants,including Beta,Delta,and Omicron BA.1,XBB and BQ1.1.Furthermore,A3 could potently inhibit SARS-CoV-2 Omicron virus in Vero E6 cells,with EC50 of 1.016μM.The mechanism was related to binding with Y453 of RBD determined by hydrogen-deuterium exchange mass spectrometry(HDX-MS)analysis combined with quantum mechanics/molecular mechanics(QM/MM)simulations.Interestingly,phosphoproteomics analysis and multi fluorescent immunohistochemistry(mIHC)respectively indicated that A3 also inhibits host inflammation by directly modulating the JNK and p38 mitogen-activated protein kinase(MAPK)pathways and rebalancing the corresponding immune dysregulation.This work supports A3 as a promising broad-spectrum small molecule drug candidate for COVID-19.展开更多
Over the past decade, we have seen an alarming number of high-profile outbreaks of newly emerging and re-emerging viruses.Recent outbreaks of avian influenza viruses, Middle East respiratory syndrome coronaviruses, Zi...Over the past decade, we have seen an alarming number of high-profile outbreaks of newly emerging and re-emerging viruses.Recent outbreaks of avian influenza viruses, Middle East respiratory syndrome coronaviruses, Zika virus and Ebola virus present great threats to global health. Considering the pivotal role of host T-cell immunity in the alleviation of symptoms and the clearance of viruses in patients, there are three issues to be primarily concerned about T-cell immunity when a new virus emerges: first, does the population possess pre-existing T-cells against the new virus through previous infections of genetically relevant viruses; second, does a proper immune response arise in the patients to provide protection through an immunopathogenic effect; lastly, how long can the virus-specific immune memory persist. Herein, we summarize the current updates on the characteristics of human T-cell immunological responses against recently emerged or re-emerged viruses, and emphasize the necessity for timely investigation on the T-cell features of these viral diseases, which may provide beneficial recommendations for clinical diagnosis and vaccine development.展开更多
Antibody-based PD-IIPD-L1 blockade therapies have taken center stage in immunotherapies for cancer, with multiple clinical successes. PD-1 signaling plays pivotal roles in tumor-driven T-cell dysfunction. In contrast ...Antibody-based PD-IIPD-L1 blockade therapies have taken center stage in immunotherapies for cancer, with multiple clinical successes. PD-1 signaling plays pivotal roles in tumor-driven T-cell dysfunction. In contrast to prior approaches to generate or boost tumor-specific T-cell responses, antibody-based PD-1/PD-L1 blockade targets tumor-induced T-cell defects and restores pre- existing T-cell function to modulate antitumor immunity. in this review, the fundamental knowledge on the expression regulations and inhibitory functions of PD-1 and the present understanding of antibody-based PD-1/ PD-L1 blockade therapies are briefly summarized. We then focus on the recent breakthrough work concerning the structural basis of the PD-IIPD-Ls interaction and how therapeutic antibodies, pembrolizumab targeting PD-1 and avelumab targeting PD-L1, compete with the binding of PD-1/PD-L1 to interrupt the PD-1/PD-L1 interaction. We believe that this structural informationwill benefit the design and improvement of therapeutic antibodies targeting PD-1 signaling.展开更多
Since its first discovery,the Omicron variant of severe acute respiratory syndrome coronavirus 2(SARS‐CoV‐2)has evoked another wave of infection and caused global concern and panic.Moreover,although the data are sti...Since its first discovery,the Omicron variant of severe acute respiratory syndrome coronavirus 2(SARS‐CoV‐2)has evoked another wave of infection and caused global concern and panic.Moreover,although the data are still limited,Omicron showed highly concerning characteristics,including higher transmissibility,extensive immune escape and potentially altered host range.We interpreted these characteristics based on currently available data and outlined some urgent questions,calling for a more comprehensive investigation.展开更多
African swine fever virus(ASFV)is the causative agent of African swine fever,a highly fatal hemorrhagic disease of pigs,which has resulted in great economic losses to the global pork industry,especially in Asia.ASFV p...African swine fever virus(ASFV)is the causative agent of African swine fever,a highly fatal hemorrhagic disease of pigs,which has resulted in great economic losses to the global pork industry,especially in Asia.ASFV particles are comprised ofmultiple layers encompassing the genomic DNA.Though the capsid structure has been determined,very little is known about the structure of the core shell.The precursor polyprotein pp62 is the structural component of the core shell that gives rise to the p35 and p15 proteins.Herein,we describe the crystal structure of p15 at a resolution of 2.2Å.The structure of p15 exhibits as a trimeric conformation that is mainly mediated by intermolecular disulfide bonds and supported bymultiple hydrogen bond interactions.The button conformation on the surface of adjacentmolecules may also play a role in trimeric formation of the ASFV p15.The center of the p15 trimer exhibits opposite electrostatic characteristics on each side.These findings benefit our understanding of ASFV core shell assembly and will aid in the design of antiviral drugs and vaccines.展开更多
基金supported by National Natural Science Foundation of China(Grant Nos.:81891010/81891011,81725023,82003614,82173950,31770192,32070187,32161133003 and 82003681)China Postdoctoral Science Foundation(Grant No:2022T150029).
文摘Currently,human health due to corona virus disease 2019(COVID-19)pandemic has been seriously threatened.The coronavirus severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)spike(S)protein plays a crucial role in virus transmission and several S-based therapeutic approaches have been approved for the treatment of COVID-19.However,the efficacy is compromised by the SARS-CoV-2 evolvement and mutation.Here we report the SARS-CoV-2 S protein receptor-binding domain(RBD)inhibitor licorice-saponin A3(A3)could widely inhibit RBD of SARS-CoV-2 variants,including Beta,Delta,and Omicron BA.1,XBB and BQ1.1.Furthermore,A3 could potently inhibit SARS-CoV-2 Omicron virus in Vero E6 cells,with EC50 of 1.016μM.The mechanism was related to binding with Y453 of RBD determined by hydrogen-deuterium exchange mass spectrometry(HDX-MS)analysis combined with quantum mechanics/molecular mechanics(QM/MM)simulations.Interestingly,phosphoproteomics analysis and multi fluorescent immunohistochemistry(mIHC)respectively indicated that A3 also inhibits host inflammation by directly modulating the JNK and p38 mitogen-activated protein kinase(MAPK)pathways and rebalancing the corresponding immune dysregulation.This work supports A3 as a promising broad-spectrum small molecule drug candidate for COVID-19.
基金supported by the National Key Research and Development Program of China(2017YFC1200202)the China Mega-Project on Infectious Disease Prevention(2016ZX10004222-003)+1 种基金the National Natural Science Foundation of China(81401312,81373141)the National Natural Science Foundation of China Innovative Research Group(81621091)
文摘Over the past decade, we have seen an alarming number of high-profile outbreaks of newly emerging and re-emerging viruses.Recent outbreaks of avian influenza viruses, Middle East respiratory syndrome coronaviruses, Zika virus and Ebola virus present great threats to global health. Considering the pivotal role of host T-cell immunity in the alleviation of symptoms and the clearance of viruses in patients, there are three issues to be primarily concerned about T-cell immunity when a new virus emerges: first, does the population possess pre-existing T-cells against the new virus through previous infections of genetically relevant viruses; second, does a proper immune response arise in the patients to provide protection through an immunopathogenic effect; lastly, how long can the virus-specific immune memory persist. Herein, we summarize the current updates on the characteristics of human T-cell immunological responses against recently emerged or re-emerged viruses, and emphasize the necessity for timely investigation on the T-cell features of these viral diseases, which may provide beneficial recommendations for clinical diagnosis and vaccine development.
基金This work was supported by the National Basic Research Program (973 Program) (Nos. 2013CB531502 and 2014CB542503), the National Natural Science Foundation of China (Grant Nos. 31390432 and 31500722), Grand S&T project of China Health and Family Planning Commission (2013ZX10004608-002 and 2016ZX10004201-009), the Strategic Priority Research Program of the Chinese Academy of Sciences (CAS XDB08020100). GFG is supported partly as a leading principal investigator of the NSFC Innovative Research Group (81321063).
文摘Antibody-based PD-IIPD-L1 blockade therapies have taken center stage in immunotherapies for cancer, with multiple clinical successes. PD-1 signaling plays pivotal roles in tumor-driven T-cell dysfunction. In contrast to prior approaches to generate or boost tumor-specific T-cell responses, antibody-based PD-1/PD-L1 blockade targets tumor-induced T-cell defects and restores pre- existing T-cell function to modulate antitumor immunity. in this review, the fundamental knowledge on the expression regulations and inhibitory functions of PD-1 and the present understanding of antibody-based PD-1/ PD-L1 blockade therapies are briefly summarized. We then focus on the recent breakthrough work concerning the structural basis of the PD-IIPD-Ls interaction and how therapeutic antibodies, pembrolizumab targeting PD-1 and avelumab targeting PD-L1, compete with the binding of PD-1/PD-L1 to interrupt the PD-1/PD-L1 interaction. We believe that this structural informationwill benefit the design and improvement of therapeutic antibodies targeting PD-1 signaling.
基金supported by the National Key R&D Program of China(2021YFC0863300).
文摘Since its first discovery,the Omicron variant of severe acute respiratory syndrome coronavirus 2(SARS‐CoV‐2)has evoked another wave of infection and caused global concern and panic.Moreover,although the data are still limited,Omicron showed highly concerning characteristics,including higher transmissibility,extensive immune escape and potentially altered host range.We interpreted these characteristics based on currently available data and outlined some urgent questions,calling for a more comprehensive investigation.
基金supported by the Intramural Special Grants for African Swine Fever Research from the Chinese Academy of Sciences(CAS)(KJZD-SW-L06-01)China National Grand S&T Special Project(2018ZX10101004-001)the National Natural Science Foundation of China(31941010).
文摘African swine fever virus(ASFV)is the causative agent of African swine fever,a highly fatal hemorrhagic disease of pigs,which has resulted in great economic losses to the global pork industry,especially in Asia.ASFV particles are comprised ofmultiple layers encompassing the genomic DNA.Though the capsid structure has been determined,very little is known about the structure of the core shell.The precursor polyprotein pp62 is the structural component of the core shell that gives rise to the p35 and p15 proteins.Herein,we describe the crystal structure of p15 at a resolution of 2.2Å.The structure of p15 exhibits as a trimeric conformation that is mainly mediated by intermolecular disulfide bonds and supported bymultiple hydrogen bond interactions.The button conformation on the surface of adjacentmolecules may also play a role in trimeric formation of the ASFV p15.The center of the p15 trimer exhibits opposite electrostatic characteristics on each side.These findings benefit our understanding of ASFV core shell assembly and will aid in the design of antiviral drugs and vaccines.