Licorice-saponin A3 is a broad-spectrum inhibitor for COVID-19 by targeting viral spike and anti-inflammation

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.

The binding and structural basis of fox ACE2 to RBDs from different sarbecoviruses

Foxes are susceptible to SARS-CoV-2 in laboratory settings,and there have also been reports of natural infections of both SARS-CoV and SARS-CoV-2 in foxes.In this study,we assessed the binding capacities of fox ACE2 to important sarbecoviruses,including SARS-CoV,SARS-CoV-2,and animal-origin SARS-CoV-2 related viruses.Our findings demonstrated that fox ACE2 exhibits broad binding capabilities to receptor-binding domains(RBDs)of sarbecoviruses.We further determined the cryo-EM structures of fox ACE2 complexed with RBDs of SARS-CoV,SARS-CoV-2 prototype(PT),and Omicron BF.7.Through structural analysis,we identified that the K417 mutation can weaken the ability of SARS-CoV-2 sub-variants to bind to fox ACE2,thereby reducing the susceptibility of foxes to SARS-CoV-2 sub-variants.In addition,the Y498 residue in the SARS-CoV RBD plays a crucial role in forming a vital cation-πinteraction with K353 in the fox ACE2 receptor.This interaction is the primary determinant for the higher affinity of the SARS-CoV RBD compared to that of the SARS-CoV-2 PT RBD.These results indicate that foxes serve as potential hosts for numerous sarbecoviruses,highlighting the critical importance of surveillance efforts.

Human T-cell immunity against the emerging and re-emerging viruses

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.

Crystal clear： visualizing the intervention mechanism of the PD-1/PD-L1 interaction by two cancer therapeutic monoclonal antibodies

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.

Omicron variant of SARS-CoV-2 imposes a new challenge for the global public health

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.

Crystal structure of the African swine fever virus core shell protein p15

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.

Distinct PD-L1 binding characteristics of therapeutic monoclonal antibody durvalumab

Dear Editor,Blockade of PD-1/PD-L1 signaling pathway by monoclonal antibodies(MAbs)to release the anti-tumor activity of pre-existing tumor specific T cell immunity has initiated a new era for tumor immunotherapy.Administration of anti-PD-1 MAbs(nivolumab and pembrolizumab)in either monotherapy or in combination with anti-CTLA-4 MAbs or traditional chemother-apy has achieved a tumor regression rate of 30%-50%in dealing with melanoma,non-small cell lung cancer,etc.(Larkin et al.,2015).