Licorice-saponin A3 is a broad-spectrum inhibitor for COVID-19 by targeting viral spike and anti-inflammation / 药物分析学报

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 1.016 pM.The mechanism was related to binding with Y453 of RBD deter-mined by hydrogen-deuterium exchange mass spectrometry(HDX-MS)analysis combined with quan-tum 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)path-ways and rebalancing the corresponding immune dysregulation.This work supports A3 as a promising broad-spectrum small molecule drug candidate for COVID-19.

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

Antibody-based PD-1/PD-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-1/PD-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 information will benefit the design and improvement of therapeutic antibodies targeting PD-1 signaling.

Distribution and antibiotic resistance of Klebsiella pneumoniae strains in terms of K1 and K2 serotypes / 中国感染与化疗杂志

Objective To investigate the distribution and antibiotic resistance of the K lebsiella pneumoniae strains isolated from clinical infections in terms of serotypes K1 ,K2 and virulence factor rmpA gene .Methods The hypermucoviscous phenotype of K .pneumoniae isolate was determined by string test .K1 and K2 serotypes and rmpA gene were detected using multiplex polymerase chain reaction .Results Of the 144 strains of K .pneumoniae ,the prevalence of hypermucoviscous phenotype ,K1 , K2 serotypes and rmpA gene was 62 .5% (90/144) ,52 .1% (75/144) and 65 .3% (94/144) ,respectively .The prevalence of K1 ,K2 and rmpA K .pneumoniae strains was 90 .7% (68/75) in K1 ,K2 serotypes .The prevalence of K1 ,K2 isolates and rmpA in hypermucoviscous or non‐hypermucoviscous phenoype was 63 .3% (57/90) ,85 .6% (77/90) and 33 .3% (18/54) , 31 .5% (17/54) ,respectively .The prevalence of serotype K1 ,K2 with or without rmpA gene was 72 .3% (68/94) and 14 .0% (7/50 ) respectively . Of the 42 K . pneumoniae strains isolated from liver abscess ,85 .7% (36/42) were hypermucoviscous phenotype and 88 .1% (37/42 ) were serotypes K1 , K2 . For the strains from other abscess , bacteremia ,community acquried pneumonia (CAP) ,urinary tract infection (UTI) and biliary tract infection ,the prevalence of hypermucoviscous phenotype was 81 .3% (13/16) ,40 .5%(15/37) ,85 .7% (12/14) ,52 .4% (11/21) and 21 .4% (3/14) ,respectively ,and the prevalence of serotypes K1 ,K2 was 56 .3% (9/16) ,29 .7% (11/37) ,64 .3% (9/14) ,38 .1% (8/21) and 7 .1% (1/14) ,respectively .K1 serotype isolate accounted for 61 .9% of the strains from liver abscess .The ratio between serotype K1 and K2 was similar in the isolates from other abscess ,CAP ,UTI or bacteremia .Non‐K1 ,K2 serotype isolates were common in biliary tract infection .The prevalence of extended‐spectrum beta‐lactamases (ESBLs ) was 5 .5% in hypermucoviscous phenotypes and 33 .3% in the non‐hypermucoviscous phenotypes .Conclusions rmpA gene is associated with the hypermucoviscous phenotype of K .pneumoniae strains and commonly identified in K1 ,K2 serotype isolates .Serotypes K1 ,K2 isolates are important pathogens in liver abscess and CAP ,and also common in other abscess ,UTI and bacteremia .K1 serotype isolate was most common in liver abscess .The prevalence of K1 or K2 serotype was similar in other infections . The prevalence of ESBLs is lower in hypermucoviscous strains than in non‐hypermucoviscous strains and is associated with lower resistance rate to most of the antibiotics tested .