Cap-dependent endonuclease(CEN)in the polymerase acidic protein(PA)of influenza A virus(IAV)represents a promising drug target due to its critical role in viral gene transcription.The CEN inhibitor,baloxavir marboxil(...Cap-dependent endonuclease(CEN)in the polymerase acidic protein(PA)of influenza A virus(IAV)represents a promising drug target due to its critical role in viral gene transcription.The CEN inhibitor,baloxavir marboxil(BXM),was approved in Japan and the US in 2018 and several other countries subsequently.Along with the clinical use of BXM,the emergence and spread of IAV variants with reduced susceptibility to BXM have aroused serious concern.Herein,we comprehensively characterized the in vitro and in vivo antiviral activities of ZX-7101A,an analogue of BXM.The active form of prodrug ZX-7101 showed broad-spectrum antiviral potency against various IAV subtypes,including pH1N1,H3N2,H7N9 and H9N2,in MDCK cells,and the 50%effective concentration(EC_(50))was calculated to nanomole level and comparable to that of baloxavir acid(BXA),the active form of BXM.Furthermore,in vivo assays showed that administration of ZX-7101A conferred significant protection against lethal pH1N1 challenge in mice,with reduced viral RNA loads and alleviated pulmonary damage.Importantly,serial passaging of H1N1 virus in MDCK cells under selection pressure of ZX-7101 led to a resistant variant at the 15th passage.Reverse genetic and sequencing analysis demonstrated that a single E18G substitution in the PA subunit contributed to the reduced susceptibility to both ZX-7101 and BXA.Taken together,our results not only characterized a new CEN inhibitor of IAV but also identified a novel amino acid substitution responsible for CEN inhibitor resistance,which provides critical clues for future drug development and drug resistance surveillance.展开更多
ADC189 is a novel drug of cap-dependent endonuclease inhibitor.In our study,its antiviral efficacy was evaluated in vitro and in vivo,and compared with baloxavir marboxil and oseltamivir.A first-in-human phase I study...ADC189 is a novel drug of cap-dependent endonuclease inhibitor.In our study,its antiviral efficacy was evaluated in vitro and in vivo,and compared with baloxavir marboxil and oseltamivir.A first-in-human phase I study in healthy volunteers included single ascending dose(SAD)and food effect(FE)parts.In the preclinical study,ADC189 showed potent antiviral activity against various types of influenza viruses,including H1N1,H3N2,influenza B virus,and highly pathogenic avian influenza,comparable to baloxavir marboxil.Additionally,ADC189 exhibited much better antiviral efficacy than oseltamivir in H1N1 infected mice.In the phase I study,ADC189 was rapidly metabolized to ADC189-I07,and its exposure increased proportionally with the dose.The terminal elimination half-life(T1/2)ranged from 76.69 to 98.28 hours.Of note,food had no effect on the concentration,clearance,and exposure of ADC189.It was well tolerated,with few treatment-emergent adverse events(TEAEs)reported and no serious adverse events(SAEs).ADC189 demonstrated excellent antiviral efficacy both in vitro and in vivo.It was safe,well-tolerated,and had favorable pharmacokinetic characteristics in healthy volunteers,supporting its potential for single oral dosing in clinical practice.展开更多
The process and regulation of cellular metabolism are extremely complex and accomplished through multiple signalling pathways that operate in parallel,and often experience significant overlap in upstream and downstrea...The process and regulation of cellular metabolism are extremely complex and accomplished through multiple signalling pathways that operate in parallel,and often experience significant overlap in upstream and downstream a signal transduction.Despite this complexity,single pathway or even single protein activations are commonly used to extrapolate broad characterizations of cellular metabolism.Furthermore,multiple routes for peptide-chain translation initiation exist,some of which may be either exclusive or overlapping depending on the state and environment of the cell.While it may be highly impractical to account for every aspect of metabolic regulation and permutation of mRNA translation,it is important to acknowledge that investigations relating to these pathways are often incomplete and not necessarily indicative of the overall metabolic status.This becomes urgent when considering the role that cellular anabolism plays in both healthy cellular functions and the aetiology of several disease's altered metabolisms.This review describes recent advances in the understanding of cellular metabolic regulation,with specific focus given to the complexity of‘downstream’mRNA translation initiation through both mTOR-dependent and mTOR-independent signallings.展开更多
基金supported by the National Science and Technology Major Project (2018ZX097110003-005-002)the Key-Area Research and Development Program of Guangdong Province (2022B1111020002)+3 种基金the National Natural Science Foundation of China (NSFC) (32170159,and 82174055)supported by the National Science Fund for Distinguished Young Scholars (81925025)the Innovative Research Group (81621005)of the NSFCthe Innovation Fund for Medical Sciences (2019-I2M-5-049)of the Chinese Academy of Medical Sciences.
文摘Cap-dependent endonuclease(CEN)in the polymerase acidic protein(PA)of influenza A virus(IAV)represents a promising drug target due to its critical role in viral gene transcription.The CEN inhibitor,baloxavir marboxil(BXM),was approved in Japan and the US in 2018 and several other countries subsequently.Along with the clinical use of BXM,the emergence and spread of IAV variants with reduced susceptibility to BXM have aroused serious concern.Herein,we comprehensively characterized the in vitro and in vivo antiviral activities of ZX-7101A,an analogue of BXM.The active form of prodrug ZX-7101 showed broad-spectrum antiviral potency against various IAV subtypes,including pH1N1,H3N2,H7N9 and H9N2,in MDCK cells,and the 50%effective concentration(EC_(50))was calculated to nanomole level and comparable to that of baloxavir acid(BXA),the active form of BXM.Furthermore,in vivo assays showed that administration of ZX-7101A conferred significant protection against lethal pH1N1 challenge in mice,with reduced viral RNA loads and alleviated pulmonary damage.Importantly,serial passaging of H1N1 virus in MDCK cells under selection pressure of ZX-7101 led to a resistant variant at the 15th passage.Reverse genetic and sequencing analysis demonstrated that a single E18G substitution in the PA subunit contributed to the reduced susceptibility to both ZX-7101 and BXA.Taken together,our results not only characterized a new CEN inhibitor of IAV but also identified a novel amino acid substitution responsible for CEN inhibitor resistance,which provides critical clues for future drug development and drug resistance surveillance.
基金sponsored by Jiaxing Andicon Biotech Co.,Ltd.Jiaxing Andicon Biotech Co.,Ltd.is responsible for the initiation,management,and funding of this study.
文摘ADC189 is a novel drug of cap-dependent endonuclease inhibitor.In our study,its antiviral efficacy was evaluated in vitro and in vivo,and compared with baloxavir marboxil and oseltamivir.A first-in-human phase I study in healthy volunteers included single ascending dose(SAD)and food effect(FE)parts.In the preclinical study,ADC189 showed potent antiviral activity against various types of influenza viruses,including H1N1,H3N2,influenza B virus,and highly pathogenic avian influenza,comparable to baloxavir marboxil.Additionally,ADC189 exhibited much better antiviral efficacy than oseltamivir in H1N1 infected mice.In the phase I study,ADC189 was rapidly metabolized to ADC189-I07,and its exposure increased proportionally with the dose.The terminal elimination half-life(T1/2)ranged from 76.69 to 98.28 hours.Of note,food had no effect on the concentration,clearance,and exposure of ADC189.It was well tolerated,with few treatment-emergent adverse events(TEAEs)reported and no serious adverse events(SAEs).ADC189 demonstrated excellent antiviral efficacy both in vitro and in vivo.It was safe,well-tolerated,and had favorable pharmacokinetic characteristics in healthy volunteers,supporting its potential for single oral dosing in clinical practice.
文摘The process and regulation of cellular metabolism are extremely complex and accomplished through multiple signalling pathways that operate in parallel,and often experience significant overlap in upstream and downstream a signal transduction.Despite this complexity,single pathway or even single protein activations are commonly used to extrapolate broad characterizations of cellular metabolism.Furthermore,multiple routes for peptide-chain translation initiation exist,some of which may be either exclusive or overlapping depending on the state and environment of the cell.While it may be highly impractical to account for every aspect of metabolic regulation and permutation of mRNA translation,it is important to acknowledge that investigations relating to these pathways are often incomplete and not necessarily indicative of the overall metabolic status.This becomes urgent when considering the role that cellular anabolism plays in both healthy cellular functions and the aetiology of several disease's altered metabolisms.This review describes recent advances in the understanding of cellular metabolic regulation,with specific focus given to the complexity of‘downstream’mRNA translation initiation through both mTOR-dependent and mTOR-independent signallings.
