The prevalence of positron emission tomography(PET)imaging has advanced biomedical applications for its ultrahigh sensitivity,deep tissue penetration and quantitative visualization of diseases in vivo.^(64)Cu with ide...The prevalence of positron emission tomography(PET)imaging has advanced biomedical applications for its ultrahigh sensitivity,deep tissue penetration and quantitative visualization of diseases in vivo.^(64)Cu with ideal half-life and decay characteristics has been designed as radioactive probes for disease diagnosis.The currently reported ^(64)Cu-labeled nanomaterials have the advantages of long circulation time in serum,good biocompatibility and mature preparation methods,and have been used in vivo PET imaging,biodistribution and pharmacokinetic monitoring,and imaging guided therapy.At the same time,suitable carrier characteristics and radiolabeling strategies are particularly important in the ^(64)Cu PET imaging process.In this review,we summarize different imaging probe designs and ^(64)Cu radiolabeling strategies,as well as their eventual applications in biomedicine.The potential challenges and prospects of ^(64)Cu labeled nanomaterials are also described,which provides broad prospects for radiolabeling strategies and further applications.展开更多
Thioredoxin reductase 1(TrxR1)is over activity in tumor cell to maintain their redox balance.Although gold clusters have great potential in antitumor drug as they could well inhibit TrxR1,the molecular mechanism has n...Thioredoxin reductase 1(TrxR1)is over activity in tumor cell to maintain their redox balance.Although gold clusters have great potential in antitumor drug as they could well inhibit TrxR1,the molecular mechanism has not been disclosed yet.In this work,we revealed gold clusters can well inhibit the activity of TrxR1 in lung tumor cells and further disclosed the inhibition mechanism by using computational simulation methods.We firstly inferred the binding sites of gold in the hydrophobic cavities on TrxR1.The simulation results show that the gold ion(released from Au cluster)interact with–SH of Cys189 in TrxR1,this greatly increase the distance between the C-terminal redox center of TrxR1 and the Trx redox center,thereby destroy the electron transfer pathway between them.Our electron transfer destroying mechanism is different from the previous hypothesis that gold binds to the Sec498 of TrxR1 which has never been proved by experimental and theory studies.This work provides a new understanding of the gold clusters to inhibit TrxR1 activity.展开更多
RNA viruses are critically dependent upon virally encoded proteases to cleave the viral polyproteins into functional proteins.Many of these proteases exhibit a similar fold and contain an essential catalytic cysteine,...RNA viruses are critically dependent upon virally encoded proteases to cleave the viral polyproteins into functional proteins.Many of these proteases exhibit a similar fold and contain an essential catalytic cysteine,offering the opportunity to inhibit these enzymes with electrophilic small molecules.Here we describe the successful application of quantitative irreversible tethering(qIT)to identify acrylamide fragments that target the active site cysteine of the 3C protease(3Cpro)of Enterovirus 71,the causative agent of hand,foot and mouth disease in humans,altering the substrate binding region.Further,we re-purpose these hits towards the main protease(Mpro)of SARS-CoV-2 which shares the 3C-like fold and a similar active site.The hit fragments covalently link to the catalytic cysteine of Mpro to inhibit its activity.We demonstrate that targeting the active site cysteine of Mpro can have profound allosteric effects,distorting secondary structures to disrupt the active dimeric unit.展开更多
基金supported by the National Natural Science Foundation of China(Nos.U2067214,21727817)Beijing municipal education commission-Beijing natural science foundation joint funding project(No.KZ202010005006)。
文摘The prevalence of positron emission tomography(PET)imaging has advanced biomedical applications for its ultrahigh sensitivity,deep tissue penetration and quantitative visualization of diseases in vivo.^(64)Cu with ideal half-life and decay characteristics has been designed as radioactive probes for disease diagnosis.The currently reported ^(64)Cu-labeled nanomaterials have the advantages of long circulation time in serum,good biocompatibility and mature preparation methods,and have been used in vivo PET imaging,biodistribution and pharmacokinetic monitoring,and imaging guided therapy.At the same time,suitable carrier characteristics and radiolabeling strategies are particularly important in the ^(64)Cu PET imaging process.In this review,we summarize different imaging probe designs and ^(64)Cu radiolabeling strategies,as well as their eventual applications in biomedicine.The potential challenges and prospects of ^(64)Cu labeled nanomaterials are also described,which provides broad prospects for radiolabeling strategies and further applications.
基金financially supported by the National Science Foundation of China(Nos.21727817,U2067214,11621505,31971311)the National Key Basic Research Program of China(No.2020YFA0710700)。
文摘Thioredoxin reductase 1(TrxR1)is over activity in tumor cell to maintain their redox balance.Although gold clusters have great potential in antitumor drug as they could well inhibit TrxR1,the molecular mechanism has not been disclosed yet.In this work,we revealed gold clusters can well inhibit the activity of TrxR1 in lung tumor cells and further disclosed the inhibition mechanism by using computational simulation methods.We firstly inferred the binding sites of gold in the hydrophobic cavities on TrxR1.The simulation results show that the gold ion(released from Au cluster)interact with–SH of Cys189 in TrxR1,this greatly increase the distance between the C-terminal redox center of TrxR1 and the Trx redox center,thereby destroy the electron transfer pathway between them.Our electron transfer destroying mechanism is different from the previous hypothesis that gold binds to the Sec498 of TrxR1 which has never been proved by experimental and theory studies.This work provides a new understanding of the gold clusters to inhibit TrxR1 activity.
基金supported by grants from Chinese Academy of Medical Sciences (CAMS) Innovation Fund for Medical Sciences (2021-I2M-1-037, China)National Key Research and Development Program of China (2016YFD0500300)+5 种基金the CRP-ICGEB Research Grant 2019 (CRP/CHN19-02, China)supported by grants from the Institute of Chemical Biology (Imperial College London, UK)the UK Engineering and Physical Sciences Research Council (Studentship award EP/F500416/1, UK)The Imperial College COVID19 Research FundThe crystallization facility at Imperial College was funded by BBSRC (BB/ D524840/1, UK)the Wellcome Trust (202926/Z/16/Z, UK)
文摘RNA viruses are critically dependent upon virally encoded proteases to cleave the viral polyproteins into functional proteins.Many of these proteases exhibit a similar fold and contain an essential catalytic cysteine,offering the opportunity to inhibit these enzymes with electrophilic small molecules.Here we describe the successful application of quantitative irreversible tethering(qIT)to identify acrylamide fragments that target the active site cysteine of the 3C protease(3Cpro)of Enterovirus 71,the causative agent of hand,foot and mouth disease in humans,altering the substrate binding region.Further,we re-purpose these hits towards the main protease(Mpro)of SARS-CoV-2 which shares the 3C-like fold and a similar active site.The hit fragments covalently link to the catalytic cysteine of Mpro to inhibit its activity.We demonstrate that targeting the active site cysteine of Mpro can have profound allosteric effects,distorting secondary structures to disrupt the active dimeric unit.
