Renal cell carcinoma （RCC）, accounting for 4% of all can- cers, is the second most common cancer in urology. The most common form of RCC is clear cell RCC （ccRCC）, with a ratio over 70%. Early-phase kidney disease...Renal cell carcinoma （RCC）, accounting for 4% of all can- cers, is the second most common cancer in urology. The most common form of RCC is clear cell RCC （ccRCC）, with a ratio over 70%. Early-phase kidney diseases usually show rare symptoms in clinic; unfortunately, most patients are di- agnosed with kidney cancer at the end stage, at which point the cancer is both resistant to chemotherapy and metastatic, thus leading to high mortality. Understanding cancer biology enables manipulation of disease targets by using small-mole- cule modulators, which eventually drive the development of novel therapeutic agents for ccRCC. In this insight, we would like to briefly outline several promising and revolutionizing targets and the target-based design of therapeutic agents for ccRCC.展开更多
Metallodrugs with fine-tuned coordination between metals and bioactive ligands can achieve cytotoxic effects in cancer therapy and have been considered as a new approach for drug design.However,it has yet to be elucid...Metallodrugs with fine-tuned coordination between metals and bioactive ligands can achieve cytotoxic effects in cancer therapy and have been considered as a new approach for drug design.However,it has yet to be elucidated whether these metallodrugs target epitranscriptomic proteins for gene expression regulation.This report describes a rhein-based Rh(l)-arene complex,Rh1,that exhibited promising antiproliferative ffects in several tumor cellines.Rh1 induced cell death through the autophagy,cell cycle arrest,and accumulation of intracllular reactive oxygen species(ROs),In addition,Rh1 upregulated the global N^(6)-methyladenosine(m^(6)A)levels in A549 cells in the fat mass-and obesity-associated protein(FTO)-dependent manner.Collectively,the metal-based FTO inhibitor Rh1 effectively suppressed tumor cell proliferation and modulated the abundance of cellular m^(6)A,highlighting the potential of metal-based agents to target and regulate epitranscriptomics for tumor suppression.展开更多
During infections,bacteria stimulate host cells to produce and release histamine,which is a key mediator of vital cellular processes in animals.However,the mechanisms underlying the bacterial cell’s ability to sense ...During infections,bacteria stimulate host cells to produce and release histamine,which is a key mediator of vital cellular processes in animals.However,the mechanisms underlying the bacterial cell’s ability to sense and respond to histamine are poorly understood.Herein,we show that HinK,a Lys R-type transcriptional regulator,is required to evoke responses to histamine in Pseudomonas aeruginosa,an important human pathogen.HinK directly binds to and activates the promoter of genes involved in histamine uptake and metabolism,iron acquisition,and Pseudomonas quinolone signal(PQS)biosynthesis.The transcriptional regulatory activity of HinK is induced when histamine is present,and it occurs when HinK binds with imidazole-4-acetic acid(Im AA),a histamine metabolite whose production in P.aeruginosa depends on the HinK-activated histamine uptake and utilization operon hin DAC-pa0222.Importantly,the inactivation of HinK inhibits diverse pathogenic phenotypes of P.aeruginosa.These results suggest that histamine acts as an interkingdom signal and provide insights into the mechanism used by pathogenic bacteria to exploit host regulatory signals to promote virulence.展开更多
Summary of main observation and conclusion To combat multidrug-resistant Gram-positive bacteria,new antimicrobials particularly those with novel mechanism of action are badly needed.Different with conventional antibio...Summary of main observation and conclusion To combat multidrug-resistant Gram-positive bacteria,new antimicrobials particularly those with novel mechanism of action are badly needed.Different with conventional antibiotics which are typical inhibitors,small-molecule activators of bacterial CIpP represent a new class of antibiotics.No ClpP activator has been developed for clinical trial.Herein,we conducted a screening on our library of benga-mide-like ring opened analogues and found that L472-2 possesses a low minimum inhibitory concentration(MIC)against S.aureus and shows no activity for ClpP activation in vitro,but it displayed reduced antibacterial activity against S.aureus with clpP deletion.In order to obtain bengamide analogues that activate ClpP in vitro as well as possess antibacterial activity,we perform further structural modifications starting from L472-2.Compound 37 re-mains the antimicrobial activity and activation of ClpP protein in vitro,which could be viewed as a new chemical scaffold for ClpP activators and worthy of further investigation.展开更多
The m^6A-RNA modification is a dynamic and reversible process,which has emerged as a new RNA code for the regulation of gene expression.The functional network of methyltransferases(writers),demethylases(erasers),and b...The m^6A-RNA modification is a dynamic and reversible process,which has emerged as a new RNA code for the regulation of gene expression.The functional network of methyltransferases(writers),demethylases(erasers),and binding proteins(readers)modulate the level of m^6A modification.Dysfunction of RNA methylation has been associated with various fundamental biological processes and human diseases.Herein,we briefly introduce an understanding-enabled manipulation on m^6A RNA modification with an emphasis on the use of small-molecule intervention.展开更多
In nature, bacteria must sense copper and tightly regulate gene expression to evade copper toxicity. Here,we identify a new copper-responsive two-component system named DsbRS in the important human pathogen Pseudomona...In nature, bacteria must sense copper and tightly regulate gene expression to evade copper toxicity. Here,we identify a new copper-responsive two-component system named DsbRS in the important human pathogen Pseudomonas aeruginosa;in this system, DsbS is a sensor histidine kinase, and DsbR, its cognate response regulator, directly induces the transcription of genes involved in protein disulfide bond formation(Dsb)(i.e., the dsbDEG operon and dsbB). In the absence of copper, DsbS acts as a phosphatase toward DsbR, thus blocking the transcription of Dsb genes. In the presence of copper, the metal ion directly binds to the sensor domain of DsbS, and the Cys82 residue plays a critical role in this process. The copperbinding behavior appears to inhibit the phosphatase activity of DsbS, leading to the activation of DsbR.The copper resistance of the dsbRS knock-out mutant is restored by the ectopic expression of the dsbDEG operon, which is a DsbRS major target. Strikingly, cognates of the dsbRS-dsbDEG pair are widely distributed across eubacteria. In addition, a DsbR-binding site, which contains the consensus sequence 5’-TTA-N8-TTAA-3’, is detected in the promoter region of dsbDEG homologs in these species. These findings suggest that the regulation of Dsb genes by DsbRS represents a novel mechanism by which bacterial cells cope with copper stress.展开更多
Resistance to conventional antibiotics has raised worldwide attention. Notably, Methicillin-resistant Staphylococcus aureus (MRSA) has become one of the most life-threatening health concerns. Although effective agains...Resistance to conventional antibiotics has raised worldwide attention. Notably, Methicillin-resistant Staphylococcus aureus (MRSA) has become one of the most life-threatening health concerns. Although effective against bacterial infections, conventional antibiotics have also showed a series of side effects such as gut microbiota imbalance.展开更多
Main observation and conclusion Methicillin-resistant Staphylococcus aureus(MRSA)has become a major threat on public health because of the increase of clinically isolated strains that exhibit resistance to many antibi...Main observation and conclusion Methicillin-resistant Staphylococcus aureus(MRSA)has become a major threat on public health because of the increase of clinically isolated strains that exhibit resistance to many antibiotics.Therefore,development of new antibiotics for the treatment of MRSA in-fection is a sustained challenge.We have previously identified a ring-opened bengamide analogue L472-2 that displays moderate ac-tivity against the growth of S.aureus.In our previous work,we started from L472-2 and identified a class of analogues containing al-kynyl groups which have the potential to activate SaCIpP activity but moderate antibacterial activity.Herein,we focused on the anti-bacterial activity of L472-2,and a novel series of ring-opened bengamide analogues were synthesized and their activities were evalu-ated against MRSA.By conducting a compact analysis of the structure-activity relationships(SAR)of these analogues,we found that an adamantane ethanol ester bengamide 2j showed excellent antibacterial activity towards six S.aureus strains,including MRSA,while it does not activate CIpP.Therefore,these bengamide analogues represent a new class of candidates that suppress MRSA via-bility..展开更多
The E3 ligase adaptor SPOP,overexpressed in the nucleus but frequently dislocated into the cytoplasm in all clear cell Renal Cell Carcinomas(ccRCC),serves as a regulatory hub to promote kidney cancer through the ubiqu...The E3 ligase adaptor SPOP,overexpressed in the nucleus but frequently dislocated into the cytoplasm in all clear cell Renal Cell Carcinomas(ccRCC),serves as a regulatory hub to promote kidney cancer through the ubiquitination and degradation of multiple downstream cancer proteins.Recently,our identification of a selective small-molecule inhibitor of the SPOP-phosphatase and tensin homolog(PTEN)interaction has demonstrated that the oncogenic SPOP-protein interaction would be a druggable target specific to ccRCC therapy.To our knowledge,this is the first time such a small-molecule inhibitor has been developed.Herein,we have identified a peptide binder for the SPOP-MATH domain that disrupts the oncogenic SPOP-protein interactions in kidney cancer cells.Computational design and biophysical characterization yielded peptide Pep38 that binds to the MATH domain of SPOP and competes on PTEN-binding to SPOP in vitro.The X-ray complex structure reveals that the peptide binder features the following combination:one,a mimic of the native peptide binder and two,an additionalβ-strand motif in sequence,which could contribute to increased binding affinity.In order to improve cellular permeability,we fused Pep38 with the delivery peptide TAT to prepare peptide TAT38,which inhibits the endogenous substrate binding to SPOP and suppresses the proliferation of the ccRCC cells.Our identification of the peptide inhibitors for SPOP-protein interactions provides further validation that the oncogenic SPOP-signaling pathway in ccRCC could be a druggable target specifically applicable to the therapy of kidney cancers.展开更多
文摘Renal cell carcinoma （RCC）, accounting for 4% of all can- cers, is the second most common cancer in urology. The most common form of RCC is clear cell RCC （ccRCC）, with a ratio over 70%. Early-phase kidney diseases usually show rare symptoms in clinic; unfortunately, most patients are di- agnosed with kidney cancer at the end stage, at which point the cancer is both resistant to chemotherapy and metastatic, thus leading to high mortality. Understanding cancer biology enables manipulation of disease targets by using small-mole- cule modulators, which eventually drive the development of novel therapeutic agents for ccRCC. In this insight, we would like to briefly outline several promising and revolutionizing targets and the target-based design of therapeutic agents for ccRCC.
基金We thank NSFC(Nos.22077066,21771109,21778033,21701195,21837006,21977052 and 21907101).
文摘Metallodrugs with fine-tuned coordination between metals and bioactive ligands can achieve cytotoxic effects in cancer therapy and have been considered as a new approach for drug design.However,it has yet to be elucidated whether these metallodrugs target epitranscriptomic proteins for gene expression regulation.This report describes a rhein-based Rh(l)-arene complex,Rh1,that exhibited promising antiproliferative ffects in several tumor cellines.Rh1 induced cell death through the autophagy,cell cycle arrest,and accumulation of intracllular reactive oxygen species(ROs),In addition,Rh1 upregulated the global N^(6)-methyladenosine(m^(6)A)levels in A549 cells in the fat mass-and obesity-associated protein(FTO)-dependent manner.Collectively,the metal-based FTO inhibitor Rh1 effectively suppressed tumor cell proliferation and modulated the abundance of cellular m^(6)A,highlighting the potential of metal-based agents to target and regulate epitranscriptomics for tumor suppression.
基金supported by the Ministry of Science and Technology(MOST)of China(2016YFA0501503 and 2019ZX09721001-004-003)the National Natural Science Foundation of China(31670136,31870127,and 81861138047)+1 种基金the Science and Technology Commission of Shanghai Municipality(19JC1416400)the State Key Laboratory of Drug Research(SIMM2003ZZ-03)。
文摘During infections,bacteria stimulate host cells to produce and release histamine,which is a key mediator of vital cellular processes in animals.However,the mechanisms underlying the bacterial cell’s ability to sense and respond to histamine are poorly understood.Herein,we show that HinK,a Lys R-type transcriptional regulator,is required to evoke responses to histamine in Pseudomonas aeruginosa,an important human pathogen.HinK directly binds to and activates the promoter of genes involved in histamine uptake and metabolism,iron acquisition,and Pseudomonas quinolone signal(PQS)biosynthesis.The transcriptional regulatory activity of HinK is induced when histamine is present,and it occurs when HinK binds with imidazole-4-acetic acid(Im AA),a histamine metabolite whose production in P.aeruginosa depends on the HinK-activated histamine uptake and utilization operon hin DAC-pa0222.Importantly,the inactivation of HinK inhibits diverse pathogenic phenotypes of P.aeruginosa.These results suggest that histamine acts as an interkingdom signal and provide insights into the mechanism used by pathogenic bacteria to exploit host regulatory signals to promote virulence.
基金We would like to thank Hanne Ingmer for providing the strains of 8325-4,ΔclpP and ΔcpP::clpP.This work was supported by Science and Technology Commission Shanghai Municipality(16ZR1407000 and 17XD1404400)the National Natural Sci-ence Foundation of China(81861138046).
文摘Summary of main observation and conclusion To combat multidrug-resistant Gram-positive bacteria,new antimicrobials particularly those with novel mechanism of action are badly needed.Different with conventional antibiotics which are typical inhibitors,small-molecule activators of bacterial CIpP represent a new class of antibiotics.No ClpP activator has been developed for clinical trial.Herein,we conducted a screening on our library of benga-mide-like ring opened analogues and found that L472-2 possesses a low minimum inhibitory concentration(MIC)against S.aureus and shows no activity for ClpP activation in vitro,but it displayed reduced antibacterial activity against S.aureus with clpP deletion.In order to obtain bengamide analogues that activate ClpP in vitro as well as possess antibacterial activity,we perform further structural modifications starting from L472-2.Compound 37 re-mains the antimicrobial activity and activation of ClpP protein in vitro,which could be viewed as a new chemical scaffold for ClpP activators and worthy of further investigation.
基金We are grateful for the support from the National Natural Science Foundation of China(No.21725801).
文摘The m^6A-RNA modification is a dynamic and reversible process,which has emerged as a new RNA code for the regulation of gene expression.The functional network of methyltransferases(writers),demethylases(erasers),and binding proteins(readers)modulate the level of m^6A modification.Dysfunction of RNA methylation has been associated with various fundamental biological processes and human diseases.Herein,we briefly introduce an understanding-enabled manipulation on m^6A RNA modification with an emphasis on the use of small-molecule intervention.
基金supported by the National Key R&D Program of China(2016YFA0501503)the National Mega-project for Innovative Drugs of China(2019ZX09721001-004-003)+2 种基金the National Natural Science Foundation of China(31670136 31870127 and 81861138047)the Science and Technology Commission of Shanghai Municipality(19JC1416400)the State Key Laboratory of Drug Research(SIMM2003ZZ-03).
文摘In nature, bacteria must sense copper and tightly regulate gene expression to evade copper toxicity. Here,we identify a new copper-responsive two-component system named DsbRS in the important human pathogen Pseudomonas aeruginosa;in this system, DsbS is a sensor histidine kinase, and DsbR, its cognate response regulator, directly induces the transcription of genes involved in protein disulfide bond formation(Dsb)(i.e., the dsbDEG operon and dsbB). In the absence of copper, DsbS acts as a phosphatase toward DsbR, thus blocking the transcription of Dsb genes. In the presence of copper, the metal ion directly binds to the sensor domain of DsbS, and the Cys82 residue plays a critical role in this process. The copperbinding behavior appears to inhibit the phosphatase activity of DsbS, leading to the activation of DsbR.The copper resistance of the dsbRS knock-out mutant is restored by the ectopic expression of the dsbDEG operon, which is a DsbRS major target. Strikingly, cognates of the dsbRS-dsbDEG pair are widely distributed across eubacteria. In addition, a DsbR-binding site, which contains the consensus sequence 5’-TTA-N8-TTAA-3’, is detected in the promoter region of dsbDEG homologs in these species. These findings suggest that the regulation of Dsb genes by DsbRS represents a novel mechanism by which bacterial cells cope with copper stress.
基金the National Natural Science Foundation of China (Nos. 81661138004 and 21725801)the Program of Shanghai Academic Research Leader.
文摘Resistance to conventional antibiotics has raised worldwide attention. Notably, Methicillin-resistant Staphylococcus aureus (MRSA) has become one of the most life-threatening health concerns. Although effective against bacterial infections, conventional antibiotics have also showed a series of side effects such as gut microbiota imbalance.
基金the Science and Technology Commission of Shanghai Municipality(No.16ZR1407000)the National Natural Science Foundation of China(Nos.81861138046 and 21725801).
文摘Main observation and conclusion Methicillin-resistant Staphylococcus aureus(MRSA)has become a major threat on public health because of the increase of clinically isolated strains that exhibit resistance to many antibiotics.Therefore,development of new antibiotics for the treatment of MRSA in-fection is a sustained challenge.We have previously identified a ring-opened bengamide analogue L472-2 that displays moderate ac-tivity against the growth of S.aureus.In our previous work,we started from L472-2 and identified a class of analogues containing al-kynyl groups which have the potential to activate SaCIpP activity but moderate antibacterial activity.Herein,we focused on the anti-bacterial activity of L472-2,and a novel series of ring-opened bengamide analogues were synthesized and their activities were evalu-ated against MRSA.By conducting a compact analysis of the structure-activity relationships(SAR)of these analogues,we found that an adamantane ethanol ester bengamide 2j showed excellent antibacterial activity towards six S.aureus strains,including MRSA,while it does not activate CIpP.Therefore,these bengamide analogues represent a new class of candidates that suppress MRSA via-bility..
基金This work was supported by the National Natural Science Foundation of China(No.21725801 to C.-G.Y,Nos.81625022 and 81430084 to C,L,and No.21807103 to 2.D.)the National Key New Urug Lreation and Manufacturing Program,Ministry of Science and Technology(No.20182X09711002 to Z.D.)+1 种基金the Science and Technology Commis-sion of Shanghal munltlpallty(NB.18YF1428500 to Y.H.alu Nu..18431907100 to H.J.Jthe China Postdoctoral Science Foun-dation(No.2018M640434 to Y.H.,No.2017M621570 to Z.D.,and Nu.2018M032187 lwT.L).
文摘The E3 ligase adaptor SPOP,overexpressed in the nucleus but frequently dislocated into the cytoplasm in all clear cell Renal Cell Carcinomas(ccRCC),serves as a regulatory hub to promote kidney cancer through the ubiquitination and degradation of multiple downstream cancer proteins.Recently,our identification of a selective small-molecule inhibitor of the SPOP-phosphatase and tensin homolog(PTEN)interaction has demonstrated that the oncogenic SPOP-protein interaction would be a druggable target specific to ccRCC therapy.To our knowledge,this is the first time such a small-molecule inhibitor has been developed.Herein,we have identified a peptide binder for the SPOP-MATH domain that disrupts the oncogenic SPOP-protein interactions in kidney cancer cells.Computational design and biophysical characterization yielded peptide Pep38 that binds to the MATH domain of SPOP and competes on PTEN-binding to SPOP in vitro.The X-ray complex structure reveals that the peptide binder features the following combination:one,a mimic of the native peptide binder and two,an additionalβ-strand motif in sequence,which could contribute to increased binding affinity.In order to improve cellular permeability,we fused Pep38 with the delivery peptide TAT to prepare peptide TAT38,which inhibits the endogenous substrate binding to SPOP and suppresses the proliferation of the ccRCC cells.Our identification of the peptide inhibitors for SPOP-protein interactions provides further validation that the oncogenic SPOP-signaling pathway in ccRCC could be a druggable target specifically applicable to the therapy of kidney cancers.
