Cardiac and renal diseases(CRDs) are characterized by extensive remodeling of the extracellular matrix(ECM)architecture of the cardiorenal system. Among the many extracellular proteolytic enzymes present in cardiorena...Cardiac and renal diseases(CRDs) are characterized by extensive remodeling of the extracellular matrix(ECM)architecture of the cardiorenal system. Among the many extracellular proteolytic enzymes present in cardiorenal cells and involved in ECM remodeling, members of the matrix metalloproteinase family and serine protease family have received the most attention. However, recent findings from laboratory and clinical studies have indicated that cysteine protease cathepsins also participate in pathogenesis of the heart and kidney.Deficiency and pharmacological inhibition of cathepsins have allowed their in vivo evaluation in the setting of pathological conditions. Furthermore, recent studiesevaluating the feasibility of cathepsins as a diagnostic tool have suggested that the serum levels of cathepsins L, S and K and their endogenous inhibitor cystatin C have predictive value as biomarkers in patients with coronary artery disease and heart and renal failure. The goal of this review is to highlight recent discoveries regarding the contributions of cathepsins in CRDs, particularly hypertensive heart failure and proteinuric kidney disease.展开更多
There are evidences indicating that cysteine proteases play an essential role in malaria parasites;therefore, an obvious area of investigation is the inhibition of these enzymes to treat malaria. Small cysteine protea...There are evidences indicating that cysteine proteases play an essential role in malaria parasites;therefore, an obvious area of investigation is the inhibition of these enzymes to treat malaria. Small cysteine protease inhibitors of malaria are well studied, but macromolecular nature of inhibitor is a new field to explore. In malarial cysteine proteases, there are macromolecular endogenous inhibitors playing important roles in regulation of the cysteine protease activity of parasite and host. Recent studies suggested that there are known and characterized endogenous inhibitors like falstatin present in P. falciparum, PbICP (inhibitor of cysteine protease in P. berghei), PyICP (inhibitor of cysteine protease in P. yoelli), and other macromolecular inhibitors which are the prodomain of enzyme itself regulating the activity of the mature enzyme. All the known macromolecular endogenous inhibitors are using specific loop-like structure to interact with malarial cysteine proteases. The majority of macromolecular inhibitors are competitive in nature, and block access to the active site of their target protease, but do not bind in a strictly substrate-like manner. They rather interact with the protease subsites and catalytic residues in a non-catalytically competent manner. In future, designing inhibitors based on these protein-protein interactions will be a new approach in the field of malaria. Since macromolecular inhibitors can gain potency through the burial of a large surface area and specificity through contacts with secondary binding sites critical for inhibition, and could be less prone to drug resistant mutation.展开更多
Aim Cysteine proteases are closely associated with many human and non-human pathological processes and are potential targets for metal ions especially Hg^2＋ and the related species. In the present work, on the basis ...Aim Cysteine proteases are closely associated with many human and non-human pathological processes and are potential targets for metal ions especially Hg^2＋ and the related species. In the present work, on the basis of to the general study on the effects of some metal ions on the activity of papain, a well-known representative of cysteine protease family, the inhibitory effects of Hg^2＋ and polysulfide complexes were studied. Results All the metal ions tested （Hg^2＋, Cu^2＋, Ag^＋, Au^3＋, Zn^2＋, Cd^2＋, Fe^3＋, Mn^2＋, Pb^2＋, Yb^3＋） inhibit the activity of papain anda good correlation between the inhibitory potency and softness-and-hardness was observed. Among the metals, Hg^2＋ was shown to be a potent inhibitor of papain with a Kiof 2 × 10^-7 mol·L^-1 among. Excessive amounts of glutathione and cysteine could reactivate the enzyme activity of papain deactivated by Hg^2＋. These evidences supported that Hg^2＋ might bind to the catalytic site of papain. Interestingly, Hg （Ⅱ） polysulfide complexes were for the first time found to inhibit papain with a Ki of 7 × 10^-6 mol·L^-1, whose potency is close to a well known mercury compound, thimerosal （Ki=2.7 × 10^-6）. In addition, Hg （Ⅱ） polysulfide complexes exhibit good permeability （ 1.9 × 10-5 cm· s^-1） to caco-2 monolayer. Conclusion These results suggested that mercury polysulfide complexes might be potential bioactive species in the interaction with cysteine proteases and other- SH-content proteins, providing a new clue to understand the mechanism of the toxicological and pharmacological actions of cinnabar and other insoluble mercury compounds.展开更多
A series of N1-substituted-3-aryl-4-alkyl-4, 5-dihydro-1H-1-pyrazolethiocarboxamide were prepared from the Mannich bases of aryl ketones in good yields. Some derivatives were found to be active against the cysteine p...A series of N1-substituted-3-aryl-4-alkyl-4, 5-dihydro-1H-1-pyrazolethiocarboxamide were prepared from the Mannich bases of aryl ketones in good yields. Some derivatives were found to be active against the cysteine protease of T.cruzi..展开更多
The oral pathogen Porphyromonas gingivalis is recognized as one of the major aetiological agents of chronic periodontitis. The gingipains, which are the principal virulence factors of P. gingivalis, are multi-domain p...The oral pathogen Porphyromonas gingivalis is recognized as one of the major aetiological agents of chronic periodontitis. The gingipains, which are the principal virulence factors of P. gingivalis, are multi-domain proteins containing an N-terminal C25 cysteine protease domain. We have conducted a bio-informatics study of the C25 cysteine protease domains and have identified related domains in over two thousand proteins from 739 organisms in 35 distinct phyla. Proteins having significant similarity to the gingipain C25 cysteine protease domain are also found in Gram +ve bacteria, Archaea, algae, higher fungi, and a wide variety of Eukaryotic species.展开更多
以鲢鱼卵为材料制备半胱氨酸蛋白酶抑制因子(CPIs)的粗提浓缩液,进而经Q Sepharose Fast Flow阴离子层析和Sephacryl S-200分子筛层析,获得部分纯化了的CPI-I。以偶氮酪蛋白(azocasein)法监测粗提液及层析纯化中CPIs的抑制活性。层析过...以鲢鱼卵为材料制备半胱氨酸蛋白酶抑制因子(CPIs)的粗提浓缩液,进而经Q Sepharose Fast Flow阴离子层析和Sephacryl S-200分子筛层析,获得部分纯化了的CPI-I。以偶氮酪蛋白(azocasein)法监测粗提液及层析纯化中CPIs的抑制活性。层析过程中,以灵敏度更高的荧光合成肽底物(Z-Phe-Arg-MCA)法监测洗脱物的CPIs抑制活性的热稳定性。最终鲢鱼卵CPI-I被纯化了72倍,酶回收率为10.25%。利用Sephacryl S-200分子筛层析Marker标准曲线以及反相酶谱法,初步判断CPI-I的分子质量为89kD。高碘酸-Schiff试剂(PAS)染色法证明该蛋白为糖蛋白。CPI-I能够抑制鲢鱼组织蛋白酶L,且具有显著的热稳定性。展开更多
Cysteine proteases continue to provide validated targets for treatment of human diseases.In neurodegenerative disorders,multiple cysteine proteases provide targets for enzyme inhibitors,notably caspases,calpains,and c...Cysteine proteases continue to provide validated targets for treatment of human diseases.In neurodegenerative disorders,multiple cysteine proteases provide targets for enzyme inhibitors,notably caspases,calpains,and cathepsins.The reactive,active-site cysteine provides specificity for many inhibitor designs over other families of proteases,such as aspartate and serine;however,a)inhibitor strategies often use covalent enzyme modification,and b)obtaining selectivity within families of cysteine proteases and their isozymes is problematic.This review provides a general update on strategies for cysteine protease inhibitor design and a focus on cathepsin B and calpain 1 as drug targets for neurodegenerative disorders;the latter focus providing an interesting query for the contemporary assumptions that irreversible,covalent protein modification and low selectivity are anathema to therapeutic safety and efficacy.展开更多
基金Supported by Grants from the Japan Heart Foundation/Novartis Research Award on Molecular and Cellular Cardiology,No.26-007523The Scientific Research Fund of the Chinese Ministry of Education,No.30960128
文摘Cardiac and renal diseases(CRDs) are characterized by extensive remodeling of the extracellular matrix(ECM)architecture of the cardiorenal system. Among the many extracellular proteolytic enzymes present in cardiorenal cells and involved in ECM remodeling, members of the matrix metalloproteinase family and serine protease family have received the most attention. However, recent findings from laboratory and clinical studies have indicated that cysteine protease cathepsins also participate in pathogenesis of the heart and kidney.Deficiency and pharmacological inhibition of cathepsins have allowed their in vivo evaluation in the setting of pathological conditions. Furthermore, recent studiesevaluating the feasibility of cathepsins as a diagnostic tool have suggested that the serum levels of cathepsins L, S and K and their endogenous inhibitor cystatin C have predictive value as biomarkers in patients with coronary artery disease and heart and renal failure. The goal of this review is to highlight recent discoveries regarding the contributions of cathepsins in CRDs, particularly hypertensive heart failure and proteinuric kidney disease.
文摘There are evidences indicating that cysteine proteases play an essential role in malaria parasites;therefore, an obvious area of investigation is the inhibition of these enzymes to treat malaria. Small cysteine protease inhibitors of malaria are well studied, but macromolecular nature of inhibitor is a new field to explore. In malarial cysteine proteases, there are macromolecular endogenous inhibitors playing important roles in regulation of the cysteine protease activity of parasite and host. Recent studies suggested that there are known and characterized endogenous inhibitors like falstatin present in P. falciparum, PbICP (inhibitor of cysteine protease in P. berghei), PyICP (inhibitor of cysteine protease in P. yoelli), and other macromolecular inhibitors which are the prodomain of enzyme itself regulating the activity of the mature enzyme. All the known macromolecular endogenous inhibitors are using specific loop-like structure to interact with malarial cysteine proteases. The majority of macromolecular inhibitors are competitive in nature, and block access to the active site of their target protease, but do not bind in a strictly substrate-like manner. They rather interact with the protease subsites and catalytic residues in a non-catalytically competent manner. In future, designing inhibitors based on these protein-protein interactions will be a new approach in the field of malaria. Since macromolecular inhibitors can gain potency through the burial of a large surface area and specificity through contacts with secondary binding sites critical for inhibition, and could be less prone to drug resistant mutation.
文摘Aim Cysteine proteases are closely associated with many human and non-human pathological processes and are potential targets for metal ions especially Hg^2＋ and the related species. In the present work, on the basis of to the general study on the effects of some metal ions on the activity of papain, a well-known representative of cysteine protease family, the inhibitory effects of Hg^2＋ and polysulfide complexes were studied. Results All the metal ions tested （Hg^2＋, Cu^2＋, Ag^＋, Au^3＋, Zn^2＋, Cd^2＋, Fe^3＋, Mn^2＋, Pb^2＋, Yb^3＋） inhibit the activity of papain anda good correlation between the inhibitory potency and softness-and-hardness was observed. Among the metals, Hg^2＋ was shown to be a potent inhibitor of papain with a Kiof 2 × 10^-7 mol·L^-1 among. Excessive amounts of glutathione and cysteine could reactivate the enzyme activity of papain deactivated by Hg^2＋. These evidences supported that Hg^2＋ might bind to the catalytic site of papain. Interestingly, Hg （Ⅱ） polysulfide complexes were for the first time found to inhibit papain with a Ki of 7 × 10^-6 mol·L^-1, whose potency is close to a well known mercury compound, thimerosal （Ki=2.7 × 10^-6）. In addition, Hg （Ⅱ） polysulfide complexes exhibit good permeability （ 1.9 × 10-5 cm· s^-1） to caco-2 monolayer. Conclusion These results suggested that mercury polysulfide complexes might be potential bioactive species in the interaction with cysteine proteases and other- SH-content proteins, providing a new clue to understand the mechanism of the toxicological and pharmacological actions of cinnabar and other insoluble mercury compounds.
文摘A series of N1-substituted-3-aryl-4-alkyl-4, 5-dihydro-1H-1-pyrazolethiocarboxamide were prepared from the Mannich bases of aryl ketones in good yields. Some derivatives were found to be active against the cysteine protease of T.cruzi..
文摘The oral pathogen Porphyromonas gingivalis is recognized as one of the major aetiological agents of chronic periodontitis. The gingipains, which are the principal virulence factors of P. gingivalis, are multi-domain proteins containing an N-terminal C25 cysteine protease domain. We have conducted a bio-informatics study of the C25 cysteine protease domains and have identified related domains in over two thousand proteins from 739 organisms in 35 distinct phyla. Proteins having significant similarity to the gingipain C25 cysteine protease domain are also found in Gram +ve bacteria, Archaea, algae, higher fungi, and a wide variety of Eukaryotic species.
文摘Cysteine proteases continue to provide validated targets for treatment of human diseases.In neurodegenerative disorders,multiple cysteine proteases provide targets for enzyme inhibitors,notably caspases,calpains,and cathepsins.The reactive,active-site cysteine provides specificity for many inhibitor designs over other families of proteases,such as aspartate and serine;however,a)inhibitor strategies often use covalent enzyme modification,and b)obtaining selectivity within families of cysteine proteases and their isozymes is problematic.This review provides a general update on strategies for cysteine protease inhibitor design and a focus on cathepsin B and calpain 1 as drug targets for neurodegenerative disorders;the latter focus providing an interesting query for the contemporary assumptions that irreversible,covalent protein modification and low selectivity are anathema to therapeutic safety and efficacy.
