天然产物中α-糖苷酶抑制剂的发现与评价体系研究
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摘要
糖尿病是一类由胰岛素分泌功能受损引起的,以持续的高血糖为主要生化特征的代谢综合征。控制血糖水平是糖尿病治疗过程中的关键要素。一种重要的策略是通过抑制淀粉水解延缓小肠中的淀粉消化及葡萄糖吸收过程来实现。肠道内淀粉消化需要三种主要的α-糖苷酶参与,首先胰腺α-淀粉酶(HPA)将淀粉水解成短的直链或支链的寡糖,寡糖随后被麦芽糖-葡萄糖苷酶(MGAM)和蔗糖-异麦芽糖酶(SI)水解为葡萄糖。其中,MGAM拥有两个功能独立的催化亚基(MGAM-N和MGAM-C)。目前α-糖苷酶已经逐渐成为降糖药物研发的重要靶点之一。
天然产物是药物开发的重要资源之一,许多有价值的酶抑制剂都来源于天然产物,而从天然产物中筛选κ-糖苷酶抑制剂并进行药物开发已成为新药研发的热点。本研究利用已构建的包含411种传统中药的提取物库,分别针对HPA,MGAM-N和MGAM-C三种靶蛋白,进行α-糖苷酶抑制剂的筛选。发现23种中药提取物对MGAM-N有明显抑制效果；20种对MGAM-C有明显抑制作用；16种对HPA有明显抑制活性。筛选结果显示出一定的规律,对HPA有抑制作用的中药与对MGAM-N/C有抑制活性的中药有较为明显的差异。
进一步对1000株土壤放线菌的发酵产物进行筛选,获得20株α-糖苷酶抑制剂生产菌。应用柱前衍生化高效液相色谱法对ακ-糖苷酶抑制剂1-脱氧野尻霉素(DNJ)产生菌进行筛选。结果发现一株编号为PW409的DNJ产生菌。通过对PW409菌株进行多相分类学研究,将PW409菌株初步确定为戈壁三素链霉菌(Streptomyces gobitrici)。在此基础上开发了基于生物学活性的高效液相色谱串联四级杆飞行时间质谱(HPLC-Q/TOF)α-糖苷酶抑制剂筛选方法,对链霉菌PW409的发酵液进行活性物质的分离和鉴定,发现其发酵产物中除含有DNJ以外,还含有α-糖苷酶抑制剂类米格列醇(miglitol),其中DNJ在发酵液中的含量为11.2mg/L, miglitol的含量为95.8mg/L,为α-糖苷酶抑制剂的开发提供了新的菌种资源。
本研究发现天蓝黄链霉菌ZG656产生的混合型抑制剂AIB656具有极强的α-淀粉酶抑制活性,同时也对MGAM-N和MGAM-C有较强的抑制作用。本课题开发了基于多靶点的生物活性发现与评价方法对AIB656中的α-糖苷酶抑制剂进行系统的筛选及鉴定。利用UPLC-Q/TOF从AIB656中共鉴定出51种阿卡他定类化合物,并发现5个馏分对MGAM-N有明显的抑制活性；8个馏分对MGAM-C有显著的抑制活性；9个馏分对HPA有较强的抑制活性。生物活性筛选结合虚拟的分子对接筛选的研究结果显示：分子量较小的阿卡他定分子(2-4个类糖环)显示出较强的MGAM-N抑制活性。3-5个类糖环的分子对MGAM-C有较强的抑制活性；分子量较大的阿卡他定分子(6-15个类糖环)具有明显的HPA抑制活性。结果表明三种α-糖苷酶对不同分子大小的阿卡他定类抑制剂的选择性有较大的差异。通过分子对接计算及相互作用研究,推测阿卡他定I0-1分子是通过与氨基酸Asp327,Asp542, His600和Asp203形成氢键,而牢固地结合于MGAM-N的活性中心,并完全占据MGAM-N活性中心的两个D-葡萄糖结合位点(-1和+1位),阿卡他定10-1分子中N-键取代了MGAM-N正常底物中的O-连糖苷键导致其抑制活性的产生。阿卡他定I01完全占据MGAM-C活性中心的结合位点(-1,+1,+2和+3位),从结构生物学角度解释了I0-1是阿卡他定类分子中最强的MGAM-N的抑制剂和I01是阿卡他定类分子中最强的MGAM-C的抑制剂的分子机制。
而DNJ为代表的α-糖苷酶抑制剂的生物利用度研究表明,a-糖苷酶抑制剂在体内的吸收速度较快,DNJ的达峰时间为0.8h,绝对生物利用度达到55.02%。考虑到DNJ被快速吸收入血会减弱DNJ抑制小肠内α-糖苷酶的作用,本论文通过考察添加不同的药用辅料来改变DNJ在体内的吸收特性。结果发现：加入0.5%羧甲基纤维素钠(CMCNa)能够显著降低DNJ的最大血药浓度,降低DNJ在大鼠体内的血药曲线下面积,表明CMCNa能够抑制和延缓DNJ在肠道内的吸收。小鼠的口服葡萄糖耐量实验也证明了CMCNa能够增强DNJ的降糖效果。
本研究分别建立了液相、质谱、分子对接与酶学检测相结合的多种α-糖苷酶抑制剂的筛选策略,并针对MGAM-N, MGAM-C和HPA,对中药提取物以及放线菌次生代谢产物进行了的系统的筛选,结合结构生物学分析使我们明确了不同的α-糖苷酶对抑制剂分子的选择偏好存在明显的差异,而多个不同大小的α-糖苷酶抑制剂分子的联合使用会对糖尿病的治疗更加有效,这对α-糖苷酶抑制剂治疗糖尿病药物的研发有重要的指导意义。
Type2diabetes mellitus, is a metabolic syndrome that is characterized by continuous high level of glucose in the blood with defects in insulin secretion, insulin action or both. Controlling blood glucose levels is critical. One efficient strategy is to slow down the digestion process of ingested carbohydrates and starches and thus delay the glucose absorption by inhibiting the enzymes involved in the hydrolysis of dietary starches into glucose. Three a-glucosidases are involved in the complete digestion of dietary starches and sugars into glucose in intestine. The digestion is initiated by human pancreatic a-amylase (HPA) that hydrolyzing starch into shorter linear and branched dextrin chains. The resultant oligoglucans is eventually hydrolyzed at the nonreducing into glucose by two small-intestinal brush-border exohydrolases:maltase-glucoamylase (MGAM) and sucrase-isomaltase (SI). MGAM has two independent functional catalytic domains. Therefore, a-glucosidase is becoming one of the crucial targets for anti-diabetes drugs research and development.
Natural products have long proved to be valuable sources, and various enzyme inhibitors are derived from natural products. Screening a-glucosidase inhibitors for anti-diabetes drugs development from natural products has been a central topic in drug discovery. Firstly, a library of TCM extracts that including411kinds of TCM was constructed. A high-throughput screening (HTS) method was established for a-glucosidase inhibitors screening against MGAM-N, MGAM-C and HP A.23kinds of TCM extracts has significant MGAM-N inhibitory activity;20kinds of TCM showed notably inhibitory effect against MGAM-C;16kinds of TCM could inhibit the activity of HPA efficiently. Compared the TCM with a-glucosidase inhibitory activity, the TCM that has inhibitory activity against MGAM-N'and MGAM-C were different from the TCM with HPA inhibitory activity.
20strains with MGAM-C inhibitory activity were found in the process of the high throughput screening of actinomycetes broth against MGAM-C. Pre-column derivatization HPLC method was applied for screening1-deoxynojirimycin (DNJ) producing strains. DNJ was detected from the broth of strain PW409. Polyphasic taxonomy studies verified strain PW409belonged to Streptomyces gobitrici. Biological activity based HPLC-Q/TOF method was established for screening and identifying a-glucosidase inhibitors in the broth of strain PW409, DNJ and miglitol was identified as the active compounds. The quantification analysis indicated the content of DNJ and miglitol were11.2mg/L and95.8mg/L. The studies provided new strain resource for α-glucosidase development.
AIB656was extracted from the broth of Strain ZG656, which has extremely strong α-amylase inhibitory activity. The efficient MGAM-N and MGAM-C inhibitory activity were also comfirmed. Multi-targets based biological activity discovery and evaluation system was established for screening and identification of α-glucosidase inhibitors.51acarviostatins was identified in AIB656by UPLC-Q/TOF.5fractions had efficient MGAM-N inhibitory activity;8fractions showed strong MGAM-C inhibitory effect;9fractions demonstrated excellent HPA inhibitory activity. The biological practical screening and molecular docking results elucidated the smaller molecules showed remarkable MGAM-N inhibitory activity; Acarviostatin with3-5mimic sugar rings showed strong inhibitory ability against MGAM-C; The larger acarviostatins molecules (6-15mimic sugar rings) had significant HPA inhibitory activity. The results clarified the selectivities of the three different α-glucsosidase to various sizes inhibitors were quite distinct. Molecular docking and interaction study showed acarviostatin10-1firmly binded to the active site of MGAM-N by forming hydrogen bond with Asp327, Asp542, His600and Asp203. acarviostatin10-1occupied the binding site (subsite-1and+1) in the catalytic center of MGAM-N perfectly. Acarviostatin101spanned the binding site (subsite-1and+1,+2,+3) in the catalytic center of MGAM-C completely and formed stable binding state. The results clarified the mechanism in structure biology that acarviostatin10-1is the best MGAM-N inhibitors and acarviostatin101is the best MGAM-C inhibitors in acarviostatins.
The pharmacokinetics and bioavailability of a-glucosidase inhibitor were studied. The result indicated that the absorption rate of a-glucosidase inhibitor was very fast. The Cmax of DNJ was0.8h, and the absolute bioavailability of DNJ was55.02%. Considering quickly absorption of DNJ would decrease the inhibitory activity in intestine, adjuvants was selected for changing the absorption characteristics. The pharmacokinetics of DNJ indicated the Cmax and AUC of DNJ were significantly decreased by CMCNa. CMCNa could postpone the absorption rate of DNJ in intestine. The oral glucose test verified the pharmacodynamics of DNJ was improved by CMCNa.
The systematically a-glucosidase inhibitor discovery and screening approaches were established based the combination of HPLC-MS, molecular docking and enzyme evaluation. Comprehensive multi-targets including MGAM-N, MGAM-C and HPA based a-glucosidase inhibitor screening were proceeded against the extracts of TCM and secondary metabolites of actinomycetes. The reaults and structure biology studies clarified the distinct selectivities of the three a-glucosidases to various sizes inhibitors. The combination of different a-glucosidase inhibitors or composite intervention was probably more effective for diabetes treatment, which was of importance for the a-glucosidase inhibitors type anti-diabetes drugs research and development.
天然产物是药物开发的重要资源之一,许多有价值的酶抑制剂都来源于天然产物,而从天然产物中筛选κ-糖苷酶抑制剂并进行药物开发已成为新药研发的热点。本研究利用已构建的包含411种传统中药的提取物库,分别针对HPA,MGAM-N和MGAM-C三种靶蛋白,进行α-糖苷酶抑制剂的筛选。发现23种中药提取物对MGAM-N有明显抑制效果；20种对MGAM-C有明显抑制作用；16种对HPA有明显抑制活性。筛选结果显示出一定的规律,对HPA有抑制作用的中药与对MGAM-N/C有抑制活性的中药有较为明显的差异。
进一步对1000株土壤放线菌的发酵产物进行筛选,获得20株α-糖苷酶抑制剂生产菌。应用柱前衍生化高效液相色谱法对ακ-糖苷酶抑制剂1-脱氧野尻霉素(DNJ)产生菌进行筛选。结果发现一株编号为PW409的DNJ产生菌。通过对PW409菌株进行多相分类学研究,将PW409菌株初步确定为戈壁三素链霉菌(Streptomyces gobitrici)。在此基础上开发了基于生物学活性的高效液相色谱串联四级杆飞行时间质谱(HPLC-Q/TOF)α-糖苷酶抑制剂筛选方法,对链霉菌PW409的发酵液进行活性物质的分离和鉴定,发现其发酵产物中除含有DNJ以外,还含有α-糖苷酶抑制剂类米格列醇(miglitol),其中DNJ在发酵液中的含量为11.2mg/L, miglitol的含量为95.8mg/L,为α-糖苷酶抑制剂的开发提供了新的菌种资源。
本研究发现天蓝黄链霉菌ZG656产生的混合型抑制剂AIB656具有极强的α-淀粉酶抑制活性,同时也对MGAM-N和MGAM-C有较强的抑制作用。本课题开发了基于多靶点的生物活性发现与评价方法对AIB656中的α-糖苷酶抑制剂进行系统的筛选及鉴定。利用UPLC-Q/TOF从AIB656中共鉴定出51种阿卡他定类化合物,并发现5个馏分对MGAM-N有明显的抑制活性；8个馏分对MGAM-C有显著的抑制活性；9个馏分对HPA有较强的抑制活性。生物活性筛选结合虚拟的分子对接筛选的研究结果显示：分子量较小的阿卡他定分子(2-4个类糖环)显示出较强的MGAM-N抑制活性。3-5个类糖环的分子对MGAM-C有较强的抑制活性；分子量较大的阿卡他定分子(6-15个类糖环)具有明显的HPA抑制活性。结果表明三种α-糖苷酶对不同分子大小的阿卡他定类抑制剂的选择性有较大的差异。通过分子对接计算及相互作用研究,推测阿卡他定I0-1分子是通过与氨基酸Asp327,Asp542, His600和Asp203形成氢键,而牢固地结合于MGAM-N的活性中心,并完全占据MGAM-N活性中心的两个D-葡萄糖结合位点(-1和+1位),阿卡他定10-1分子中N-键取代了MGAM-N正常底物中的O-连糖苷键导致其抑制活性的产生。阿卡他定I01完全占据MGAM-C活性中心的结合位点(-1,+1,+2和+3位),从结构生物学角度解释了I0-1是阿卡他定类分子中最强的MGAM-N的抑制剂和I01是阿卡他定类分子中最强的MGAM-C的抑制剂的分子机制。
而DNJ为代表的α-糖苷酶抑制剂的生物利用度研究表明,a-糖苷酶抑制剂在体内的吸收速度较快,DNJ的达峰时间为0.8h,绝对生物利用度达到55.02%。考虑到DNJ被快速吸收入血会减弱DNJ抑制小肠内α-糖苷酶的作用,本论文通过考察添加不同的药用辅料来改变DNJ在体内的吸收特性。结果发现：加入0.5%羧甲基纤维素钠(CMCNa)能够显著降低DNJ的最大血药浓度,降低DNJ在大鼠体内的血药曲线下面积,表明CMCNa能够抑制和延缓DNJ在肠道内的吸收。小鼠的口服葡萄糖耐量实验也证明了CMCNa能够增强DNJ的降糖效果。
本研究分别建立了液相、质谱、分子对接与酶学检测相结合的多种α-糖苷酶抑制剂的筛选策略,并针对MGAM-N, MGAM-C和HPA,对中药提取物以及放线菌次生代谢产物进行了的系统的筛选,结合结构生物学分析使我们明确了不同的α-糖苷酶对抑制剂分子的选择偏好存在明显的差异,而多个不同大小的α-糖苷酶抑制剂分子的联合使用会对糖尿病的治疗更加有效,这对α-糖苷酶抑制剂治疗糖尿病药物的研发有重要的指导意义。
Type2diabetes mellitus, is a metabolic syndrome that is characterized by continuous high level of glucose in the blood with defects in insulin secretion, insulin action or both. Controlling blood glucose levels is critical. One efficient strategy is to slow down the digestion process of ingested carbohydrates and starches and thus delay the glucose absorption by inhibiting the enzymes involved in the hydrolysis of dietary starches into glucose. Three a-glucosidases are involved in the complete digestion of dietary starches and sugars into glucose in intestine. The digestion is initiated by human pancreatic a-amylase (HPA) that hydrolyzing starch into shorter linear and branched dextrin chains. The resultant oligoglucans is eventually hydrolyzed at the nonreducing into glucose by two small-intestinal brush-border exohydrolases:maltase-glucoamylase (MGAM) and sucrase-isomaltase (SI). MGAM has two independent functional catalytic domains. Therefore, a-glucosidase is becoming one of the crucial targets for anti-diabetes drugs research and development.
Natural products have long proved to be valuable sources, and various enzyme inhibitors are derived from natural products. Screening a-glucosidase inhibitors for anti-diabetes drugs development from natural products has been a central topic in drug discovery. Firstly, a library of TCM extracts that including411kinds of TCM was constructed. A high-throughput screening (HTS) method was established for a-glucosidase inhibitors screening against MGAM-N, MGAM-C and HP A.23kinds of TCM extracts has significant MGAM-N inhibitory activity;20kinds of TCM showed notably inhibitory effect against MGAM-C;16kinds of TCM could inhibit the activity of HPA efficiently. Compared the TCM with a-glucosidase inhibitory activity, the TCM that has inhibitory activity against MGAM-N'and MGAM-C were different from the TCM with HPA inhibitory activity.
20strains with MGAM-C inhibitory activity were found in the process of the high throughput screening of actinomycetes broth against MGAM-C. Pre-column derivatization HPLC method was applied for screening1-deoxynojirimycin (DNJ) producing strains. DNJ was detected from the broth of strain PW409. Polyphasic taxonomy studies verified strain PW409belonged to Streptomyces gobitrici. Biological activity based HPLC-Q/TOF method was established for screening and identifying a-glucosidase inhibitors in the broth of strain PW409, DNJ and miglitol was identified as the active compounds. The quantification analysis indicated the content of DNJ and miglitol were11.2mg/L and95.8mg/L. The studies provided new strain resource for α-glucosidase development.
AIB656was extracted from the broth of Strain ZG656, which has extremely strong α-amylase inhibitory activity. The efficient MGAM-N and MGAM-C inhibitory activity were also comfirmed. Multi-targets based biological activity discovery and evaluation system was established for screening and identification of α-glucosidase inhibitors.51acarviostatins was identified in AIB656by UPLC-Q/TOF.5fractions had efficient MGAM-N inhibitory activity;8fractions showed strong MGAM-C inhibitory effect;9fractions demonstrated excellent HPA inhibitory activity. The biological practical screening and molecular docking results elucidated the smaller molecules showed remarkable MGAM-N inhibitory activity; Acarviostatin with3-5mimic sugar rings showed strong inhibitory ability against MGAM-C; The larger acarviostatins molecules (6-15mimic sugar rings) had significant HPA inhibitory activity. The results clarified the selectivities of the three different α-glucsosidase to various sizes inhibitors were quite distinct. Molecular docking and interaction study showed acarviostatin10-1firmly binded to the active site of MGAM-N by forming hydrogen bond with Asp327, Asp542, His600and Asp203. acarviostatin10-1occupied the binding site (subsite-1and+1) in the catalytic center of MGAM-N perfectly. Acarviostatin101spanned the binding site (subsite-1and+1,+2,+3) in the catalytic center of MGAM-C completely and formed stable binding state. The results clarified the mechanism in structure biology that acarviostatin10-1is the best MGAM-N inhibitors and acarviostatin101is the best MGAM-C inhibitors in acarviostatins.
The pharmacokinetics and bioavailability of a-glucosidase inhibitor were studied. The result indicated that the absorption rate of a-glucosidase inhibitor was very fast. The Cmax of DNJ was0.8h, and the absolute bioavailability of DNJ was55.02%. Considering quickly absorption of DNJ would decrease the inhibitory activity in intestine, adjuvants was selected for changing the absorption characteristics. The pharmacokinetics of DNJ indicated the Cmax and AUC of DNJ were significantly decreased by CMCNa. CMCNa could postpone the absorption rate of DNJ in intestine. The oral glucose test verified the pharmacodynamics of DNJ was improved by CMCNa.
The systematically a-glucosidase inhibitor discovery and screening approaches were established based the combination of HPLC-MS, molecular docking and enzyme evaluation. Comprehensive multi-targets including MGAM-N, MGAM-C and HPA based a-glucosidase inhibitor screening were proceeded against the extracts of TCM and secondary metabolites of actinomycetes. The reaults and structure biology studies clarified the distinct selectivities of the three a-glucosidases to various sizes inhibitors. The combination of different a-glucosidase inhibitors or composite intervention was probably more effective for diabetes treatment, which was of importance for the a-glucosidase inhibitors type anti-diabetes drugs research and development.
引文
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