唐古特红景天的脯氨酰寡肽酶抑制活性成分研究

目的研究唐古特红景天的脯氨酰寡肽酶抑制作用及其活性成分。方法采用改进的Kato法测定唐古特红景天水提物和从中分离得到的10个化合物的脯氨酰寡肽酶抑制作用,并采用RP-HPLC法对水提物的活性成分进行分析和指认。结果水提物的脯氨酰寡肽酶抑制活性显著(质量浓度为100 mg.L-1,抑制率为91.7%),其中,apigenin 7-O-β-D-apiofuranosyl(1→2)-β-D-glucopyr-anoside(IC50=30.4μmol.L-1)和isolariciresinol 9-O-β-D-xylopyranoside(IC50=25.2μmol.L-1)显示出较强的活性。结论唐古特红景天水提物具有显著的脯氨酰寡肽酶抑制作用,从中发现了2个主要活性成分。     

用于治疗肥胖和糖尿病的二酰甘油酰基转移酶抑制剂研究进展

人体内的二酰甘油酰基转移酶是催化三酰甘油最终合成的关键酶,其基因缺失或酶活受抑时,机体不会因高脂饮食而发生肥胖,且对胰岛素的敏感性增强,因此该酶可作为肥胖和糖尿病治疗药物的靶点。综述二酰甘油酰基转移酶的功能研究以及天然来源和合成的二酰甘油酰基转移酶抑制剂的药理活性和构效关系。     

血管肽酶抑制剂的研究进展

目的阐述血管肽酶抑制剂(VPIs)的作用机制、构效关系以及临床研究等方面的进展。方法根据近期对VPIs的作用机制、构效关系以及研究开发现状的25篇相关文献进行整理和归纳。结果与结论数种血管肽酶抑制剂正在进行治疗高血压、心力衰竭等心血管疾病的临床试验。VPIs有望成为新一代治疗高血压和心力衰竭的药物。     

低氧诱导因子脯氨酰羟化酶抑制剂的研究进展

目的 综述低氧诱导因子脯氨酰羟化酶抑制剂的研究进展。方法 查找近年低氧诱导因子脯氨酰羟化酶抑制剂的相关文献,对已上市脯氨酰羟化酶抑制剂罗沙司他、伐度司他和达普司他等,正在进行临床试验的在研药物以及新型结构的脯氨酰羟化酶抑制剂进行了归纳和总结。结果与结论脯氨酰羟化酶抑制剂用于治疗慢性肾脏病引起的贫血,与传统药物相比具有很多优点,已经成为了当前研究热点。此外,发现新型结构的脯氨酰羟化酶抑制剂也是重点研究方向之一。     

海洋来源的天然α-糖苷酶抑制剂研究进展

α-葡萄糖苷酶抑制剂(AGIs)是一类以延缓肠道糖类吸收而达到治疗糖尿病的口服降糖药物。从海洋天然产物宝库中寻找新型α-葡萄糖苷酶抑制剂对发现高效低毒的治疗II型糖尿病(T2DM)药物具有重要意义。本文综述了45个海洋动物、植物以及微生物来源的天然α-葡萄糖苷酶抑制剂的结构、活性及其生物来源,还简要探讨了其构效关系,即酚羟基、卤素和不饱和双键、叁键的存在有助于增强化合物的α-葡萄糖苷酶抑制活性。     

抗纤维化药物研究进展

抗纤维化药物研究为近年来药物研究的热点之一。目前，新的抗纤维化药物的研究大多围绕着拮主要的致纤维化细胞因子的活性进行的。此外，与胶原蛋白翻译后加工有关的两个关键酶抑制剂：脯氨酰－４－羟化酶抑制剂及赖氨酰氧化酶抑制剂的研究正引起越来越多研究者的兴趣，其中针对脯氨酰－４－羟化酶的一个抑制剂ＨＯＥ０７７（ｌｕｆｉｒｏｎｉ）有可能成为一个有效的抗革纤维化药物应用于临床。     

α-葡萄糖苷酶抑制剂的来源、筛选模型及临床研究进展

目的:综述α-葡萄糖苷酶抑制剂的来源、筛选模型及临床应用研究进展,为研发高效、安全的α-葡萄糖苷酶抑制剂提供参考。方法:以"α-葡萄糖苷酶抑制剂""筛选模型""临床应用"等组合作为关键词,检索Pub Med、美国化学文摘(CA)、中国期刊全文数据库等数据库中有关α-葡萄糖苷酶抑制剂的来源、筛选模型及临床应用的研究进展。结果与结论:共收集到90余篇相关文献,有效文献34篇。α-葡萄糖苷酶抑制剂来源主要包括通过化学方法合成、从天然植物中提取与从海洋生物中分离以及从微生物与其次级代谢产物中提取得到;其筛选模型主要有高血糖动物筛选模型、酶抑制剂模型、人克隆结肠腺癌(Caco-2)细胞筛选模型及计算机辅助药物筛选模型等;临床主要应用于糖尿病、溶酶体贮存病的治疗以及肝炎、艾滋病等病毒性感染疾病的治疗。其未来的研究应着重于从天然植物与微生物中提取物活性物质进行分离纯化,并在充分研究其构效关系的基础上,运用化学方法对活性基团结构进行分子修饰,以期获得抑制活性更强的α-葡萄糖苷酶抑制剂。     

靶向c-Met激酶小分子抑制剂的研究进展

目的为进一步研究具有新颖结构的小分子c-Met激酶抑制剂提供参考。方法以"c-Met激酶"、"c-Met激酶抑制剂"、"酪氨酸激酶抑制剂"、"HGF/c-Met通路"、"构效关系"等为关键词,组合查询相关文献,对靶向小分子c-Met激酶抑制剂不同结构骨架的结构改造、构效关系进行综述。结果靶向小分子c-Met激酶抑制剂按结构骨架可分为喹啉类化合物、吡咯(噻吩)并吡啶(嘧啶)类化合物、吡啶类化合物、吲哚酮类化合物、三环类化合物及其他类化合物。总结此类化合物的结构改造和构效关系发现,除对c-Met激酶有显著抑制活性以外,还对其他靶点也表现出较好的抑制作用。结论 c-Met激酶已经成为抗肿瘤药物研究的一个重要靶点,对已进入临床研究的化合物进行结构改造和构效关系研究,为设计有效、低毒的小分子c-Met激酶抑制剂提供重要的借鉴作用,也加速了c-Met抑制剂类药物的开发进程。     

降尿酸药物黄嘌呤氧化酶抑制剂的研究进展

综述黄嘌呤氧化还原酶及黄嘌呤氧化酶抑制剂的研究进展,并对黄嘌呤氧化酶抑制剂的构效关系进行初步分析,为该类药物的深入研究提供参考。血中尿酸水平过高是痛风的第一大诱因,以黄嘌呤氧化酶抑制剂作为降尿酸药物,可以抑制黄嘌呤氧化酶的活性,减少体内尿酸的合成,从而达到治疗痛风的目的。     

3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂的构效关系研究进展

3-羟基-3-甲基戊二酰辅酶A（HMG CoA）还原酶抑制剂是治疗高胆固醇血症的有效药物。现综述该类药物的发展概况和作用机制，并从母环、连接链和侧链三部分总结其构效关系，为国内研发新的HMG CoA还原酶抑制剂提供参考。     

Substrate-dependent,non-hyperbolic kinetics of pig brain prolyl oligopeptidase and its tight binding inhibition by JTP-4819

Prolyl oligopeptidase (POP) is a cytosolic serine protease that hydrolyses small peptides at the carboxyl end of the proline residue. It has raised pharmaceutical interest, since its inhibitors have been shown to have antiamnesic properties. We studied prolyl oligopeptidase kinetics with two 7-amino-4-methylcoumarin derivatives: Z-Gly-Pro-AMC and Suc-Gly-Pro-AMC. Z-Gly-Pro-AMC was found to obey standard Henri-Michaelis-Menten kinetics with a K(m) of 30+/-3 microM, whereas Suc-Gly-Pro-AMC exhibited substrate inhibition kinetics with K(m) and K(is) of 510+/-150 and 270+/-90 microM, respectively. Autodock simulations revealed that either the succinyl or the AMC-end of Suc-Gly-Pro-AMC may bind to the S'1 subsite of the active site. We believe that non-specifically bound Suc-Gly-Pro-AMC allows the simultaneous binding of second substrate molecule to the active site and this leads in substrate inhibition. In addition, we demonstrated that the inhibition type of a well characterized prolyl oligopeptidase inhibitor, JTP-4819, is competitive tight binding with a K(ic) of 0.045+/-0.008 nM. We suggest that due to the high concentration of prolyl oligopeptidase in the brain (0.12 nmol/g pig brain), the tight binding nature of the inhibition should be considered when using brain homogenate as the enzyme source in prolyl oligopeptidase inhibition measurements. This is of importance in studying structure-activity relationships of potent prolyl oligopeptidase inhibitors.     

Molecular modeling studies of prolyl endopeptidase inhibitors

Prolyl endopeptidase, a serine protease is considered to play an important role in the degradation of neuropeptides capable of changing the performance in learning and memory tasks in both animal and human. The inhibitors seem to be promising drug candidates to treat and prevent diseases with associated memory loss such as senile dementia. In the last decade advanced and improved new technologies have appeared to stimulate ideas in the design and synthesis of new drug molecules. The goal of this short communication is to review our results and observations, exemplified by our research on the inhibitors of prolyl endopeptidase. Among them qualitative and quantitative structure-activity relationship studies using conformational analyses, NMR measurements, pharmacophoric plots and CoMFA models are summarised.     

Prolyl endopeptidase inhibitors from the leaves of Ginkgo biloba

Prolyl endopeptidase (PEP, EC 3.4.21.26) hydrolyzes proline-containing neuropeptides, such as vasopressin, substance P, and thyrotropin-releasing hormone (TRH), and is suggested to participate in learning and memory processes. Ginkgo biloba leaves, upon examination for anti-amnestic constituents as new types of PEP inhibitors, showed significant PEP inhibition. PEP activity-guided fractionation and column chromatography of the MeOH extracts of G. biloba leaves resulted in the isolation of 6-(8'Z-pentadecenyl)salicylic acid (1) and 6-(10'Z-heptadecenyl)salicylic acid (2). The kinetic study indicated that compounds 1 and 2 are non-competitive inhibitors of prolyl endopeptidase with Ki values of 0.87 and 0.80 microM, respectively.     

Translational research on prolyl oligopeptidase inhibitors: the long road ahead

Despite the fact that some have passed early phases of clinical trials, no prolyl oligopeptidase inhibitors are currently on the market. Yet, since 2003, there has been a boost in patent applications claiming prolyl oligopeptidase inhibitors for the treatment of Alzheimer's and Parkinson's diseases, and other neurodegenerative and psychiatric disorders. While experts in the field call for innovative scaffolds to develop more potent inhibitors with more favorable properties, they also relate a lack of knowledge of the toxicology, bioavailability, pharmacokinetics and pharmacodynamics of existing compounds that hinders their assessment. Yet, with the current insights, it is difficult to correlate specific inhibitor effects with the postulated functions of prolyl oligopeptidase in the brain.     

Plant phenolics as prolyl endopeptidase inhibitors

Prolyl endopeptidase (PEP, EC 3.4.21.26), a serine protease, is widely distributed in various organs, particularly in the brains of Alzheimer's disease patients. The expression of PEP in Alzheimer's patients has been found to be significantly higher than that of the normal person, suggesting that a specific PEP inhibitor can be a good candidate for an anti-amnestic drug. In the current study, thirty-nine plant phenolics were investigated to determine their roles as prolyl endopeptidase (PEP) inhibitors. Nineteen compounds such as 1,2,3-trigalloyl glucopyranoside, 1,2,6-trigalloyl glucopyranoside, 1,2,3,4,6-pentagalloyl gluco-pyranoside, 1,2,6-trigalloyl alloside, 1,3,6-trigalloyl alloside, 1,2,3,6-tetragalloyl alloside, acetonyl geraniin, corilagin, elaeocarpusin, euphorscopin, geraniin, helioscopin B, helioscopinin A, helioscopinin B, jolkinin, macranganin, rugosin E, supinanin, and teracatain exhibited strong inhibition against PEP (IC50 26.7 - 443.7 x 10(-9) M). Rugosin E (IC50 26.7 x 10(-9) M) showed the most effective inhibition followed by 1,2,6-trigalloyl glucopyranoside (IC5031.4 x 10(-9) M) and macranganin (IC5042.6 x 10(-9) M). No significant structure-activity relationship was found; however, at least, three pyrogallol groups seem to be a minimal requirement for stronger activity against PEP All 19 active compounds inhibited PEP in a non-competitive mode with a substrate in Dixon plots. They did not show significant effects against other serine proteases such as trypsin, chymotrypsin and elastase, indicating that they were relatively specific PEP inhibitors.     

Proteinases of Trypanosoma cruzi: patential targets for the chemotherapy of Changas desease

Trypanosoma cruzi, the agent of the American Trypanosomiasis, Chagas Disease, contains cysteine, serine, threonine and metallo proteinases. Aspartic proteinases have not been found so far. The most abundant among these enzymes is cruzipain, a cysteine proteinase expressed as a complex mixture of isoforms by the major developmental stages of the parasite, including some membrane-bound isoforms. The enzyme is an immunodominant antigen in human chronic Chagas disease and seems to be important in the host/parasite relationship. Inhibitors of cruzipain kill the parasite and cure infected mice, thus making the enzyme a very promising target for the development of new drugs against Chagas disease. In addition 30 kDa cathepsin B-like enzymes have been described. Serine peptidases described in the parasite include oligopeptidase B, a member of the prolyl oligopeptidase family involved in Ca(2+)-signalling during mammalian cell invasion; a prolyl endopeptidase (Tc80), against which inhibitors are being developed, and a serine carboxypeptidase belonging to the S10 family. Metalloproteinases homologous to the gp63 of Leishmania spp. are also present. The proteasome has properties similar to those of other eukaryotes, and its inhibition by lactacystin blocks some differentiation steps in the life cycle of the parasite.     

Dicarboxylic acid bis(L-prolyl-pyrrolidine) amides as prolyl oligopeptidase inhibitors

New dicarboxylic acid bis(L-prolyl-pyrrolidine) amides were synthesized, and their inhibitory activity against prolyl oligopeptidase from pig brain was tested in vitro. As compared with earlier described prolyl oligopeptidase inhibitors, these new compounds have in common an L-prolyl-pyrrolidine moiety, but the typical lipophilic acyl end group is replaced by another L-prolyl-pyrrolidine moiety connected symmetrically with a short dicarboxylic acid linker. These compounds are a new type of peptidomimetic prolyl oligopeptidase inhibitor.     

New prolyl oligopeptidase inhibitors developed from dicarboxylic acid bis(l-prolyl-pyrrolidine) amides

Isophthalic acid bis(l-prolyl-pyrrolidine) amide is a very potent prolyl oligopeptidase inhibitor, but it has a log P value of -0.2, which is very low for a compound targeted to the brain. Therefore, these types of compounds were further modified to improve the structure-activity relationships, with the focus on increasing the log P value. The inhibitory activity against prolyl oligopeptidase from pig brain was tested in vitro. The most promising compounds resulted from replacing the pyrrolidinyl group at the P5 site by cycloalkyl groups, such as cyclopentyl and cyclohexyl groups, and by a phenyl group. These compounds are slightly more potent, and they have a significantly higher log P value. The potency of these compounds was further increased by replacing the pyrrolidinyl group at the P1 site by 2(S)-cyanopyrrolidinyl and 2(S)-(hydroxyacetyl)pyrrolidinyl groups.     

Proline specific peptidases and their specific inhibitors]

Several proline specific peptidases were newly isolated from mammalian organs, plants and microorganisms, and their enzymatic properties characterized. The genes of prolyl endopeptidase, aminopeptidase P and proline iminopeptidase from some microorganisms were cloned and their nucleotide sequences determined. By high expression of these genes in Escherichia coli, the enzymes became possible to be used for the industrial application as well as its basic research. Novel inhibitors specific for the prolyl endopeptidase and dipeptidyl aminopeptidase IV were synthesized and some inhibitors for prolyl endopeptidase found to show an anti-amnesic effect.