张礼和
长期从事核酸化学及抗肿瘤抗病毒药物研究。
个性化签名
- 姓名:张礼和
- 目前身份:
- 担任导师情况:
- 学位:
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学术头衔:
博士生导师, 中国科学院院士
- 职称:-
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学科领域:
有机化学
- 研究兴趣:长期从事核酸化学及抗肿瘤抗病毒药物研究。
张礼和,男,1937年09月生,汉族,中共党员,江苏省扬州人。1958年毕业于北京医学院药学系;1967年北京医学院药学系研究生毕业。1967年至1981年在北京医学院任助教、讲师;1981年至1983年在美国弗吉尼亚大学化学系做访问学者;1983年至1985年在北京医科大学药学院任副研究员;1985年至1999年在北京医科大学任教授;1999年至今在北京大学药学院任教授。张礼和教授1995年当选为中国科学院化学学部院士。张礼和现为北京大学药学院(系)教授,天然药物及仿生药物国家重点实验室学术委员会主任。1993年开始享受国务院颁发的政府特殊津贴待遇。
张礼和院士长期从事核酸化学及抗肿瘤抗病毒药物研究。系统地研究了细胞内环核苷酸类(c-AMP和c-ADPR)信使分子的构效关系,对酶性核酸断裂RNA机理以及结构修饰的寡核苷酸对核酸序列识别、稳定性和酶诱导活性进行了研究。共发表论文200多篇;获得中国专利3项,并先后获1988 年日本大谷科研奖、1993年国际药联(FIP)Colorcon 奖、1994年吴阶平•保罗杨森医药奖、1996年国家教委科技进步二等奖、1998年国家教委科技进步一等奖、1999年何梁何利科技进步奖、2000年国际药联(FIP)千禧年药学家奖、2002年国家教委科技进步二等奖、2004年国家自然科学奖二等奖。张礼和院士目前还担任中国药学会副理事长,国务院学位委员会学科评议组药学学科召集人,国际纯化学和应用化学协会(IUPAC)中有机和生物分子化学( Organic & Biomolecular Chemistry)委员会委员等职务;《药物化学杂志》主编,《高等学校化学学报》副主编,国际刊物 “Medicinal Research Reviews” 、“Current Topics of Medicinal Chemistry”和“Organic & Biomolecular Chemistry”、 “ChemMedChem”编委。
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成果数
9
张礼和, Jun Chen, Liang Ren Zhang, Ji Mei Min and Li He Zhang
Nucleic Acids Research, 2002, Vol. 30, No. 13 3005-3014,-0001,():
-1年11月30日
The octaoligoisonucleotide (isoT)2(isoG)4(isoT)2 (I), consisting of isonucleoside units 6′-O -allyl-4′-deoxy-4′-(nucleobase)-2′,5′-anhydro-L-mannitol, was synthesized by the phosphotriester approach in solution phase. Based on CD spectra and capillary electrophoresis, it was confirmed that iso-oligomer I could form a parallel intermolecular G-quadruplex structure. K+, Na+ and Li+ can prompt the formation of G-quartet structures and stabilize them. The effective order of these cations is K+ > Na+ > Li+.
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张礼和, Li-Jun Huang, Yong-Yuan Zhao, Lan Yuan, Ji-Mei Min, and Li-He Zhang*,
J. Med. Chem. 2002, 45, 5340-5352,-0001,():
-1年11月30日
Cyclic ADP-ribose (cADPR) is not only a potent endogenous calcium modulator but also a second messenger. However, studies on the mechanism of cADPR action were limited due to its instability and lack of available structural modifications in the N1-glyosyl unit of cADPR. In the present work, a series of N1-glycosyl mimics with different configurational glycosyls or an ether strand were designed and synthesized mimicking the furanose ring. SN2 substitutions were carried out between the protected inosine and glycosyl triflates to form the N1-glycosylinosine derivatives, accompanied with some O6-glycosyl-substituted as side products. The intramolecular cyclization was followed the strategy described by Matsuda et al. It was found that the 8-unsubstituted substrate could also be used to construct the intramolecular cyclic pyrophosphate. The activities of N1-glycosyl-substituted cADPR mimics were evaluated by induced Ca2+ release in rat brain microsomes and HeLa cells. It was found that the configuration of the N1-glycosyl moiety in cADPR is not a critical structural factor for retaining the activity of mobilizing Ca2+ release. More interestingly, the N1-acyclic analogue 6 exhibited strong activity by inducing Ca2+ release in both rat brain microsomes and HeLa cells. It constitutes a useful tool for further studies.
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张礼和, Chang-Po Chen, Xiao-Xu Li, Liang-Ren Zhang, Ji-Mei Min, Judy Yuet-Wah Chan, Kwok-Pui Fung, Sheng-Qi Wang, and Li-He Zhang,
Bioconjugate Chem. 2002, 13, 525-529,-0001,():
-1年11月30日
A simple procedure for the preparation of oligonucleotide-peptide conjugate was developed. p-Hydroxybenzoic acid was used as a linker for the connection of the fragments of peptide and oligonucleotide. It was found that such formed linkage was stable under the conditions of conjugate synthesis. The designed conjugate targeting to GLUT-1 showed up to 50% inhibition of cell proliferation in HepG-2 and MCF-7 cells. Comparing to the results from the expressed antisense RNA in cancer cells, it was proposed that the conjugate of signal peptide mimic and antisense oligonucleotide could improve the permeability of antisense oligonucleotide through cell membrane.
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张礼和, Xiaoxu Li, Liangren Zhang, Jingfen Lu, Yaozu Chen, Jimei Min, and Lihe Zhang,
Bioconjugate Chem. 2003, 14, 153-157,-0001,():
-1年11月30日
The specific binding ability and biostability of PNA (peptide nucleic acid) with DNA or RNA make PNA not only a good tool for the studies of molecular biology but also the candidate for gene-targeting drugs. However, the main obstacle for its potential usage as a therapeutic is the low cell uptake caused by the poor cell membrane permeability. In this paper the hydrophobic pentadecapeptide and two signal peptide mimics, hexa- and decapeptides ending with a positively charged amino acid, were proposed as the linked carrier for the transportation of PNA T10 through the cell membrane; stable spin label was coupled to the peptide-PNA conjugate so that the ESR measurements can be used for the assessment of their transmembrane movements. The syntheses of spin-labeled peptide-PNA conjugates were carried out on MBHA resin with Boc strategy. The cell membrane permeability of the spin-labeled conjugates of peptides and PNA can be determined with ESR, during the incubation of erythrocyte with the samples. According to ESR measurements, the three conjugates exhibit enhanced uptake into erythrocytes. The hexa- and decapeptide-modified PNA showed suitable water solubility. The peptide-PNA conjugates retained their binding ability to complementary DNA. The results suggest that peptide modification of PNA might be a promising solution for improving cell membrane permeability toward PNA.
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张礼和, Chang-Po Chen, Liang-Ren Zhang, Yue-Feng Peng, Xiao-Bo Wang, Sheng-Qi Wang, and Li-He Zhang,
Bioconjugate Chem. 2003, 14, 532-538,-0001,():
-1年11月30日
Peptide-oligonucleotide conjugates were synthesized using two strategies: a mimetic signal peptideconjugated oligonucleotide was assembled stepwise on CPG by using 2,2-dimethyl-3-hydroxypropionic acid as a linker. To solve the precipitation problem in the coupling reaction caused by the electrostatic interaction of arginine-rich peptides and oligonucleotide, oligonucleotides were absorbed on an anionexchange resin, and then the on-resin fragment was applied for the conjugation with arginine-rich peptide. The peptide-antisense oligonucleotides showed permeability to the cell membrane of HepG-2 cells.
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张礼和, Xianfeng Gu, Zhenjun Yang, Liangren Zhang, Svenja Kunerth, Ralf Fliegert, Karin Weber, Andreas H. Guse, and Lihe Zhang,
J. Med. Chem. 2004, 47, 5674-5682,-0001,():
-1年11月30日
N1-[(5”-O-Phosphorylethoxy)methyl]-5’-O-phosphorylinosine 5’,5”-cyclicpyrophosphate (cIDPRE 2a) and the 8-substituted derivatives 8-bromo-, 8-azido-, 8-amino-, and 8-Cl-cIDPRE (2b-e) were synthesized from N1-[(5”-acetoxyethoxy)methyl]-2’,3’-O-isopropylideneinosine (5) in good yields. The pharmacological activities of cIDPRE and the 8-substituted derivatives (2a-e) were analyzed in intact and permeabilized human Jurkat T-lymphocytes. The results indicate that cIDPRE permeates the plasma membrane, releases Ca2+ from an intracellular, cADPR-sensitive Ca2+ store, and subsequently initiates Ca2+ release-activated Ca2+ entry. The Ca2+-releasing activity of cIDPRE was confirmed directly in permeabilized cells. Using time-resolved confocal Ca2+ imaging at the single cell level, the development of global Ca2+ signals starting from local small Ca2+ signals evoked by cIDPRE was observed. 8-N3-cIDPRE 2c and 8-NH2-cIDPRE 2d were similarly effective in their agonistic activity as compared to cIDPRE 2a, showing almost indistinguishable concentration-response curves for 2a, 2c, and 2d and very similar kinetics of Ca2+ signaling. In contrast, the halogenated derivatives 8-Br- and 8-Cl-cIDPRE (2b and 2e) did not significantly elevate [Ca2+] i. Therefore, cIDPRE 2a, 8-N3-cIDPRE 2c, and 8-NH2-cIDPRE 2d are novel membrane permeant cADPR mimic and may provide important novel tools to study cADPR-mediated Ca2+ signaling in intact cells.
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张礼和, Svenja Kunerth, Matthias F. Langhorst, Nadine Schwarzmann, *, Xianfeng Gu, Lijun Huang, Zhenjun Yang, Liangren Zhang, Steven J. Mills, Li-he Zhang, Barry V.L. Potter and Andreas H. Guse, ‡
,-0001,():
-1年11月30日
Ligation of the T-cell receptor/CD3 complex results in global Ca2+ signals that are essential for T-cell activation. We have recently reported that these global Ca2+ signals are preceded by localized pacemaker Ca2+ signals. Here, we demonstrate for the first time for human T cells that an increase in signal frequency of subcellular pacemaker Ca2+ signals at sites close to the plasma membrane, in the cytosol and in the nucleus depends on the type 3 ryanodine receptor (RyR) and its modulation by cyclic ADP-ribose. The spatial distribution of D-myo-inositol 1,4,5-trisphosphate receptors and RyRs indicates a concerted action of both of these receptors/Ca2+ channels in the generation of initial pacemaker signals localized close to the plasma membrane. Inhibition or knockdown of RyRs resulted in significant decreases in (1) the frequency of initial pacemaker signals localized close to the plasma membrane, and (2) the frequency of localized pacemaker Ca2+ signals in the inner cytosol. Moreover, upon microinjection of cyclic ADP-ribose or upon extracellular addition of its novel membrane-permeant mimic N-1- ethoxymethyl-substituted cyclic inosine diphosphoribose, similarly decreased Ca2+ signals were observed in both type 3 RyR-knockdown cells and in control cells microinjected with the RyR antagonist Ruthenium Red. Taken together, our results show that, under physiological conditions in human T cells, RyRs play crucial roles in the local amplification and the spatiotemporal development of subcellular Ca2+ pacemaker signals.
Ca2+, signaling,, Ryanodine receptor,, Cyclic ADP-ribose,, T cell,, D-myo-inositol 1,, 4,, 5-trisphosphate receptor
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张礼和, Andreas H. Guse, , Xianfeng Gu, Liangren Zhang, Karin Weber, Elisabeth Kra
Vol. 280, No. 16, Issue of April22, pp. 15952-15959, 2005,-0001,():
-1年11月30日
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张礼和, Jianfeng Xu, Zhenjun Yang, Werner Dammermann, † Liangren Zhang,
J. Med. Chem. 2006, 49, 5501-5512,-0001,():
-1年11月30日
Novel analogues of cADPR with adenine as base and ether (10a) or different alkane chain (10b-d) substitutions of the northern ribose were synthesized from protected imidazole nucleoside 1 in good yields. The pharmacological activities of cyclic inosine diphosphoribose ether (cIDPRE) and the compounds (10ad) were analyzed in intact human Jurkat T-lymphocytes. The results indicate that the analogues 10a-d permeate the plasma membrane and are weak agonists of the ADPR/ryanodine receptor signaling system in intact human Jurkat T cells. They are the first membrane-permeant and biologically active cADPR analogues that contain ether or alkane bridges instead of the northern ribose and retain adenine as its base.
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