耿美玉
从事糖类药物药理学及糖生物学研究
个性化签名
- 姓名:耿美玉
- 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
- 职称:-
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学科领域:
药物化学
- 研究兴趣:从事糖类药物药理学及糖生物学研究
耿美玉,女,博士、教授、博士生导师,“973”项目首席科学家。1986年毕业于山东大学医学院(原山东医科大学),获医学学士学位,1989年毕业于山东大学获医学硕士学位,1996年毕业于日本东京大学获药学博士学位,1997年获中国海洋大学农学博士。现兼任中国药理学会理事、中国药理学会海洋药物专业委员会主任委员;Acta Pharmacologica Sinica、《中国药理通讯》、《海洋科学》等杂志编委。
主要从事糖类药物药理学及糖生物学研究。在糖类药物研究开发方面,主持研制的抗老年痴呆候选药物971是国际上第一个兼具靶向Aβ纤丝形成与促进纤丝解聚双重功能的抗老年痴呆药物,该药物经采用APPxPS-1双转基因小鼠多角度验证了其体内靶向Aβ分子的药效特性,发现971能够同时抑制可溶性与不可溶性Aβ分泌、减少脑组织Aβ纤丝沉积;该药已获得新药临床研究批件,目前正在I期临床研究阶段。
在糖类药物药理学及糖生物学基础研究方面,①在国际上首次系统阐释了抗老年痴呆药物971具有抑制Aβ纤丝形成,特别是对已形成的聚集态的Aβ纤丝具有明显的解聚作用。首次发现971抑制纤丝的形成是通过与Aβ分子上HHQK区域结合,进而阻止Aβ分子由α螺旋向β折叠的转变;首次证明I型葡萄糖转运子(GLUT1)介导971透过血脑屏障,对非葡萄糖型糖类化合物不易透过血脑屏障的传统观念提出了挑战。②系统阐释了硫酸多糖类抗艾滋病药物聚甘古酯抑制病毒进入(II期临床)是通过阻断gp120与CD4的特异结合实现。发现Mitochondrial Import Protein和ATP/ADP Carrier Protein共同介导聚甘古酯进入T细胞、靶向线粒体、抑制T细胞凋亡,展示了糖类药物全新作用模式。确证了聚甘古酯抗HIV病毒的最小寡糖活性片断,为糖类抗艾滋病药物理性设计提供了重要的分子模板。③创建了基于糖抗体的糖类药物药代动力学免疫学评价方法,为糖类药物药代动力学研究提供了重要的方法。④首次发现人胃肠道潘氏细胞能够合成、分泌糖蛋白pIgR受体,提出了潘氏细胞作为人体免疫防御器官的重要靶细胞参与了人胃肠道获得性免疫,打破了潘氏细胞只参与先天性免疫的传统观点。
近年来,主持完成国家“863”计划、国家自然科学基金等课题10余项;目前主持国家“973”计划项目、 “863”计划、国家自然基金项目等课题3项。近年来,发表论文近百篇,其中SCI收录49篇;部分成果发表在Cancer Res, Mol Pharmacol,Mol Cancer Ther,Am J Gastroent,J Neurochem,Glycobiology,Biochem Pharmacol,Antivir Res等药理学、肿瘤学、糖生物学、神经科学等研究领域国际著名刊物上;在TiPs撰写综述性文献。申请国内外专利11项,获授权国家发明专利4项,已培养硕博研究生47名。
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耿美玉, Geng Meiyu∗, Li Fuchuan, Xin Xianliang, Li Jing, Yan Zuowei, Guan Huashi
Antiviral Research 59(2003)127-135,-0001,():
-1年11月30日
The potential targets of marine sulfated polymannuroguluronate (SPMG) involved in inhibition of HIV-1 entry were investigated by surface plasmon resonance and flowcytometry. Results indicated that binding of SPMG either to soluble oligomeric rgp120 or to complexed rgp120–sCD4 mainly resided in V3 loop region. In addition,SPMGwas shown to be less accessible for sCD4 when sCD4 had pre-interacted with rgp120, though SPMG per se multivalently bound to sCD4 with relatively low affinity. While the pre-incubation of SPMG with rgp120 caused a partial blockade of rgp120 binding to sCD4, suggesting that SPMG either shared common binding sites on gp120 with sCD4 or masked the docking sites of gp120 for sCD4. Taken together, V3 domain was demonstrated to be the major site mediating interaction of SPMG with complexed rgp120–sCD4. It seems likely that SPMG binds to both rgp120 and sCD4, but has less accessibility for sCD4 when sCD4 has already bound to rgp120. Nevertheless, addition of SPMG either prior to or after the interaction of rgp120 with sCD4 may suppress rgp120 binding to sCD4. The exact pattern of this trimolecular complex formation at the cell membrane-anchored virus level requires further clarification.
Sulfated polymannuroguluronate, rgp120, V3 loop, sCD4, Surface plasmon resonance, Flow cytometry
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耿美玉, Benchun Miaoa, Meiyu Genga, , Jing Lia, Fuchuan Lia, Haixia Chena, Huashi Guana, Jian Dingb, *
Biochemical Pharmacology 68(2004)641-649,-0001,():
-1年11月30日
Sulfated polymannuroguluronate (SPMG), a marine sulfated polysaccharide, has entered the Phase II clinical trial in China as the first anti-acquired immune deficiency syndrome (AIDS) drug candidate obtained from marine organisms. To determine the binding site(s) (receptors) of SPMG in lymphocytes mediating its anti-AIDS activities, fluorescein-5-isothiocyanate (FITC)-labeled SPMG was used to investigate SPMG binding to lymphocytes. Flow cytometry (FCM) and fluorescence microscopy analysis showed that the SPMG binds to lymphocytes in a rapid, specific, reversible, and saturable fashion. Several SPMG binding proteins were purified by affinity chromatography from lymphocyte membrane preparations. Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and Western blotting analysis revealed that a 55 kDa lymphocyte membrane protein is CD4. To characterize the SPMG and CD4 interaction, inhibition assay and surface plasmon resonance (SPR) assay were carried out. SPMG bound to CD4 in a multivalent fashion with specificity. The binding of SPMG to human lymphocyte CD4 was competitively inhibited by human soluble CD4 (hsCD4). Likewise, the binding between hsCD4 and immobilized SPMG was blocked by excess free SPMG. These results indicate that CD4 is one of the specific SPMG binding sites (receptors) in lymphocytes. The interaction between SPMG and CD4 may provide a mechanistic explanation of the immunopotentiating and anti-AIDS activities of SPMG in human immunodeficiency virus (HIV) infected individuals.
SPMG, Lymphocytes, Binding sites (, receptors), , CD4, FCM, SPR
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