2,3-Benzodiazepine(2,3-BDZ) compounds represent a group of structurally diverse,smallmolecule antagonists of(R,S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid(AMPA)receptors.Antagonists of AMPA receptors ...2,3-Benzodiazepine(2,3-BDZ) compounds represent a group of structurally diverse,smallmolecule antagonists of(R,S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid(AMPA)receptors.Antagonists of AMPA receptors are drug candidates for potential treatment of a number of neurological disorders such as epilepsy,stroke and amyotrophic lateral sclerosis(ALS).How to make better inhibitors,such as 2,3-BDZs,has been an enduring quest in drug discovery.Among a few available tools to address this specific question for making better 2,3-BDZs,perhaps the best one is to use mechanistic clues from studies of the existing antagonists to design and discover more selective and more potent antagonists.Here I review recent work in this area,and propose some ideas in the continuing effort of developing newer 2,3-BDZs for tighter control of AMPA receptor activities in vivo.展开更多
Objective:To isolate and characterize RNA aptamers that are specific to human CD36 protein using systematic evolution of ligands by exponential enrichment(SELEX)technology to identify candidates for adjunct therapy to...Objective:To isolate and characterize RNA aptamers that are specific to human CD36 protein using systematic evolution of ligands by exponential enrichment(SELEX)technology to identify candidates for adjunct therapy to reverse the binding of Plasmodiuminfected erythrocytes.Methods:RNA aptamers were isolated using nitrocellulose membrane-based SELEX and binding analysis was screened using an electrophoretic mobility shift assay and enzyme-linked oligonucleotide assay.Results:Thirteen cycles of nitrocellulose membrane-based SELEX yielded three aptamers(RC60,RC25,RC04)exhibiting high binding against CD36 protein as shown on electrophoretic mobility shift assay.The sequence analysis revealed a G-quadruplex sequence within all the isolated aptamers that might contribute to aptamer binding and thermodynamic stability.The specificity assay further showed that RC60 and RC25 were highly specific to CD36.The competitive inhibition assay demonstrated that RC60 and RC25 shared a similar binding epitope recognized by m Ab FA6-152,a specific monoclonal antibody against CD36.Conclusions:RC60 and RC25 are promising candidates as anticytoadherence for severe malaria adjunct therapy.展开更多
文摘乙型肝炎病毒(hepatitis Bvirus,HBV)导致的慢性感染已经成为威胁全球健康的主要问题之一.传统的抗乙肝药物如以拉米夫定和阿德福韦为代表的核苷类似物以及干扰素类药物在临床上都存在一定的局限性,因此寻找新的抗乙肝药物已经成为当务之急.本文主要从小干扰RNA(small interfering RNA,siRNA)、微小RNA(microRNA,miRNA)和配体指数富集的系统进化技术(systematic evolution of ligands by exponential enrichment,SELEX)筛选的RNA适配子这3个方面来分别阐述用小分子RNA药物抗HBV的研究进展和展望.
基金supported by NIH/NINDS Grant R01 NS060812a grant from Muscular Dystrophy Association(MDA)
文摘2,3-Benzodiazepine(2,3-BDZ) compounds represent a group of structurally diverse,smallmolecule antagonists of(R,S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid(AMPA)receptors.Antagonists of AMPA receptors are drug candidates for potential treatment of a number of neurological disorders such as epilepsy,stroke and amyotrophic lateral sclerosis(ALS).How to make better inhibitors,such as 2,3-BDZs,has been an enduring quest in drug discovery.Among a few available tools to address this specific question for making better 2,3-BDZs,perhaps the best one is to use mechanistic clues from studies of the existing antagonists to design and discover more selective and more potent antagonists.Here I review recent work in this area,and propose some ideas in the continuing effort of developing newer 2,3-BDZs for tighter control of AMPA receptor activities in vivo.
基金supported by an Exploratory Research Grant Scheme(ERGS203/CIPPM/6730106)+2 种基金Higher Institution Centre of Excellent(HICo E311/CIPPM/4401005)from the Malaysian,Ministry of Higher EducationUniversiti Sains Malaysia Fellowship Scheme.
文摘Objective:To isolate and characterize RNA aptamers that are specific to human CD36 protein using systematic evolution of ligands by exponential enrichment(SELEX)technology to identify candidates for adjunct therapy to reverse the binding of Plasmodiuminfected erythrocytes.Methods:RNA aptamers were isolated using nitrocellulose membrane-based SELEX and binding analysis was screened using an electrophoretic mobility shift assay and enzyme-linked oligonucleotide assay.Results:Thirteen cycles of nitrocellulose membrane-based SELEX yielded three aptamers(RC60,RC25,RC04)exhibiting high binding against CD36 protein as shown on electrophoretic mobility shift assay.The sequence analysis revealed a G-quadruplex sequence within all the isolated aptamers that might contribute to aptamer binding and thermodynamic stability.The specificity assay further showed that RC60 and RC25 were highly specific to CD36.The competitive inhibition assay demonstrated that RC60 and RC25 shared a similar binding epitope recognized by m Ab FA6-152,a specific monoclonal antibody against CD36.Conclusions:RC60 and RC25 are promising candidates as anticytoadherence for severe malaria adjunct therapy.
