Functionalized Congeners Of Bioactive Compounds

生物活性化合物的功能化同系物

基本信息

批准号：
7734051
负责人：
Kenneth Alan Jacobson
金额：
$ 30.04万
依托单位：
NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/7734051
关键词：
ADORA3 gene ATP Receptors Adenosine Adenosine A3 Receptor Adverse effects Affinity Agonist Binding Binding Sites Biological Blood Platelets Calcium-Sensing Receptors Cell Therapy Cells Chemicals Delayed-Action Preparations Dendrimers Development Distal Docking Drug Kinetics Engineering Evaluation Extracellular Domain Fluorescent Dyes Future G-Protein-Coupled Receptors Genes Homology Modeling Human Immobilization Knowledge Laboratories Lead Ligand Binding Ligands Masks Metabolic Modification Nanotechnology Natural regeneration Organ P2X-receptor Parents Peptides Pharmaceutical Chemistry Pharmaceutical Preparations Polymers Positioning Attribute Prodrugs Purinergic P1 Receptors Purines Purinoceptor Receptor Activation Reporter Reporting Signal Pathway Site Site-Directed Mutagenesis Structure-Activity Relationship Surface System Testing Therapeutic Time Tissues Transmembrane Domain Trees Work analog base concept desensitization design extracellular functional group in vivo molecular modeling pharmacophore purine receptor size small molecule success targeted delivery

项目摘要

Work in our laboratory spanning more than two decades has demonstrated that certain drugs may be attached to well-defined carrier molecules and still retain the ability to bind to the receptor site and effect biological activity. This synthetic strategy for the attachment of drugs to carriers is termed the functionalized congener approach. The carrier molecule may be many times larger than the parent drug; indeed there is practically no maximum size limitation for a fully potent analog. Unlike the prodrug approach or the immobilization of drugs for slow release, the functionalized congener approach is designed to produce analogs for which no metabolic cleavage step is necessary for activation. Moreover, the attachment of the drug to a carrier such as a peptide may result in enhanced affinity at an extracellular receptor site and an improvement in the pharmacological profile of the parent drug through energetically favorable interaction with distal sites on a receptor. Purine derivatives containing attached chains to target distal sites of GPCRs have been developed as functionalized congeners that either activate or antagonize adenosine receptors, and a similar strategy has been used for ATP receptors. For example, the 2-position of the purine moiety has been identified for attachment of functionalized chains in ATP derivatives as P2X and P2Y receptor agonists. Reporter groups such as fluorescent dyes have been covalently attached resulting in receptor probes of relatively high affinity. The targeting of distal sites on the calcium sensing receptor has also been studied. Other means of altering pharmacokinetics of a known drug include the prodrug approach. We have prepared prodrugs of adenosine A3 agonists and antagonists, e.g. nuceloside derivatives, that are not themselves biologically active, but are able to be regenerated in biological systems. Studies of the cleavage of the blocked ligands indicates that the prodrugs are suitable as masked forms of the biologically active A3AR agonists and antagonists for future evaluation in vivo. The use of GPCR agonists for therapy has inherent limitations. The distribution of a given receptor in multiple tissues may lead to undesired side effects. Also, the desensitization of a receptor upon repeated agonist exposure may limit agonist utility. We are developing an alternate approach to achieve the beneficial effects of GPCR activation in a more spatially and temporally selective manner than the systemic administration of agonists to the native GPCR. This approach of neoceptors combines small molecule classical medicinal chemistry and gene or cell therapy. By this rational design approach, complementary structural changes are made in the receptor and ligand for selective enhancement of affinity. The spatially-selective activation of a neoceptor would be dependent on cell- or organ-target delivery of the gene. Molecular modeling, of GPCRs has been used widely to arrive at hypotheses for recognition of antagonists and agonists by ligand docking. We have are validated hypotheses for docking of ligands at purine receptors using site-directed mutagenesis. Site-directed mutagenesis and molecular modeling have been used to characterize the ligand binding sites of the P2Y1 and A3 receptors to predict which regions of a given ligand may be amenable to a chain attachment approach. With this knowledge and the ability to tailor-make new analogues of a native agonist, one may design a matched neoceptor and neoligand, i.e. the binding site of a given GPCR may be engineered to recognize synthetic agonist ligands that do not activate the native receptor. Distal sites of interaction on the engineered receptor may be targeted to allow selective enhancement of affinity in a functionalized congener. Based on predictions from molecular modeling, we have designed neoceptors for A2A and A3 adenosine receptors, in which a tailored ligand activates only engineered receptor. The success of the neoceptor strategy for the ARs validates the use of homology modeling, as well as suggests options for future therapeutics. We have explored the application of nanotechnology to the study of GPCRs. For example, dendrimers are tree-like polymers that have multiple functional sites on the periphery for attachment of ligands. We recently reported the first PAMAM dendrimer to which a GPCR ligand had been attached. This was a conjugate to which A2AAR functionalized congeners were covalently attached. The conjugate displayed potent antithrombotic activity in human platelets, while the parent dendrimer was inactive. We are using the multivalency of dendrimer conjugates to test for interactaction with dimeric and higher order multimeric GPCR assemblies.

跨越二十年的实验室中的工作表明，某些药物可能附在定义明确的载体分子上，并且仍然保留与受体位点结合并影响生物学活性的能力。这种将药物附着在携带者上的合成策略称为功能化的同类物方法。载体分子可能比母体药物大很多倍。确实，完全有效的类似物实际上没有最大尺寸限制。与前药方法或药物固定以缓慢释放不同，功能化的同类物方法旨在产生类似物，该类似物无需代谢裂解步骤即可激活。此外，该药物附着在载体上（例如肽）可能会导致细胞外受体部位的亲和力增强，并通过与受体上的远端位点的能量相互作用来改善父母药物的药理特征。嘌呤衍生物含有附着在GPCR的目标远端位点的嘌呤衍生物已作为功能化的同类物开发，可激活或拮抗腺苷受体，并且已针对ATP受体使用类似的策略。例如，已经确定了嘌呤部分的2位，以将功能化链的附着在ATP衍生物中作为P2X和P2Y受体激动剂。报告基团（例如荧光染料）已共价附着，导致受体探针相对较高。还研究了钙传感受体上远端位点的靶向。改变已知药物的药代动力学的其他方法包括前药方法。我们已经准备了腺苷A3激动剂和拮抗剂的前药，例如核苷衍生物本身并非生物学活性，而是能够在生物系统中再生。对被阻塞配体的裂解的研究表明，这些前药适合作为生物活性A3AR激动剂的掩盖形式，并在体内进行评估。 GPCR激动剂用于治疗具有固有的局限性。给定受体在多个组织中的分布可能导致不希望的副作用。同样，反复的激动剂暴露时受体的脱敏可能会限制激动剂效用。我们正在开发一种替代方法，以更加空间和时间选择性的方式实现GPCR激活的有益作用，而不是全身对天然GPCR的激动剂。这种Neoceptors的这种方法结合了小分子经典药物化学和基因或细胞疗法。通过这种合理的设计方法，在受体和配体中进行了互补的结构变化，以选择性增强亲和力。 Neoceptor的空间选择性激活将取决于基因的细胞或器官靶向递送。 GPCR的分子建模已被广泛用于通过配体对接识别拮抗剂和激动剂的假设。我们已经有验证的假设使用位置定向的诱变，用于在嘌呤受体上对接配体的假设。位置定向的诱变和分子建模已被用来表征P2Y1和A3受体的配体结合位点，以预测给定配体的哪些区域可能与链附着方法相吻合。凭借这种知识和量身定制天然激动剂的新类似物的能力，人们可能会设计匹配的新受感染者和新群体，即给定GPCR的结合位点可以设计用于识别未激活本地受体的合成激动剂配体。工程受体上相互作用的远端位点可能是针对性的，以允许在功能化的同类物中选择性增强亲和力。根据分子建模的预测，我们为A2A和A3腺苷受体设计了新受体，其中量身定制的配体仅激活工程受体。 Neoceptor策略在ARS上的成功验证了同源性建模的使用，并提出了未来治疗剂的选择。我们已经探索了纳米技术在GPCR研究中的应用。例如，树枝状聚合物是树状聚合物，在外围有多个功能位点用于配体的附着。我们最近报道了第一个附着GPCR配体的PAMAM树枝状聚合物。这是一个共轭的，A2AAR功能化的同类物是共价附加的。共轭物在人血小板中表现出有效的抗血栓性活性，而母体树枝状聚合物则不活跃。我们使用树枝状聚合物偶联物的多价性来测试与二聚体和高阶多聚体GPCR组件的相互作用。

项目成果

期刊论文数量（48）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Molecular recognition in P2 receptors: ligand development aided by molecular modeling and mutagenesis.

P2 受体中的分子识别：分子建模和诱变辅助的配体开发。

DOI：
10.1016/s0079-6123(08)63550-5
发表时间：
1999
期刊：
Progress in brain research
影响因子：
0
作者：
Jacobson,KA;Hoffmann,C;Kim,YC;Camaioni,E;Nandanan,E;Jang,SY;Guo,DP;Ji,XD;vonKügelgen,I;Moro,S;Ziganshin,AU;Rychkov,A;King,BF;Brown,SG;Wildman,SS;Burnstock,G;Boyer,JL;Mohanram,A;Harden,TK
通讯作者：
Harden,TK

Adenosine and ischemic preconditioning.

腺苷和缺血预处理。

DOI：
发表时间：
1999
期刊：
Current pharmaceutical design
影响因子：
3.1
作者：
Liang,BT;Jacobson,KA
通讯作者：
Jacobson,KA

Liquid chromatographic assay for cerebrospinal fluid normetanephrine.

脑脊液去甲肾上腺素的液相色谱测定。

DOI：
10.1016/0024-3205(87)90384-5
发表时间：
1987
期刊：
Life sciences
影响因子：
6.1
作者：
Marshall,TH;Jacobson,KA;Kirk,KL;Linnoila,M
通讯作者：
Linnoila,M

Exploring human adenosine A3 receptor complementarity and activity for adenosine analogues modified in the ribose and purine moiety.

探索核糖和嘌呤部分修饰的腺苷类似物的人腺苷 A3 受体互补性和活性。

DOI：
10.1016/j.bmc.2004.11.044
发表时间：
2005
期刊：
Bioorganic & medicinal chemistry
影响因子：
3.5
作者：
VanRompaey,Philippe;Jacobson,KennethA;Gross,ArielS;Gao,Zhan-Guo;VanCalenbergh,Serge
通讯作者：
VanCalenbergh,Serge

Chronic administration of adenosine A3 receptor agonist and cerebral ischemia: neuronal and glial effects.