多靶点药物及其研发

某些疾病产生的根源在于多种因素引起基因表达的改变,单靶点药物在治疗这些多因素引起的复杂性疾病时疗效欠佳或毒性较大,而多靶点药物可以同时调节人类疾病网络中的多个环节,对各靶点产生协同效应,故对癌症、神经系统疾病、糖尿病、高血压及艾滋病等有较好的治疗效果。综述多靶点药物的分类、作用特点及其分子设计和筛选策略的研究进展。     

多靶点配体与药物设计

综述有关多靶点配体药物设计的基本原理和方法,包括整合共有药效团法、轭合药效团法、可分解轭合药效团法及筛选法;并讨论多靶点配体与合理药物设计的关系以及设计中应注意的问题,为新药的研究与开发提供参考。     

多靶点作用药物及其设计

疾病起因的多因素性导致单靶点作用药物活性的降低或副作用的增加,利用多靶点作用的药物有可能有利于解决这些问题,本文就多靶点作用药物设计所存在的问题和解决方法进行探讨,提出利用药效团模型法设计多靶点作用药物的理念。     

多靶标作用的药物分子设计

以生物靶标为中心的药物研发，已是当今创制新药的主导模式，该模式的前提是，所有疾病都是由于体内某个蛋白的功能出现障碍所致，若化合物能够调节该蛋白的功能则应具有治疗价值。由此延伸或派生出的各种技术，如新靶标的发现和确证、靶标蛋白的纯化、通量筛选、基于受体结构的分子设计等，[第一段]     

信号传导分子作为药物设计的靶点

近１０多年间分子生物学技术的爆炸式发展,确实并克隆许多调节正常生理功能的蛋白质,部分阐明了它们在疾病状态下的作用,许多疾病与信号传导途径异常有关,因此信号分子可以作为治疗药物设计的靶点,这年来已经成功应用于Ｒａｓ法尼基化合物作为肿瘤抑制剂,ＪＡＫ２阻断剂中作为治疗前Ｂ细胞急性淋巴细胞白血病的有效药物,本简述近年来有关信号传导分子作为疾病的靶点的研究进展。     

多靶点药物治疗进展

近几十年的药物发现研究几乎均集中于寻找或设计作用于单个靶点的高选择性配体药物分子,但是针对单个分子靶点的药物在治疗疾病时通常很难达到预期效果或者毒性很大,很难治愈多基因疾病如肿瘤,以及影响多个组织或细胞的疾病如糖尿病等。多角度攻击疾病系统可以克服许多单靶点药物的局限性,由此产生的多靶点药物治疗（multi—target therapeutics）可以同时调节疾病网络系统中的多个环节,不易产生抗药性,现已在很多晕大疾病的治疗中开始应用。     

新型多靶点抗阿尔茨海默症药物设计的研究进展

阿尔茨海默病(AD)是一种发病率很高的神经系统疾病,最初表现于前脑根部胆酰能神经元选择性丢失,接着是意识和行为能力受损,导致不能自理和适应外界生活,最后导致死亡.目前,临床药物都只能改善症状,不能逆转病理改变.近年来,多种作用于多靶点的新型抗阿尔茨海默症的药物被设计出来,有望成为新一代的AD治疗药物.     

多靶点抗癌药物研究进展

多靶点抗癌药物可提高单靶点药物和多种药物联合用药的治疗效果,且有可能避免联合用药时产生的药物相互作用,降低副作用。在多靶点抗癌药物研究中,可采用"药效团拼合"的方法,将两种或两种以上的药效团拼合成一个分子,使其或其代谢产物作用于两个或两个以上靶点,从而产生协同作用,例如组蛋白去乙酰酶-酪氨酸激酶抑制剂和DNA损伤剂-EGFR抑制剂等。或者,根据靶标结合位点的相似性,设计与合成同时作用于两个或多个靶点的抗癌药物,例如VEGFR-PDGFR抑制剂和TS-DHFR双重抑制剂。本文将对这些多靶点抗癌药物的设计思路及生物活性进行归纳和总结。     

基于Sigma-1受体的多靶点药物研究进展

多靶点药物治疗针对疾病网络系统中的两个或多个相关靶点,同时调节疾病网络系统中的多个环节,从而发挥更好的临床疗效,具有更优越的安全性,现已在多种复杂疾病的治疗中开始应用。Sigma-1受体是一种独特的Ca²⁺敏感伴侣蛋白,主要位于内质网和质膜中,在应激或病理条件下被激活,并通过作用于神经递质受体和离子通道受体等伴侣蛋白调节多种神经信号传导。近年来,研究发现基于Sigma-1受体的多靶点药物对神经痛、阿尔茨海默病、抑郁症、精神分裂症、帕金森病等具有良好的治疗效果,是开发神经系统疾病治疗药物的热门靶点。本文作者对近年来文献报道的Sigma-1受体多靶点药物进行综述,以期为基于Sigma-1受体多靶点药物的研发提供新的思路。     

作用于FTase和Raf-1激酶的新型抗肿瘤药物的设计

Ras/Raf/MEK/ERK信号通路,在肿瘤细胞的增殖、分化、凋亡、转移、代谢等过程中起着重要的作用,本文着眼于Ras/Raf/MEK/ERK信号通路中的关键靶点,以法尼基转移酶(FTase)为主靶点,以Raf-1激酶为次靶点,借助计算机辅助药物设计(CADD),构建法尼基转移酶抑制剂(FTIs)和Raf-1激酶抑制剂的药效团模型,设计出同时与这两个靶点相匹配的多靶点配体药物。所设计的多靶点配体药物以氨甲基苯甲酸为母核结构,具有较好的预测活性。     

分子靶向抗肿瘤药物十年历程启迪

本文综合分析近十年来分子靶向抗肿瘤药物的历程,回顾各类分子靶向抗肿瘤药物的特点,提出分子靶向抗肿瘤药物开发中值得关注的几个问题:如药物的毒副作用、耐受性,个体化治疗与生物标志物,以及预测敏感患者生物标志物研究等。     

多靶点抗肿瘤药物索拉非尼的研究进展

索拉非尼(sorafenib)是小分子的多靶点口服抗癌新药,不仅能抑制RAF-MEK-ERK通路,还能抑制VEGFR,PDGFR,Flt-3c,-Kit等多种受体型酪氨酸激酶的活性,从而达到抑制肿瘤细胞增殖和肿瘤新生血管生成的作用。美国FDA先后批准其用于晚期肾癌和肝癌的治疗,推荐剂量为400 mg,bid。与安慰剂比较,索拉非尼可明显延长患者的无进展生存期和总生存期。索拉非尼的主要不良反应有手足综合征、高血压、腹泻、皮疹、乏力。大多数不良反应可通过减少药物用量或停药而得到缓解。     

Cell-specific aptamers and their conjugation with nanomaterials for targeted drug delivery

Introduction: Aptamers are short, single-stranded DNA or RNA sequences that can fold into complex secondary and tertiary structures and bind to various target molecules with high affinity and specificity. These properties, as well as rapid tissue penetration and ease of chemical modification, make aptamers ideal recognition elements for in vivo targeted drug delivery and attractive molecules for use in disease diagnosis and therapy.

Areas covered: The general properties of aptamers as well as advantages over their counterpart antibodies are briefly discussed. Next, aptamer selection by cell- systematic evolution of ligands by exponential enrichment is described in detail. Finally, the review summarizes recent progress in the field of targeted drug delivery based on aptamers and their conjugation to liposomes, micelles and other nanomaterials.

Expert opinion: Advances in nanotechnology have led to new and improved nanomaterials for biomedical applications. Conjugation of nanoparticles (NPs) with aptamers exploits both technologies, making aptamer-NP conjugates ideal agents for drug delivery with proven therapeutic effects and the reduction of toxicity to normal tissue. The use of multivalent aptamer-conjugated nanomaterials represents one of the new directions for drug development in the future; as such, continuing studies of these multivalent aptamers and bioconjugates should result in important clinical applications in targeted drug delivery.     

Polymeric micelles for targeted tumor therapy of platinum anticancer drugs

Introduction: Platinum anticancer drugs are effective against a wide range of tumors, though their severe adverse effects and resistance remain unresolved. A breakthrough in these drawbacks could be achieved by using polymeric micelles, i.e. nanoassemblies having a drug loaded core and a protective hydrophilic shell, incorporating platinum drugs for tumor-targeted delivery.

Areas covered: The development of cisplatin- (NC-6004) and DACHPt-loaded micelles (NC-4016) has been reviewed, particularly, from the viewpoint of the effect of their structural features on the tumor-targeting efficacy. We have also described new approaches for molecular targeting by installing ligand moieties on the surface of micelles. Moreover, small platinum drugs and platinum drug-loaded nanocarriers are introduced to explain the context for developing platinum drug-loaded polymeric micelles.

Expert opinion: NC-6004 and NC-4016 micelles meet critical structural and functional requirements for achieving safe and effective tumor targeting, enhancing efficacy even against drug resistant cancer cells, and have been translated into human studies, aiming to be the first-of-their-kind in the clinic. Due to their flexible design, polymeric micelles could readily integrate new features based on the knowledge arising from the human clinical trials toward the development of innovative formulations with superior performance.     

肝靶向给药系统的研究进展

通过对近年来国内外报道的肝靶向研究相关文献进行检索,根据肝靶向药物的不同作用机制对肝靶向给药系统的研究进展进行分析和总结。有关肝靶向药物的研究结果表明,肝靶向给药系统能选择性地将药物输送至肝脏病变部位,通过提高其在肝脏病变组织的药物浓度,从而达到增强药物疗效、减少其毒副作用的目的。因此,肝靶向给药系统在肝脏疾病治疗方面具有广阔的应用前景。     

基于多元回归-灰色模型的非小细胞肺癌靶向药物用量预测分析

目的 建立非小细胞肺癌(NSCLC)常用靶向药物的用量预测模型,为指导医疗机构抗肿瘤靶向药物的采购和库存管理提供数据支撑.方法 参考天津市肿瘤医院2019年各月的靶向药物用量数据,以4种临床常用的NSCLC靶向药物(吉非替尼、埃克替尼、奥希替尼和克唑替尼)为例,建立多元回归模型、GM(1,1)灰色模型以及多元回归-灰色...     

Liposomes for targeted delivery of antithrombotic drugs

Background: Targeted delivery of antithrombotic (thrombolytic) drugs is expected to increase their efficacy and decrease side effects, especially in the case of thrombolytic enzymes. Liposomes, phospholipid nanosized bubbles with a bilayered membrane structure, have drawn a lot of interest as pharmaceutical carriers for drugs and genes. In particular, several attempts have been made to use liposomes as vehicles for antithrombotic agents. Objective: This review analyzes the available data on the application of liposomes, including liposomes targeted by specific ligands, for the delivery of antithrombotic/thrombolytic agents in order to increase their efficacy and decrease side effects. Methods: The papers published on the subject of liposomes loaded with antithrombotic agents, mainly over the last 10 – 15 years, will be discussed. Conclusion: Liposomes loaded with various antithrombotic drugs, though they have been the subject of a significant number of experimental papers, can hardly be considered as real candidates for clinical application in the near future.     

依据药物作用的靶分子结构进行新药设计的方法

依据药物作用的靶分子结构进行新药设计,作为药物研究中的新方法使新药的研发过程正在从一种偶然性,经验性的过程逐渐走向一种合理的,科学的研发过程,作者在结合国内外有关文献基础上对这一方法的基本原理和基本过程进行综述。