神经系统多肽（蛋白）药物研发现状与前景

首先介绍体内神经肽是最可能成为神经系统多肽药物的,进而介绍已成功应用于临床治疗神经系统疾患有关的多肽蛋白药物和正在研发的多肽蛋白神经系统药物。     

长效化融合蛋白药物及其药动学分析技术的研究进展

融合蛋白技术应用于生物制药行业已超过25年,其目的为改善原来天然蛋白的性质,从而具有新的理化特征和生物学功能,其中最为显著的特点是改善了小分子蛋白及多肽半衰期短的缺陷。基于该技术所诞生的融合蛋白类药物已成为当前生物药研发的热点。结合已上市融合蛋白类药物,通过与传统多肽蛋白类药物比较,重点突出融合蛋白类药物自身特点,主要从融合抗体Fc段和人血清白蛋白以延长小分子蛋白及多肽半衰期的角度对融合蛋白药物长效化策略进行评述;对融合蛋白类药物在体内的吸收、分布、代谢和排泄的显著特征进行概述;综述该类药物在体内的分析技术并指出当前分析技术的优缺点及发展方向,为长效化融合蛋白药物的设计、分析研究与开发提供依据和思路。     

一种多肽固相合成方法与纯化策略研究

目的: 多肽与小分子化学药物相比,具有生物活性高、特异性强、不容易产生耐药性等特点,是目前新型药物研发的重点领域。多肽的合成直接影响到多肽药物的作用机制以及药物效果,因此需要建立一种更加便捷、高效的多肽合成方法。方法: 采用Fmoc固相合成法合成多肽HF01,通过比较氨基酸连接的反应体系以及氨基酸脱保护的反应体系,从中确定最优体系。利用乙酰化基团进行肽链末端保护,经肽链剪切制备干燥的粗肽,最后采用高效液相色谱仪与高分辨质谱仪联用对粗肽进行纯化。结果: 确定多肽合成的连接和脱保护反应体系,并获得纯度高达98.3%的线性多肽。结论: 建立了一种高效、便捷的多肽合成及纯化方法,提高了实验室合成多肽的效率,为多肽类药物的研发提供技术支撑。     

多肽介导的核酸药物递送系统研究进展

核酸药物作为新型基因治疗药物备受关注,但生物学稳定性差、易被体内核酸酶降解、生物利用度低、靶组织内聚集浓度低等是制 约其发展的主要因素。新的药物递送技术的快速发展在一定程度上解决了核酸药物的稳定性及靶向递送问题,极大地推动了核酸药物的研 发进展。尤其是多肽蛋白类递送载体,已成为核酸药物递送系统研究领域的热点之一。介绍核酸药物递送载体多肽修饰的两种主要方式—— 共价缀合和非共价络合,重点综述近年来多肽缀合物和复合物以及多肽修饰的载体在核酸药物递送系统中的应用研究,探讨多肽介导的核 酸药物递送系统在应用中存在的问题,为新型核酸药物递送系统研发提供参考。     

糖尿病相关VPAC、PAC受体及其药物研发的进展

VPAC、PAC受体是近年发现的开发2型糖尿病药物的重要靶标,垂体腺苷酸环化酶激活多肽(PACAP)、血管活性肠肽(VIP)则是它们的天然配体,与受体结合激活后能促进葡萄糖依赖性胰岛素分泌,既能保护细胞又不引起胰高血糖素分泌和糖原分解,因此其配体相关化合物的开发研究成为开发2型糖尿病药物的重要方向。目前针对VPAC、PAC受体开发的配体类似物主要包括了肽类和非肽类小分子两大类,但它们仍然存在诸多不足,至今仅有一个药物进入到临床研究阶段。本综述系统总结了目前针对VPAC、PAC受体为靶标的肽类和非肽小分子药物的开发研究现状,可为将来此类药物的研发提供参考。     

动物毒素及相关药物研究进展

动物毒素是指有毒动物毒器分泌的毒液中,结构和功能丰富多样的蛋白质和多肽,其具有高活力、高结构多样性、高专一性等特点, 是药物开发的重要资源。综述了动物毒素药物的特点以及进入临床药物和候选药物分子的研究进展,同时分析了我国动物毒素类药物研发 中需要重视的问题。     

噬菌体肽库的构建策略

目的多肽的筛选可通过亲和筛选直接得到富集,并具有繁殖性,目前已广泛应用于多肽药物的开发,蛋白分子结构与功能的研究,疫苗研制等多种领域,特别是对于抗原决定簇的精确定位,蛋白分子之间,蛋白与核酸分子之间相互作用的结合模型和生物活性小配体的获得以及在未知蛋白分子一级结构的情况下直接获取其空间结构方面是一个非常有效的研究工具。     

细胞穿膜肽介导蛋白/多肽类药物输送的研究进展

在当前药物研发中,蛋白/多肽类药物占据着重要地位。然而,此类药物大多需进入细胞内才能发挥作用,故细胞摄取率低的问 题成为制约其发展的关键因素。细胞穿膜肽是一类富含精氨酸的短肽,自身具有较强的生物膜穿透能力,可携带多种大分子甚至是纳米 粒入胞。因此,穿膜肽被广泛应用于药物输送,且基于穿膜肽介导药物胞内输送,成为解决蛋白/多肽类药物入胞问题的优选策略。主 要综述穿膜肽介导蛋白/多肽类药物输送用于不同疾病治疗的研究进展。     

综述与专论：蛋白质错误折叠相关疾病的多肽药物研究进展

蛋白质和多肽发生错误折叠形成不可溶的淀粉样纤维的过程,与阿尔茨海默病、帕金森病等多种神经退行性疾病密切相关。这些疾病可导致认知能力下降以及运动缺陷等症状。虽然已有多种相关治疗方案处于临床试验中,但目前仍无明确有效的方法可治愈或长期减缓疾病的进展。探寻和研究抑制淀粉样聚集、识别并促进毒性聚集物清除的抑制剂分子是药物研发的重要策略之一。在不同类型的抑制剂中,多肽类抑制剂因具有高特异性、低毒性、多样性,以及修饰后的抗水解稳定性和血脑屏障通透性,有望成为候选药物分子。本文总结了针对阿尔茨海默病相关的Aβ和Tau蛋白以及帕金森病相关的α-synuclein蛋白淀粉样纤维化的多肽抑制剂研究进展。基于淀粉样纤维化核心序列及纤维核心结构进行合理设计,或通过随机筛选,均可获得多肽抑制剂。这些天然和非天然的多肽分子大多具有抑制淀粉样纤维化、解聚成熟纤维和降低细胞毒性的作用,其中一些多肽在退行性疾病动物模型实验中,显示出降低脑损伤和缓解认知及运动障碍的效果。这些研究揭示了多肽作为蛋白质错误折叠和聚集相关疾病药物的特点,为研发一类新的有效药物奠定了基础。     

蛋白质错误折叠相关疾病的多肽药物研究进展

蛋白质和多肽发生错误折叠形成不可溶的淀粉样纤维的过程,与阿尔茨海默病、帕金森病等多种神经退行性疾病密切相关。这些疾病可导致认知能力下降以及运动缺陷等症状。虽然已有多种相关治疗方案处于临床试验中,但目前仍无明确有效的方法可治愈或长期减缓疾病的进展。探寻和研究抑制淀粉样聚集、识别并促进毒性聚集物清除的抑制剂分子是药物研发的重要策略之一。在不同类型的抑制剂中,多肽类抑制剂因具有高特异性、低毒性、多样性,以及修饰后的抗水解稳定性和血脑屏障通透性,有望成为候选药物分子。本文总结了针对阿尔茨海默病相关的Aβ和Tau蛋白以及帕金森病相关的α-synuclein蛋白淀粉样纤维化的多肽抑制剂研究进展。基于淀粉样纤维化核心序列及纤维核心结构进行合理设计,或通过随机筛选,均可获得多肽抑制剂。这些天然和非天然的多肽分子大多具有抑制淀粉样纤维化、解聚成熟纤维和降低细胞毒性的作用,其中一些多肽在退行性疾病动物模型实验中,显示出降低脑损伤和缓解认知及运动障碍的效果。这些研究揭示了多肽作为蛋白质错误折叠和聚集相关疾病药物的特点,为研发一类新的有效药物奠定了基础。     

多肽类药物的研究进展

多肽在包括细胞增殖分化、免疫防御、肿瘤病变等在内的生命活动过程中起着至关重要的作用。自 1953 年首个人工合成的具有生 物活性的多肽问世至今,全球上市的多肽药物有 80 多个,有大量多肽药物进入临床研究。多肽类药物具有独特的优势：活性显著、特异性 强、毒性较弱,在体内不易产生蓄积,与其他药物的相互作用比较少。综述了目前国内外多肽药物的发展情况,希望对从事多肽类药物研 发的同行有所帮助。     

Invasive aspergillosis: clinical manifestations and treatment

During the last decade the incidence of invasive aspergillosis has substantially grown due to the increasing use of powerful immunosupressive drugs in more patients. Unfortunately, the associated mortality with this infection is still very high and has not decreased in recent years. Pulmonary aspergillosis is by far the most frequent clinical picture of this infection, followed by sinus, tracheo-bronchial and central nervous system disease. The degree of immunosupression is the main factor influencing the evolution and dissemination of aspergillosis. Conventional amphotericin B has been the first-line therapy of invasive aspergillosis for the last 30 years, and most authors have long considered amphotericin B related toxicity as one of the main causes for the poor results obtained in the outcome of patients who developed this infection. Fortunately, in the last few years new safer and more effective drugs have been developed for the treatment of this entity. However, if we are really trying to substantially decrease invasive aspergillosis associated-mortality we should use these drugs earlier in the development of the infection, using new more sensitive diagnostic tests and/or a riskbase strategy which could identify patients at the highest risk to develop this infection.     

Structure aided design of chimeric antibiotics

The rise of antibiotic resistance is of great clinical concern. One approach to reducing the development of resistance is to co-administer two or more antibiotics with different modes of action. However, it can be difficult to control the distribution and pharmacokinetics of two drugs to ensure both concentrations remain within the range of therapeutic efficacy whilst avoiding adverse effects. Hybrid drugs, where two drugs are linked together with a flexible linker, have been explored, but the resultant large, flexible molecules can have poor bioavailability. We have developed a chimeric approach using click chemistry where the pharmacophores of two drugs are overlapped into a single smaller, more drug-like molecule. Design and selection of compounds were assisted by in silico structural docking. We prepared a series of compounds that include candidates showing activity against the targets of both trimethoprim; dihydrofolate reductase, and ciprofloxacin; DNA gyrase and topoisomerase IV. The resultant triazole containing molecules show modest, but broad spectrum activities against drug sensitive and resistant Gram-negative and Gram-positive bacteria, with no observable cytotoxicity.     

Exoproteome and Secretome Derived Broad Spectrum Novel Drug and Vaccine Candidates in Vibrio cholerae Targeted by Piper betel Derived Compounds

Vibrio cholerae is the causal organism of the cholera epidemic, which is mostly prevalent in developing and underdeveloped countries. However, incidences of cholera in developed countries are also alarming. Because of the emergence of new drug-resistant strains, even though several generic drugs and vaccines have been developed over time, Vibrio infections remain a global health problem that appeals for the development of novel drugs and vaccines against the pathogen. Here, applying comparative proteomic and reverse vaccinology approaches to the exoproteome and secretome of the pathogen, we have identified three candidate targets (ompU, uppP and yajC) for most of the pathogenic Vibrio strains. Two targets (uppP and yajC) are novel to Vibrio, and two targets (uppP and ompU) can be used to develop both drugs and vaccines (dual targets) against broad spectrum Vibrio serotypes. Using our novel computational approach, we have identified three peptide vaccine candidates that have high potential to induce both B- and T-cell-mediated immune responses from our identified two dual targets. These two targets were modeled and subjected to virtual screening against natural compounds derived from Piper betel. Seven compounds were identified first time from Piper betel to be highly effective to render the function of these targets to identify them as emerging potential drugs against Vibrio. Our preliminary validation suggests that these identified peptide vaccines and betel compounds are highly effective against Vibrio cholerae. Currently we are exhaustively validating these targets, candidate peptide vaccines, and betel derived lead compounds against a number of Vibrio species.     

蛋白多肽类药物制剂的研究进展

相对于其他的给药途径,蛋白质多肽类药物的口服、经鼻、肺部给药途径更具可行性和商业价值。利用制剂学方法可提高蛋白质多肽类药物生物利用度。通过蛋白多肽类给药系统的评价,对近年来国内外此类药物在剂型、体内外稳定性及生物利用度等方面的研究进展予以综述。     

Animal experimentation: a rational approach towards drug development

Man's observation of animals as objects of study undoubtedly began in prehistoric times. The first recorded attempt involving the use of live animals for research was by Ersistratis in Alexandria in 300 B.C. Animal investigation has clearly made possible the enormous advances in drug development in this century. A cursory review of any modern text book of pharmacology or medicine will attest the many drugs currently available to benefit mankind in the struggle to eradicate and control diseases. The main purpose of this article is to describe some of the experimental work on animals which contributed to the discovery and development of drugs benefiting human beings and other animal species. Since animal experimentation has occupied a focal position in all the research leading to useful drugs, one will appreciate that it will be necessary to limit the discussion to certain aspects of this broad and interesting topic. With this in mind, an attempt is made to relate briefly the nature of animal investigations which were instrumental in the development of major classes of drugs. Some attention has also been focused on legislation's on animal experimentation of some developed countries with emphasis on India and to views on animal experimentation. We hope this article will stimulate the minds of the scientists for a rational debate on the future of animal experimentation.     

我国核酸药物市场分析及对策建议

近年来,因兼具基因修饰和传统药物的双重特点,核酸药物已逐渐成为精准生物医学和疾病治疗的热点。为进一步推动我国核酸药物行业创新发展,采用定量分析和定性分析相结合的方法,对国内外核酸药物获批/授权、市场和研发情况进行分析,揭示全球ASO、siRNA、RNA aptamer及mRNA等四大类核酸药物的产业发展态势,系统梳理我国支持核酸药物创新发展的政策与措施,明确未来的技术主攻方向和应用潜力。面对国内基因治疗的迫切需求及核酸药物创制的严峻形势,研究提出推动源头创新、完善成果转移转化机制和营造良好竞争环境等对策建议。     

Applications of viral nanoparticles in medicine

Several nanoparticle platforms are currently being developed for applications in medicine, including both synthetic materials and naturally occurring bionanomaterials such as viral nanoparticles (VNPs) and their genome-free counterparts, virus-like particles (VLPs). A broad range of genetic and chemical engineering methods have been established that allow VNP/VLP formulations to carry large payloads of imaging reagents or drugs. Furthermore, targeted VNPs and VLPs can be generated by including peptide ligands on the particle surface. In this article, we highlight state-of-the-art virus engineering principles and discuss recent advances that bring potential biomedical applications a step closer. Viral nanotechnology has now come of age and it will not be long before these formulations assume a prominent role in the clinic.     

Cell penetrating peptide-modified pharmaceutical nanocarriers for intracellular drug and gene delivery

Cell-penetrating peptides (CPPs) including TAT peptide (TATp) have been successfully used for intracellular delivery of a broad variety of cargos including various nanoparticulate pharmaceutical carriers (liposomes, micelles, nanoparticles). Here, we will consider the main results in this area, with a special emphasis on TATp-mediated delivery of liposomes and DNA. We will also address the development of "smart" stimuli-sensitive nanocarriers, where cell-penetrating function can be activated by the decreased pH only inside the biological target minimizing thus the interaction of drug-loaded nanocarriers with nontarget cells.     

EmPLiCS: an empirical approach for structure-based design of natural peptide drugs

The computer implementation of a peptide drug-design strategy has been developed. The system is named EmPLiCS (Empirical Peptide Ligand Construction System) according to the strategy of the system, which searches for peptide-ligand structures by referring to empirical rules that are derived from known protein 3D structures. The system was tested on several known peptide-protein complexes. The results demonstrated the ability of this system to detect key residues of peptides that are crucial for interaction with their specific proteins. The system also showed the ability to detect the main chain trace of these peptides. Some of the main chain atoms were detected even though the complete primary structures were not reproduced, suggesting that main chain structure is important in peptide-protein recognition. The results of the present study demonstrated that the empirical rules-based system can generate significant information for use in the design of natural peptide drugs.