两亲α-螺旋抗菌肽的分子设计研究现状与进展

抗菌肽以其广谱、快速、特异性作用及抗菌、抗病毒、抗肿瘤等活性,成为具有重要潜在价值的新型药物.最大限度地发挥其活性和降低毒性,是抗菌肽新药开发的首要问题.用分子设计手段改造抗菌肽已成为解决这一问题的关键.以两亲α-螺旋抗菌肽为对象,对分子设计过程中遵守阳离子性和两亲性的原则及影响活性的物理化学参数,可以采取序列修饰或全新设计的方法,以达到定向改造的目的.对分子设计在医药上的应用和发展前景进行了综述和展望.     

阳离子抗菌肽的作用机理及构效关系

阳离子抗菌肽是一类具有广谱抗菌、抗病毒活力,能抑制肿瘤细胞和调节免疫能力的带正电荷的短肽.本文对其作用机理及构效关系作出综述.     

贻贝抗菌肽贻贝素研究进展

抗菌肽作为一种免疫因子在无脊椎动物中广泛存在,能够在生物体内迅速合成;具有广谱抗菌活性,对细菌、真菌、原生动物等都有作用,但对真核细胞无毒害;分子质量一般在9．92ku以下;多数是阳离子分子。对贻贝免疫防御中扮演重要角色的抗菌肽一贻贝素（Mytilins）的分子结构与分类、基因结构、抗菌谱、表达定位及其作用机制进行了综述。     

阳离子抗菌肽的研究进展

阳离子抗菌肽是一类具抗微生物活性的小分子多肽，按结构特征可分为α－螺旋肽和β－折叠肽，不同来源或同一抗菌肽的不同结构形式生物活性差别较大，部分抗菌肽之间或抗菌肽与抗生素之间存在协同作用，特别是最近发现一些抗菌肽具有抗内毒素活性。阳离子抗菌肽的结构特征是其发挥作用的重要基础，α－螺旋肽通过其两亲性的α－螺旋上的正电茶与细菌细胞膜磷脂分子的负电荷之间的静电吸引而结合在细菌膜上，并借助于疏水段分子中连接结构的柔性插入到细胞膜中，最终通过膜内分子间的相互位移使抗菌肽分子相互聚集在一起形成离子通道，使细菌失去膜势，不能保持正常的渗透压而死亡。一般认为β－折叠肽也是和细胞膜结合后，结构发生变化而发挥作用。抗菌肽和细胞膜结合及形成离子通道受多种因素的影响，如阳离子抗菌肽的结构、浓度，环境 pH、温度，介质的离子强度。阳离子抗菌肽杀菌力强，抗菌谱广，不良反应少，因此在食品、农业，特别是在医药领域都有很好的应用前景，极可能发展成为一类全新的抗生素。     

抗菌肽开发与应用的研究进展

抗菌肽是一类普遍存在于生物体内的阳离子两亲性多肽,是机体免疫防御的重要组成部分,具有抗菌谱广、作用强且迅速、不易产生耐药等众多优点.随着多药耐药菌临床感染的日趋加重,抗菌肽引起了人们的广泛关注,成为一类极具开发潜力的新型抗感染制剂.但生产成本高、毒副作用大和体内药动学资料匮乏严重制约了抗菌肽的开发和应用.针对上述瓶颈,国内外进行了大量的研究,已取得显著的成果.本文主要针对抗菌肽的作用特点、作用机制、研究现状,及其在医药领域中的应用前景和存在问题进行综述.     

抗菌肽protegrin的开发现状与作用机制研究

目的针对抗菌肽protegrin的开发现状、作用机制及研究方法等方面的文献进行了检索及总结,希望有助于同行在现有工作的基础上开发新型的抗菌肽。方法对国内外最新发表的抗菌肽protegrin的相关研究结果进行分析、整理和综合。结果抗菌肽protegrin是目前国际上研究比较深入的抗菌肽之一,而国内还没有相关的开发报道。结论抗菌肽protegrin是一种非常有应用价值和开发前途的新型抗菌物质。     

抗菌肽protegrin的开发现状与作用机制研究

目的针对抗菌肽protegrin的开发现状、作用机制及研究方法等方面的文献进行了检索及总结,希望有助于同行在现有工作的基础上开发新型的抗菌肽。方法对国内外最新发表的抗菌肽protegrin的相关研究结果进行分析、整理和综合。结果抗菌肽protegrin是目前国际上研究比较深入的抗菌肽之一,而国内还没有相关的开发报道。结论抗菌肽protegrin是一种非常有应用价值和开发前途的新型抗菌物质。     

抗菌肽buforinⅡ结构及其抗菌和抗癌活性研究进展

抗生素滥用加速了细菌产生抗生素耐药性,抗菌肽作为对抗抗生素耐药细菌的潜在候选药物备受关注.buforinⅡ作为其中一种潜力分子成为目前的研究热点.buforinⅡ的结构类似于阳离子α螺旋抗菌肽,其"螺旋-脯氨酸铰链-双亲性螺旋"的独特结构在抗菌和抗癌等方面起决定性作用.通过截短、替换和拼接等策略对buforinⅡ及其同...     

天然抗生素—抗菌肽

目的概述抗菌肽的分类、结构特征、生物活性、作用机制,指出抗菌肽研究的存在问题及应用前景。方法查阅中、英文相关文献20篇,对蟾饲五谷虫抗菌肽进行详细的概括总结。结果通过对抗菌肽的了解,了解到抗菌肽的种类,理化性质,结构特点以及家蝇抗菌肽的作用特点。结论抗菌肽的性质明确,作用机制完善,适合未来抗生素的开发利用。     

肿瘤坏死因子诱导人角质形成细胞β-防御素-2表达的研究

<正>人体的皮肤组成了抵抗外来病原微生物的第一道屏障,其中各种细胞因子和抗菌肽发挥着重要作用,近来发现的一种阳离子小分子多肽——β-防御素-2(hBD-2)是抗菌肽家族的一员。hBD-2主要由上皮细胞产生,广泛存在于皮肤、黏膜上皮组织中,具有广谱的抗菌作用,也有实验表明肿瘤组织中有hBD-2表达,而这些hBD-2有助于机体的抗肿瘤免疫[1],为     

Antimicrobial peptides in animals and their role in host defences

Domesticated animals have a large variety of antimicrobial peptides that serve as natural innate barriers limiting microbial infection or, in some instances, act as an integral component in response to inflammation or microbial infection. These peptides differ in size, composition, mechanisms of activity and range of antimicrobial specificities. They are expressed in many tissues, polymorphonuclear leukocytes, macrophages and mucosal epithelial cells. There is a small group of anionic antimicrobial peptides found in ruminants and a much larger group of cationic antimicrobial peptides found in all domesticated animals. The cationic peptides include linear, helical peptides, linear peptides rich in proline and cysteine-stabilized peptides with a beta-sheet and are commonly referred to as cathelicidins and defensins. These peptides are generally broad-spectrum for Gram-positive bacteria, Gram-negative bacteria and fungi (e.g. myeloid antimicrobial peptides, alpha-, beta-defensins, and protegrins) or are specific to one of these groups (e.g. porcine cecropin P1, Bac5, Bac7, PR-39 and prophenin).     

Synthesis of cationic antimicrobial β(2,2)-amino acid derivatives with potential for oral administration

We have prepared a series of highly potent achiral cationic β(2,2)-amino acid derivatives that fulfill the Lipinski's rule of five and that contain the basic structural requirements of short cationic antimicrobial peptides. Highest antimicrobial potency was observed for one of the smallest β(2,2)-amino acid derivatives (M(w) 423.6) exhibiting a MIC of 3.8 μM against methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus epidermidis (MRSE), and Staphylococcus aureus, and 7.7 μM against Escherichia coli. The β(2,2)-amino acid derivatives were shown to have similar absorption properties as several commercially available drugs, and the results implied a resembling membrane disrupting mechanism of action as reported for much larger cationic antimicrobial peptides. By their high potency, nontoxicity, absorption properties, and ease of synthesis, the β(2,2)-amino acid derivatives demonstrate a way to modify a vastly investigated class of cationic antimicrobial peptides into small drug-like molecules with high commercial potential.     

Antimicrobial peptides: Their physicochemical properties and therapeutic application

Antibiotic resistance has become a global public health problem, thus there is a need to develop a new class of antibiotics. Natural antimicrobial peptides have got an increasing attention as potential therapeutic agents. Antimicrobial peptides are small cationic peptides with broad antimicrobial activity. They can serve as critical defense molecules protecting the host from the invasion of bacteria. Even though they possess a different mode of action compared to traditional antibiotics, antimicrobial peptides couldn’t go into the drug markets because of problems in application such as toxicity, susceptibility to proteolysis, manufacturing cost, size, and molecular size. Nevertheless, antimicrobial peptides can be new hope in developing novel, effective and safe therapeutics without antibiotic resistance. Thus, it is necessary to discover new antimicrobial sources in nature and study their structures and physicochemical properties more in depth.     

Survey of small antifungal peptides with chemotherapeutic potential

Many cationic peptides with antimicrobial properties have been isolated from bacteria, fungi, plants, and animals. These peptides vary in molecular size, potency and spectra of activities. This report surveyed the literature to highlight the peptides that have antifungal activity and greatest potential for development as new therapeutic agents. Thus, to be included in the evaluation, each peptide had to fulfil the following criteria: (i) potent antifungal activity, (ii) no, or minimal, mammalian cell toxicity, (iii) of ≤25 amino acids in length, which minimises the costs of synthesis, reduces immunogenicity and enhances bioavailability and stability in vivo, (iv) minimal post-translational modifications (also reduces the production costs). The ~80 peptides that satisfied these criteria are discussed with respect to their structures, mechanisms of antimicrobial action and in vitro and in vivo toxicities. Certainly, some of these small peptides warrant further study and have potential for future exploitation as new antifungal agents.     

Synthetic antimicrobial peptidomimetics with therapeutic potential

A series of synthetic antimicrobial peptidomimetics (SAMPs) have been prepared and found to be highly active against several Gram-negative and Gram-positive bacterial strains. These derivatives comprise the minimal structural requirements for cationic antimicrobial peptides and showed high selectivity for Gram-negative and/or Gram-positive bacteria compared to human red blood cells. We have found that SAMPs share many of the attractive properties of cationic antimicrobial peptides inasmuch that a representative SAMP was found to insert into the bilayers of large unilamellar vesicles, permeabilized both the outer and cytoplasmic membrane of Escherichia coli ML-35p, and displayed an extremely rapid bacterial killing for Staphylococcus aureus. However, while antimicrobial peptides are prone to proteolytic degradation, high in vitro stability in human blood plasma was shown for SAMPs. A combination of high antibacterial activity against methicillin-resistant staphylococci and low toxicity against human erythrocytes makes these molecules promising candidates for novel antibacterial therapeutics.     

Cationic antimicrobial peptides: towards clinical applications

Cationic antimicrobial peptides are important components of the innate immune defences of all species of life. Variants of these natural molecules have a broad range of antibiotic, antifungal, antiviral and anti-endotoxic activity. Two of these cationic peptides have shown signs of efficacy in early clinical trials of oral mucositis and the sterilisation of central venous catheters, respectively and are currently proceeding through Phase III clinical trials. Thus, cationic antimicrobial peptides are currently being investigated as topical agents. In addition, the cationic protein rBPI 21 has recently completed Phase III clinical trials of parenteral use for meningococcaemia.     

Cationic antimicrobial peptides: towards clinical applications

Cationic antimicrobial peptides are important components of the innate immune defences of all species of life. Variants of these natural molecules have a broad range of antibiotic, antifungal, antiviral and anti-endotoxic activity. Two of these cationic peptides have shown signs of efficacy in early clinical trials of oral mucositis and the sterilisation of central venous catheters, respectively and are currently proceeding through Phase III clinical trials. Thus, cationic antimicrobial peptides are currently being investigated as topical agents. In addition, the cationic protein rBPI 21 has recently completed Phase III clinical trials of parenteral use for meningococcaemia.     

Effects of lysine-to-arginine substitution on antimicrobial activity of cationic stapled heptapeptides

We previously reported a series of amphipathic helices of stapled heptapeptides as membrane-lytic antimicrobial peptides. These peptides possess three lysine residues as the sole cationic amino acid residues in their hydrophilic face of the helix. Lysine-to-arginine substitution is often shown to increase antimicrobial activity of many natural AMPs due to the more favorable interactions of guanidinium moiety of arginine with membranes. In an effort to further improve the pharmacological properties of our novel AMP series, we here examined the impact of lysine-to-arginine substitution on their structures and antimicrobial and hemolytic activities. Our results indicate that the lysine-to-arginine substitution does not always guarantee enhancement in the antimicrobial potency of AMPs. Instead, we observed varied potency and selectivity depending on the number of substitutions and the positions substituted. Our results imply that, in the given helical scaffold stabilized by a hydrocarbon staple, antimicrobial potency and selectivity are influenced by a complex effect of various structural and chemical changes accompanied by lysine-to-arginine substitution rather than solely by the type of cationic residue. These data show potential for use in our scaffold-assisted development of short, selective, and metabolically stable AMPs.     

Society for general microbiology - 148th ordinary meeting. Activities and actions of antimicrobial peptides. 26-30 March 2001, Edinburgh, UK

The rapidly expanding field of antimicrobial peptides is one that is attracting increasing interest from research groups around the world. The importance of antimicrobial agents in providing alternatives to conventional antibiotics has been highlighted in recent years by the emergence of a number of multidrug-resistant pathogens, such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). Indeed, bacteria refractory to treatment by all known antibiotics are now a reality and the need for developing novel antimicrobial agents is urgent. This meeting brought together researchers working in a number of varied, but ultimately related areas. The functional diversity and putative mechanisms of action of antimicrobial peptides were discussed in depth, along with recent developments in the design of synthetic peptides with enhanced antimicrobial properties. Several ongoing studies were described, ranging from research into cystic fibrosis to work in the food industry. It was emphasized that cationic antimicrobial peptides have a range of properties to offer the world of scientific research and may play an important role in the ongoing battle against pathogenic microorganisms. Oral presentation sessions of the conference were co-chaired by Dr Deirdre A Devine (University of Leeds, UK) and Dr David G Smith (University of Edinburgh, UK).     

The pharmacology of radiolabeled cationic antimicrobial peptides

Cationic antimicrobial peptides are good candidates for new diagnostics and antimicrobial agents. They can rapidly kill a broad range of microbes and have additional activities that have impact on the quality and effectiveness of innate responses and inflammation. Furthermore, the challenge of bacterial resistance to conventional antibiotics and the unique mode of action of antimicrobial peptides have made such peptides promising candidates for the development of a new class of antibiotics. This review focuses on antimicrobial peptides as a topic for molecular imaging, infection detection, treatment monitoring and additionally, displaying microbicidal activities. A scintigraphic approach to studying the pharmacokinetics of antimicrobial peptides in laboratory animals has been developed. The peptides were labeled with technetium-99m and, after intravenous injection into laboratory animals, scintigraphy allowed real-time, whole body imaging and quantitative biodistribution studies of delivery of the peptides to the various body compartments. Antimicrobial peptides rapidly accumulated at sites of infection but not at sites of sterile inflammation, indicating that radiolabeled cationic antimicrobial peptides could be used for the detection of infected sites. As the number of viable micro-organisms determines the rate of accumulation of these peptides, radiolabeled antimicrobial peptides enabled to determine the efficacy of antibacterial therapy in animals to be monitored as well to quantify the delivery of antimicrobial peptides to the site of infection. The scintigraphic approach provides to be a reliable method for investigating the pharmacokinetics of small cationic antimicrobial peptides in animals and offers perspective for diagnosis of infections, monitoring antimicrobial therapy, and most important, alternative antimicrobial treatment infections with multi-drug resistant micro-organisms in humans.