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1.
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。  相似文献   

2.
多肽/蛋白质类药物普遍存在体内半衰期短的问题,使其应用受到了限制。近年来,蛋白质半衰期的研究取得了很大的进展,许多技术已经被提出并测试延长治疗性蛋白的作用时间,如与其他蛋白基因融合(免疫球蛋白域或血清蛋白,如白蛋白)、与聚合物结合(PEG化修饰、聚唾液酸化、HEP化等)。这些技术主要基于本身较长的半衰期及循环机制调控以延长多肽/蛋白质类药物的半衰期。针对上述的多种长效化方式及相关产品进行了综述与讨论,以期为此类药物的长效化研究提供思路。  相似文献   

3.
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。  相似文献   

4.
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。  相似文献   

5.
长效重组药物研究进展   总被引:2,自引:0,他引:2  
生物重组药物半衰期的长短显著影响药物在使用时的剂量以及治疗的效果,所以延长其在体内的生物半衰期,防止药物在体内迅速降解成为现在药物研究的重要方向之一.针对目前较为广泛使用的几种重组药物长效化方法.如定点突变、化学修饰、基因融合、药物剂型和给药方式的改变等,结合目前已经上市的和正在研发中的长效重组药物进行了综述.  相似文献   

6.
长效缓释微球是将药物溶解或分散在高分子骨架材料中的微米级别的药物释放载体,这种新剂型可以显著降低给药频率,同时大分子材料的包裹可以提高药物的稳定性,降低药物的毒副作用,目前广泛应用在蛋白多肽等药物。已有一些用于治疗糖尿病、精神病、子宫内膜异位等疾病的长效缓释微球制剂被批准上市。然而,因为微球的制备工艺繁杂、质量控制困难,至今只在少数产品上应用,现在越来越多的口服难吸收的生物药物开始产品化,长效缓释微球在提高患者依从性方面备受瞩目。本综述对目前典型的微球制备技术做出分析和评判,以期对完善微球制备工艺有所帮助。  相似文献   

7.
重组蛋白/多肽类药物在人体血清内半衰期较短, 很大程度上限制了其临床应用。人血清白蛋白(HSA)具有半衰期长、生物相容性好、低免疫原性等优点,是理想的药物载体。各种基于HSA的蛋白质药物长效化技术得到了广泛的应用和发展,目前主要包括构建HSA融合蛋白,通过共价化学键与HSA偶联,通过非共价键与HSA可逆性结合。总结了近年来基于白蛋白药物长效化技术的发展,各项技术的优缺点及药物开发现状。  相似文献   

8.
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。  相似文献   

9.
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。  相似文献   

10.
抗肿瘤小分子多肽具有分子量小、低毒性、高活性、易于穿透肿瘤细胞等特点,一些抗肿瘤小分子多肽已进入临床研究,成为肿瘤药物研发的新热点。本文从抗肿瘤小分子多肽的不同来源途径、结构改造及生物活性等方面,对其近年来的研究进展作简要概述。  相似文献   

11.
Solid-state NMR and CD spectroscopy were used to study the effect of antimicrobial peptides (aurein 1.2, citropin 1.1, maculatin 1.1 and caerin 1.1) from Australian tree frogs on phospholipid membranes. 31P NMR results revealed some effect on the phospholipid headgroups when the peptides interact with DMPC/DHPC (dimyristoylphosphatidylcholine/dihexanoylphosphatidylcholine) bicelles and aligned DMPC multilayers. 2H NMR showed a small effect of the peptides on the acyl chains of DMPC in bicelles or aligned multilayers, suggesting interaction with the membrane surface for the shorter peptides and partial insertion for the longer peptides. 15N NMR of selectively labelled peptides in aligned membranes and oriented CD spectra indicated an alpha-helical conformation with helix long axis approximately 50 degrees to the bilayer surface at high peptide concentrations. The peptides did not appear to insert deeply into PC membranes, which may explain why these positively charged peptides preferentially lyse bacterial rather than eucaryotic cells.  相似文献   

12.
大豆肽体外抗氧化活性研究   总被引:4,自引:0,他引:4  
研究大豆肽的体外抗氧化的作用。采用邻二氮菲-Fe^2+检测大豆肽对羟自由基(·OH)的清除作用,邻苯三酚检测大豆肽对超氧阴离子(·O2^-)的清除作用,用硫代巴比妥酸法测定小鼠肝匀浆丙二醛(MDA)的含量,用比色法测定小鼠红细胞溶血度,来研究大豆肽的抗氧化效果。结果表明:大豆肽可以清除·OH和·O2^-,抑制·OH所致的丙二醛的产生,减少H2O2所致的红细胞溶血,在2~15g/L内均具有明显的量效关系。表明大豆肽在体外具有明显的抗氧化效果。  相似文献   

13.
Neuropeptides, acting on structures within the central nervous system influence body temperature. Non-opioid peptides induce hypothermia usually, while opioid peptides are mostly hyperthermic. Neuropeptides exert their effect only when injected into specific brain areas.

Hypo- Or hyperthermic effect of neuropeptides may be either due to changes in threshold body temperatures for induction of thermoregulatory effectors or due to changes in hypothalamic thermosensitivity.

At the cellular level the opioid peptides also act differently than the non-opioid peptides. The opioid peptides mostly inhibit spontaneous neuronal firing, while the non-opioid peptides usually stimulate it. Neuropeptides exert their influence on all neurones in the hypothalamus, independently on their temperature characteristics.

Neuropeptides may play a role in the regulation of body temperature under stressful conditions and during fever or hibernation, in particular. Some neuropeptides, namely AVP, -MSH and ACTH, act as natural antipyretic substances by lowering the threshold for cold thermogenesis.

Neuropeptides also modulate food intake, reproduction and many other functions which are substantially changed during hibernation. There appears to be a correlation between the effect of peptides on the control of food intake and on the control of body temperature. Opioid peptides, which increase food intake, induce hyperthermia, while non-opioid peptides, which are appetite inhibiting, induce hypothermia. The exact role o neuropeptides in the regulation of body temperature, food intake and gonadal activity of hibernators remains unclear, however.  相似文献   


14.
One common and characteristic feature of the extension peptides of mitochondrial enzyme precursors is the presence of repeating short stretches of uncharged amino acids linked by basic amino acids. We synthesized several model peptides having this particular feature of the extension peptides. The peptides contained arginine or lysine as a basic amino acid residue linking sequences of two to four residues of leucine and alanine. We examined the effects of the peptides on the import of the precursors of two mitochondrial enzymes, cytochrome P-450(SCC) and adrenodoxin, and found that the peptides were generally inhibitory to the import of the precursors into mitochondria. The effective concentrations of some of the inhibitory peptides were as low as a few microM. The peptides containing lysine instead of arginine had an essentially similar inhibitory effect on the import. The peptides did not inhibit the binding of pre-P450(SCC) to the surface of mitochondria. The synthetic model peptides uncoupled oxidative phosphorylation of mitochondria prepared from either rat liver or bovine adrenal cortex, and induced leakage of enzymes from the inner compartments of mitochondria. However, the synthetic model peptides did not solubilize membrane-bound enzymes from mitochondria, suggesting that their effect on the membranes is different from that of detergents. The synthetic model peptides seem to bind to the membranes causing significant perturbation in the membrane structure, which is possibly related to the functions of the particular common sequence found in the extension peptides of mitochondrial enzyme precursors.  相似文献   

15.
The catalytic activity of lactate dehydrogenase isoenzymes (LDH) depends on their tetrameric structure. Stabilization of this quaternary structure is achieved by interaction of the N-terminal part of one subunit with the C-terminal region of the other subunit. The N-terminal peptides from pig M-LDH and H-LDH which are responsible for this stabilization were obtained by CNBr-fragmentation and purification on reversed-phase HPLC. The effect of these peptides on the formation of the quaternary structure of LDH-isoenzymes was investigated by monitoring the reconstitution of the catalytic activity after acid-dissociation. Low concentrations of the N-terminal peptides led to an increased, and high concentrations to a decreased yield of reconstituted LDH activity. The effects of these two peptides were isoenzyme specific. The 32 residue peptide derived from M-LDH showed the highest effect when tested with M-LDH as target enzyme but only a poor effect with H-LDH. On the other side the 33 residue peptide generated from H-LDH showed a moderate effect with both isoenzymes. The effects of the N-terminal LDH peptides are antagonized by the coenzymes NAD+ and NADH. The most significant influence was observed with NAD+ in the M-LDH peptide-M-LDH enzyme system. Comparison of the properties of the reactivation antagonists isolated from human origin with the N-terminal CNBr-peptides of LDH revealed identity in all essential properties, suggesting that the former peptides are generated by degradation of LDH.  相似文献   

16.
The impact of peptides on lipid membranes   总被引:1,自引:0,他引:1  
We review the fundamental strategies used by small peptides to associate with lipid membranes and how the different strategies impact on the structure and dynamics of the lipids. In particular we focus on the binding of amphiphilic peptides by electrostatic and hydrophobic forces, on the anchoring of peptides to the bilayer by acylation and prenylation, and on the incorporation of small peptides that form well-defined channels. The effect of lipid-peptide interactions on the lipids is characterized in terms of lipid acyl-chain order, membrane thickness, membrane elasticity, permeability, lipid-domain and annulus formation, as well as acyl-chain dynamics. The different situations are illustrated by specific cases for which experimental observations can be interpreted and supplemented by theoretical modeling and simulations. A comparison is made with the effect on lipids of trans-membrane proteins. The various cases are discussed in the context of the possible roles played by lipid-peptide interactions for the biological, physiological, and pharmacological function of peptides.  相似文献   

17.
Tentacle ball formation (TBF) in Hydra elicited by S-methylglutathione (GSM) was modulated by a number of biologically active peptides. Hydra fed on Artemia, which had been hatched in a common salt solution supplemented with LiCl and ZnCl(2), easily induced TBF in response to GSM after pretreatment with trypsin. After Hydra were treated with 100 pg/ml trypsin for 10 min, the response to GSM (TBF) was sensitively suppressed by acidic fibroblast growth factor and other biologically active peptides for >10 h. Various peptides, but not transforming growth factor beta (TGF-beta), suppressed GSM-induced TBF in a specific pattern for each peptide. However, TGF-beta was unique in that it did not suppress the response to GSM, but nullified the suppressive effect of other peptides. Only active TGF-beta nullified the suppressive effect of the peptides, and the latent form of TGF-beta neither suppressed GSM-induced TBF nor nullified the suppressive effect of other peptides. Members of the TGF-beta family suppressed GSM-induced TBF. These results indicate that all peptides examined, except for TGF-beta suppressed the response to GSM in a manner specific to each peptide. This assay system would be useful in identification of biologically active peptides.  相似文献   

18.
Elastin peptides were shown to act on a cell membrane receptor coupled to a G-protein, phospholipase C, and its activation increases IP3 and DAG and opens receptor-dependent Ca(++)-channels. As some growth factors also produce similar modifications in intracellular Ca++, we wanted to explore the effect of elastin peptides on cell proliferation using 3H-thymidine incorporation and cell counting. The concentration of peptides needed for the stimulation of cell proliferation varied between large limits (1 microgram/ml to 10 mg/ml) according to the origin of the cells and the nature of the peptides. The proliferation of CCL 39 chinese hamster lung fibroblasts was enhanced in a dose-dependent fashion in the concentration range of 3 to 10 mg/ml. The proliferation of human skin fibroblasts was enhanced in the concentration range of 0.5 to 3.3 mg/ml and inhibited at higher concentrations. This effect depended little on the average molecular weight (MW) of the peptide preparation, high MW peptides (average 75 kDa) and lower MW peptides (average MW 10 kDa) were both efficient approximately to the same extent. It appears probable that only a small fraction of these peptides possesses this growth promoting property; other sequences might have the opposite effect. The conformation of the peptides may also play an important role. Human sera contain circulating elastin peptides in the concentration range of 1.0 to 10 micrograms/ml, increasing in obstructive arteriopathies and in some hyperlipidemias. It appears therefore that the above findings may have physiopathological significance in the regulation of cell proliferation in normal and pathological conditions.  相似文献   

19.
AIM: To study the effect of casein-derived peptides, accumulated during growth of Lactococcus lactis in milk, on its oligopeptide transport (Opp) function. METHODS AND RESULTS: This effect was estimated by analysing the ability of casein-derived peptides to compete for the transport of a reporter peptide by whole L. lactis cells. The transport of the reported peptide was monitored by determining the intracellular concentrations of the corresponding amino acids by means of reverse-phase high-performance liquid chromatography (HPLC). Uptake of the reporter peptide was competitively inhibited by casein-derived peptides. The competition was only because of charged casein-derived peptides, including anionic peptides. The design of specific pure peptides made it possible to evidence for a positive (or negative) influence exerted by the positively (or negatively) charged side chain of the N-terminal amino acid on the competition. CONCLUSIONS: Charged casein-derived peptides impaired the oligopeptide transport function of L. lactis. SIGNIFICANCE AND IMPACT OF THE STUDY: These results demonstrate an inhibition of Opp when too many peptides are produced by the proteinase. Peptide transport by Opp therefore represents a bottleneck for increasing the growth rate of L. lactis in milk.  相似文献   

20.
The mechanisms underlying antimicrobial and anti-endotoxic effects were investigated for a series of structurally related peptides derived from the C-terminal region of S1 peptidases. For this purpose, results on bacterial killing were compared to those on peptide-induced liposome leakage, and to ellipsometry and dual polarization interferometry results on peptide binding to, and disordering of, supported lipid bilayers. Furthermore, the ability of these peptides to block endotoxic effects caused by bacterial lipopolysaccharide (LPS), monitored through NO production in macrophages, was compared to the binding of these peptides to LPS, and to secondary structure formation in the peptide/LPS complex. Bacteria killing, occurring through peptide-induced membrane lysis, was found to correlate with liposome rupture, and with the extent of peptide binding to the lipid membrane, no adsorption threshold for peptide insertion being observed. Membrane and LPS binding was found to depend on peptide net charge, illustrated by LPS binding increasing with increasing peptide charge, and peptides with net negative charge being unable to lyse membranes, kill bacteria, and block LPS-induced endotoxic effect. These effects were, however, also influenced by peptide hydrophobicity. LPS binding was furthermore demonstrated to be necessary, but not sufficient, for anti-endotoxic effect of these peptides. Circular dichroism spectroscopy showed that pronounced helix formation occurs in peptide/LPS complexes for all peptides displaying anti-endotoxic effect, hence potentially linked to this functionality. Similarly, ordered secondary structure formation was correlated to membrane binding, lysis, and antimicrobial activity of these peptides. Finally, preferential binding of these peptides to LPS over the lipid membrane was demonstrated.  相似文献   

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