Cyclic analogues of Thr6-bradykinin,N8-Lys-bradykinin and endo-Lys8a-vespulakinin 1

Syntheses are described of the endo-Lys^8a-vespulakinin 1 and of cyclo-Thr⁶- and cyclo-N^ε-Lys-bradykinin. The linear peptides covering the entire sequences of endo-Lys^8a-VSK-1 and Thr⁶-BK, and the decapeptide containing all residues constituting Lys-BK, with a Arg-Lys peptide bond involving the ε-amino function of lysine, were prepared by the solid-phase procedure based on Fmoc chemistry. Cyclization was carried out by the diphenylphosphorazide method. The amino-terminal octapeptide sequence of vespulakinin 1, Fmoc-Thr(tBu)-Ala-Thr(tBu)-Thr(tBu)-Arg(Pmc)-Arg(Pmc)-Arg(Pmc)-Gly-OH, and its N^α-Boc-[(Gal β)Thr³, (Gal β)Thr⁴]-analogue, were used to prepare N^α-(1–8 VSK 1)-cyclo-N^ε-kallidin and N^α-[(Gal β)Thr³, (Gal β)Thr⁴, 1–8 VSK 1]-cyclo-N^ε-kallidin. Peptides and glycopeptides were characterized by amino-acid analysis, optical rotation, analytical HPLC and FAB-MS. Consistent with previous findings, preliminary pharmacological experiments on smooth muscle preparations showed that the cyclic, or partially cyclic, analogues were significatively less potent than the linear ones. © Munksgaard 1995.     

Antitumor action of glycopeptides from the cell wall of Lactobacillus bulgaricus

The antitumor action of the substance blastolysin, the main components of which are glycopeptide fragments from the cell wall ofLactobacillus bulgaricus, was studied. Blastolysin exhibits a specific antitumor effect against sarcoma S-180, leukemia P-388, plasmacytoma MOPC-315, adenocarcinoma AKATOL, melanosarcoma B-16, carcinoma LLC, and spontaneous tumors of mice. It has low toxicity, does not depress hematopoiesis, and in the character of its action on tumor tissue it differs essentially from known chemotherapeutic preparations.M. M. Shemyakin Institute of Bioorganic Chemistry, Academy of Sciences of the USSR, Moscow. Scientific-Production Laboratory of Biologically Active Substances, Sofia, Bulgaria. Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 84, No. 12, pp. 709–712, December, 1977.     

Vancomycin-resistant enterococci colonization in a neonatal intensive care unit: who will be infected?

Objective: To determine the incidence of vancomycin-resistant enterococcus (VRE) colonization in our neonatal intensive care unit (NICU) over five-year period, rate of progression to VRE infection and associated risk factors.

Methods: A retrospective analysis of a prospective surveillance for VRE colonization and health care-associated infections was made. Contact precautions were taken against colonization, although the application varied over the years due to repairs in the unit.

Results: VRE rectal colonization was detected in 200/1671 neonates (12%) admitted to NICU. It showed great interannual variability from 1.9% to 30.3%. Sytemic VRE infection developed in 6/200 VRE-colonized patients (3%) within a median of 9 days (range: 3–58 days). The risk factors for VRE infection development identified in the univariate analysis were long hospital stay (≥30 days), necrotizing enterocolitis, surgical procedure, extraventricular drainage, receipt of amphotericin B and receipt of glycopeptides after detection of VRE colonization. Crude in-hospital mortality was higher in neonates who developed a systemic VRE infection (p?<?0.001).

Conclusion: Maintaining physical conditions in the unit favorable for infection control and rational use of antibiotics are essential in the control of VRE colonization and resultant infections. Special attention should be directed to VRE-colonized babies carrying the risk factors.     

利奈唑胺与糖肽类对HAP治疗效果及安全性的Meta分析

目的利用Meta分析法比较利奈唑胺与糖肽类对HAP的疗效及安全性。方法计算机检索Pub Med、EMBASE、Cochrane Central Register of Controlled Trials、CNKI、CBM等数据库,检索时限从1995-01-2013-03,纳入比较利奈唑胺与糖肽类治疗HAP疗效及安全性的随机对照试验,并用Rev Man 5.0.2软件对其进行Meta分析。结果纳入10个试验包括2136例患者。荟萃分析结果显示,在临床可评估患者中,治疗结束后[OR 2.06,95%CI（1.41,3.00）,Z=3.76,P=0.0002]和随访结束后[OR 1.30,95%CI（1.01,1.63）,Z=2.02,P=0.04]利奈唑胺的临床治愈率优于糖肽类,而在ITT患者中,随访结束后利奈唑胺其临床治愈率亦优于糖肽类[OR 1.16,95%CI（0.93,1.44）,Z=1.34,P=0.18]。同时,在微生物可评估患者中,随访结束后的微生物学总治愈率[OR 1.33,95%CI（0.88,2.01）,Z=1.38,P=0.18]、耐甲氧西林金黄色葡萄球菌（MRSA）清除率[OR=1.36,95%CI（0.51,3.61）,P=0.54]及金黄色葡萄球菌清除率[OR=1.45,95%CI（0.84,2.51）,P=0.18]方面,利奈唑胺亦优于糖肽类。而在链球菌清除率[OR=0.29,95%CI（0.03,2.98）,P=0.30]方面,利奈唑胺低于糖肽类抗生素。另外,利奈唑胺与糖肽类在病死率[OR=0.81,95%CI（0.61,1.09）,P=0.17]及不良反应总发生率[OR=0.93,95%CI（0.70,1.23）,P=0.60]略优于糖肽类。结论在治疗HAP患者中,利奈唑胺的疗效优于糖肽类。     

A concise methodology for the stereoselective synthesis of O-glycosylated amino acid building blocks: complete 1HNMR assignments and their application in solid-phase glycopeptide synthesis

A facile strategy for the stereoselective synthesis of suitably protected O-glycosylated amino acid building blocks, namely, N^α-Fmoc-Ser-[Ac₄-β-d -Gal-(1-3)-Ac₂α or β-d -GalN₃]-OPfp and N^α-Fmoc-Thr-[Ac₄-β-d -Gal-(1-3)-Ac₂-α or β-d -GalN₃]-OPfp is described. What is new and novel in this report is that Koenigs-Knorr type glycosylation of an aglycon serine/threonine derivative (i.e. N^α-Fmoc-Ser-OPfp or N^α-Fmoc-Thr-OPfp) with protected β-d -Gal(1-3)-d -GalN₃ synthon mediated by silver salts resulted in only α-and/or β-isomers in excellent yields under two different reaction conditions. The subtle differences in stereoselectivity were demonstrated clearly when glycosylation was carried out using only AgClO₄ at -40°C which afforded α-isomer in a quantitative yield (α:β= 5:1). On the other hand, the β-isomer was formed exclusively when the reaction was performed in the presence of Ag₂CO₃AgClO₄ at room temperature. A complete assignment of ¹H resonances to individual sugar ring protons and the characteristic anomeric α-1H and β-1H in Ac₄Galβ(1-3)Ac₂GalN₃α and/or β linked to Ser/Thr building blocks was accomplished unequivocally by two-dimensional double-quantum filtered correlated spectroscopy and nuclear Overhauser enhancement and exchange spectroscopy NMR experiments. An unambiguous structural characterization and documentation of chemical shifts, including the coupling constants for all the protons of the aforementioned a- and p-isomers of the O-glycosylated amino acid building blocks carrying protected β-d -Gal(1-3)-d -GalN₃, could serve as a template in elucidating the three-dimensional structure of glycoproteins. The synthetic utility of the building blocks and versatility of the strategy was exemplified in the construction of human salivary mucin (MUC7)-derived, O-linked glycopeptides with varied degrees of glycosylation by solid-phase Fmoc chemistry. Fmoc/tert-butyl-based protecting groups were used for the peptidic     

NMR analysis of human salivary mucin (MUC7) derived O-linked model glycopeptides: comparison of structural features and carbohydrate–peptide interactions

Abstract: Two series of glycopeptides with mono- and disaccharides, [GalNAc and Galβ (1–3)GalNAc]O-linked to serine and threonine at one, two or three contiguous sites were synthesized and characterized by ¹H NMR. The conformational effects governed by O-glycosylation were studied and compared with the corresponding non-glycosylated counterparts using NMR, CD and molecular modelling. These model peptides encompassing the aa sequence, PAPPSSSAPPE (series I ) and APPETTAAPPT (series II ) were essentially derived from a 23-aa tandem repeat sequence of low molecular weight human salivary mucin (MUC7). NOEs, chemical shift perturbations and temperature coefficients of amide protons in aqueous and non-aqueous media suggest that carbohydrate moiety in threonine glycosylated peptides (series II ) is in close proximity to the peptide backbone. An intramolecular hydrogen bonding between the amide proton of GalNAc or Galβ (1–3)GalNAc and the carbonyl oxygen of the O-linked threonine residue is found to be the key structure stabilizing element. The carbohydrates in serine glycosylated peptides (series I ), on the other hand, lack such intramolecular hydrogen bonding and assume a more apical position, thus allowing more rotational freedom around the O-glycosidic bond. The effect of O-glycosylation on peptide backbone is clearly reflected from the observed overall differences in sequential NOEs and CD band intensities among the various glycosylated and non-glycosylated analogues. Delineation of solution structure of these (glyco)peptides by NMR and CD revealed largely a poly l -proline type II and/or random coil conformation for the peptide core. Typical peptide fragments of tandem repeat sequence of mucin (MUC7) showing profound glycosylation effects and distinct differences between serine and threonine glycosylation as observed in the present investigation could serve as template for further studies to understand the multifunctional role played by mucin glycoproteins.     

Synthesis and biological activity of substance P analogues

The synthesis of the hexapeptide [Glu⁶]SP_6-11 and its glycosylated analogue at the Glu⁶γ-carboxyl position by solution procedures according to several strategies is discussed. The biological activity of SP, [GIu⁶]SP_6-11 (VI) and [Glu(β-d -Glcp)⁶]SP_6-11 (VIII) have been determined and compared to SP by the GPI and RVD assays. The introduction of a β-d -glucopyranosyl moiety at the sixth position of the [Glu⁶]SP_6-11 did not affect to a great extent the in vitro activity pattern of the parent hexapeptide.     

甘露聚糖肽皮试液浓度与皮试结果的临床观察与研究

目的:通过对420例肿瘤患者甘露聚糖肽注射液皮试方法及结果的研究,以确定安全可靠的皮试液浓度,从而指导临床正确、科学的使用甘露聚糖肽。方法:予甘露聚糖肽注射液(多抗)以生理盐水稀释至100倍配制成皮试液,吸取皮试液0.1ml进行皮内注射。皮试期间注意观察病人有无药物过敏等不良反应发生,皮试阴性患者予甘露聚糖肽注射液10mg加入0.9%氯化钠注射液250ml缓慢静脉滴注,40滴/min。观察滴注期间和滴注后24小时患者一般情况、有无过敏、出现不良反应的时间和异常症状。结果:420例患者阳性3例(0.71%),可疑阳性2例(0.48%),阴性415例(98.81%);皮试阴性者输注过程中无一例发生速发型变态反应,8例患者发生轻微不良反应,经吸氧、止吐等处理措施后,症状消失。结论:甘露聚糖肽输注前进行皮试可减少过敏反应的发生;将甘露聚糖肽注射液(多抗)稀释100倍进行皮试,安全可靠,为较佳的甘露聚糖肽皮试液。鉴于不同生产厂家生产工艺不同,相应的皮试研究结论可能存在一些差别。