Antiretroviral activity of semisynthetic derivatives of glycopeptide antibiotics

A variety of semisynthetic derivatives of natural antibacterial glycopeptide antibiotics such as vancomycin, eremomycin, ristocetin A, teicoplanin A(2)-2, DA-40926, their aglycons, and also the products of their partial degradation with a destroyed or modified peptide core show marked anti-retroviral activity in cell culture. In particular, aglycon antibiotic derivatives containing various substituents of a preferably hydrophobic nature displayed activity against human immunodeficiency virus type 1 (HIV-1), HIV-2, and Moloney murine sarcoma virus at a 50% inhibitory concentration in the lower micromolar (1-5 microM) concentration range while not being cytostatic against human lymphocytic cells at 250 microM or higher. The mode of anti-HIV action of the antibiotic aglycon derivatives could be ascribed to inhibition of the viral entry process.     

Role of the glycopeptide framework in the antibacterial activity of hydrophobic derivatives of glycopeptide antibiotics

The antibacterial properties of glycopeptide antibiotics are based on their interaction with the d-Ala-d-Ala containing pentapeptide of bacterial peptidoglycan. The hydrophobic amides of vancomycin (1), teicoplanin (2), teicoplanin aglycon (3), and eremomycin (4) were compared with similar amides of minimally or low active des-(N-methyl-d-leucyl)eremomycin (5), eremomycin aglycon (6), des-(N-methyl-d-leucyl)eremomycin aglycon (7), and a teicoplanin degradation product TB-TPA (8). All hydrophobic amides of 1, 3, 4, and 6 were almost equally active against glycopeptide-resistant enterococci (GRE) [minimum inhibitory concentrations (MIC) 相似文献   

Polycyclic peptide and glycopeptide antibiotics and their derivatives as inhibitors of HIV entry

Antiviral activity and other biological properties of two groups of polycyclic peptides are discussed. Antibiotics of the complestatin-kistamycin group have a structural motif similar to that of the peptide core of antibacterial antibiotics of the vancomycin-teicoplanin group though no amino acid component in the chloropeptin-kistamicin antibiotics is identical to an amino acid incorporated in the peptide core of the antibiotics of the vancomycin-teicoplanin group. Chloropeptins and the hydrophobic several derivatives of antibacterial antibiotics are inhibitors of HIV and some other viruses. They interfere with the viral (i.e. HIV) entry process. Chemical modifications of natural glycopeptide antibiotics led to the compounds with antiviral properties whereas antibacterial properties were lost. These glycopeptide aglycons derivatives can be envisaged as potential lead compounds for application as microbicides against sexual HIV transmission.     

Inhibition of feline leukemia virus replication by human leukocyte interferon

The replication of feline leukemia virus (FeLV) is inhibited by treatment of cat cell cultures with crude human leukocyte interferon (HuIFN-alpha) as evidenced by titration of the infectious progeny. The inhibition can be demonstrated in three different cell lines in which the production of hemagglutinin by encephalomyocarditis (EMC) virus, and plaque formation by vesicular stomatitis virus (VSV) are also inhibited by the HuIFN-alpha. The dose dependency of the inhibition of EMC virus by the HuIFN-alpha is similar to that obtained with feline interferon in each of the three cell lines. VSV and EMC virus are less than 10 times more sensitive than FeLV to the inhibitory action of HuIFN-alpha if responses to a single interferon treatment are compared for each of the viruses tested in the most sensitive cell line, FEA. The interferon effect on FeLV is more pronounced when it is added within one day after the inoculation of the cells rather than applied before cell infection. The induction of focus formation by FeLV can also be inhibited by HuIFN-alpha in cat cells (CCC-81) which contain the murine sarcoma virus genome.     

Bioinformatics research on the SARS coronavirus (SARS_CoV) in China

Severe acute respiratory syndrome (SARS) first appeared in 2002 in China, which fastly affected about 8000 patients over 29 countries and caused 774 fatalities. As its pathogen was identified as a new kind of coronavirus (SARS_CoV), its genome was quickly sequenced on several isolates. Studies on its functional genomics were performed by combinatorial application of all the available bioinformatics tools and the development of new programs. In this way, it was found that the four proteins were absolutely responsible for nosogenesis of SARS, i.e. spike (S) protein; small envelop (E) protein; membrane (M) protein; and nucleocaspid (N) protein. Molecular evolution studies have revealed that SARS must be originated from wild animals, and it was demonstrated that the major genetic variations in some critical genes, particularly the Spike gene, was essential for the transition from animal-to-human transmission to human-to-human transmission. Theoretical models, either Logistic model or SIR model, were developed to describe the transmission of SARS. The recorded difference of SARS spreading in Beijing and Hong Kong was also reasonably analyzed according to these models. The whole process of fruitful bioinformatics studies, along with other related scientific investigations have set up an unprecedented paradigm for human of how to battle against sudden-breaking and catastrophic epidemics.     

Inhibition of human tyrosyl-DNA phosphodiesterase by aminoglycoside antibiotics and ribosome inhibitors

DNA topoisomerase I (Top1) is the target of camptothecin, and novel Top1 inhibitors are in development as anticancer agents. Top1 inhibitors damage DNA by trapping covalent complexes between the Top1 catalytic tyrosine and the 3'-end of the broken DNA. Tyrosyl-DNA phosphodiesterase (Tdp1) can repair Top1-DNA covalent complexes by hydrolyzing the tyrosyl-DNA bond. Inhibiting Tdp1 has the potential to enhance the anticancer activity of Top1 inhibitors (http://discover.nci.nih.gov/pommier/pommier.htm) and to act as antiproliferative agents. In the present study, we report that neomycin inhibits Tdp1 more effectively than the related aminoglycosides paromomycin and lividomycin A. Inhibition of Tdp1 by neomycin is observed both with single- and double-stranded substrates but is slightly stronger with duplex DNA, which is different from aclarubicin, which only inhibits Tdp1 with the double-stranded substrate. Inhibition by neomycin can be overcome with excess Tdp1 and is greatest at low pH. To our knowledge, aminoglycoside antibiotics and the ribosome inhibitors thiostrepton, clindamycin-2-phosphate, and puromycin are the first reported pharmacological Tdp1 inhibitors.     

Inhibition of human coronavirus 229E infection in human epithelial lung cells (L132) by chloroquine: involvement of p38 MAPK and ERK

The antiviral effects of chloroquine (CQ) on human coronavirus 229E (HCoV-229E) infection of human fetal lung cell line, L132 are reported. CQ significantly decreased the viral replication at concentrations lower than in clinical usage. We demonstrated that CQ affects the activation of p38 mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinase (ERK). Furthermore, p38 MAPK inhibitor, SB203580, inhibits CPE induced by HCoV-229E infection and viral replication. Our findings suggest that CQ affects the activation of MAPKs, involved in the replication of HCoV-229E.     

Izupeptins A and B, new glycopeptide antibiotics produced by an actinomycete

In the course of screening for new high molecular weight peptidoglycan synthesis inhibitors, izupeptins A and B, antibiotics active against Gram-positive bacteria including methicillin-resistant Staphylococci and Clostridium were discovered. The antibiotics were found to be new members of the glycopeptide antibiotic family, namely of the vancomycin type, based on chemical and spectroscopic data. The molecular weight of izupeptin A was determined to be 1,475 by SI (secondary ion)-MS (integer molecular weight, 1,473), and it contains two chlorine atoms.     

Inhibition of human erythrocyte glutathione S-transferase by some flavonoid derivatives

Glutathione transferase is one of the important enzymes for xenobiotic metabolism. Glutathione transferases catalyze the conjugation of various electrophilic endogenous and exogenous xenobiotics with γ-glutamyl-cysteinyl-glycine (GSH). GST activity can be changed by natural plant products. The present study’s goal is to examine the interaction of human erythrocyte GST with the natural plant compounds baicalin, baicalein, phloridzin, and phloretin. First, GST was purified from human erythrocyte with 1654-fold purification and 19.27% recovery by glutathione agarose affinity chromatography. The purity of the enzyme was checked by SDS-PAGE, showing single band, because it had a homodimer structure. Baicalin, baicalein, phloridzin, and phloretin flavonoids were shown to inhibit human erythrocyte GST with the IC₅₀ values of 28.75, 57.50, 769.10, and 99.02?μM, respectively. The K_i constants for baicalin, baicalein, phloridzin, and phloretin flavonoids were 14.50?±?0.71, 24.33?±?2.08, 762.50?±?85.97, and 86.49?±?1.11?μM, respectively. According to these results, baicalin is the best inhibitor for human erythrocyte GST.     

Inhibition of human platelet 5-hydroxytryptamine uptake by beta-phenethylamine derivatives

Forty-eight derivatives of ß-phenethylamine have been studied as inhibitors of 5-hydroxytryptamine uptake by human blood platelets in vitro. Inhibitory potency was found to be increased by para-substitution with electronegative groups, by α-methylation in the D-configuration and by addition of N-alkyl groups, and to be reduced by saturation of the ring, by ortho-methoxylation, meta- or ß-hydroxylation and by hydrazine formation. It is suggested that optimal affinity involves folding of the molecule to fit a cleft-like carrier site. The structural requirements for activity show features of similarity to those of tryptamine and tricyclic antidepressant derivatives and some resemblance with requirements for inhibition of the adrenergic uptake₁ mechanism of the heart. No obvious correlation exists between the activity of these drugs as inhibitors of platelet 5-HT uptake and their ability to exert effects thought to involve central tryptaminergic mechanisms.     

Gastroprotective and cytotoxic effect of semisynthetic ferruginol derivatives

The gastroprotective abietane diterpene ferruginol has been shown to present high cytotoxicity. In order to obtain active compounds with less cytotoxicity, 18 semisynthetic ferruginol derivatives and totarol were assessed for their gastroprotective effects in the HCl/ethanol-induced gastric lesion model in mice, as well as for cytotoxicity in human gastric epithelial cells (AGS) and human lung fibroblasts (MRC-5). At 20 mg kg(-1), the greatest gastroprotective effects were provided by abieta-8,11,13-triene (1), abieta-8,11,13-trien-12-yl-2-chloropropanoate (8), abieta-8,11,13-trien-12-yl propenoate (9), 12-(2,3,4,6-tetra-O-acetyl-beta-D-glucopyranosyloxy)-abieta-8,11,13-triene (17) and 12-(beta-D-galactopyranosyloxy)-abieta-8,11,13-triene (18), all of which were as active as the reference drug lansoprazole at 20 mg kg(-1), reducing gastric lesions by 69, 76, 67, 72 and 61%, respectively. No relation was observed between lipophilicity and the gastroprotective effect. Compounds that showed the greatest cytotoxicity towards AGS cells were ferruginol (2), the corresponding formate (5), acetate (6), propionate (7), 8, 9, 12-(beta-D-glucopyranosyloxy)-abieta-8,11,13-triene (16), 18 and totarol (20) (IC50 18-44 microM). Ferruginol and compounds 5-9, 16, 18 and 20 were the most toxic compounds against fibroblasts (IC50 19-56 microM), with a correlation to AGS cells. The derivative 19 was much more active against AGS cells than towards fibroblasts. The best activity/cytotoxicity ratio was found for compound 17, with a lesion index comparable with lansoprazole at 20 mg kg(-1) and cytotoxicity >1000 microM towards MRC-5 and AGS cells, respectively. In conclusion, some derivatives showed a better gastroprotective effect/cytotoxicity ratio than the parent compound ferruginol. A total of 13 new compounds are reported here for the first time.     

Gastroprotective effect and cytotoxicity of semisynthetic jatropholone derivatives

The gastroprotective effect of the diterpenes jatropholone A, jatropholone B and 16 semisynthetic derivatives was assessed in the HCl/ethanol-induced gastric lesion model in mice and the cytotoxicity was determined towards fibroblasts and AGS cells. In a dose-response study, jatropholone B reduced gastric lesions by 65% at 6 mg/kg and jatropholone A by 54% at 100 mg/kg. The jatropholone B derivatives 9 - 14 and the compounds 15 - 18 were compared at a single oral dose of 25 mg/kg while the jatropholone A derivatives 2 - 7 were assessed at 100 mg/kg. A decrease in gastroprotective activity was observed for the ether as well as for the ester derivatives of jatropholone B. The methyl and propyl ethers of jatropholone A were more gastroprotective than the natural product. The placement of an additional methyl group at C-2 in the jatropholone B derivatives led to a loss of selectivity, the methyl and propyl ethers lack a gastroprotective effect. Jatropholone B was not toxic towards AGS cells and fibroblasts. Jatropholone A was active only against AGS cells. The gastroprotective effect of the epimeric jatropholones was selective showing a higher effect for jatropholone B. These results further support that the stereochemistry of the methyl group at C-2 in the jatropholones plays a relevant role in preventing the gastric lesions in mice. The compounds 3, 5 - 7, 10 and 12 - 18 are described for the first time.     

Inhibition by antibiotics of Rb Salmonella binding to human peripheral blood lymphocytes

Several lines of evidence point out that Salmonella minnesota R345 (Rb) possesses the capacity to adhere spontaneously to human peripheral blood lymphocytes. The binding is mediated via the lipopolysaccharide moiety of the bacterial outer membrane. In this report, we have evaluated the effects of various antibiotics on bacterial binding. Our data show that trimethoprim/sulphamethoxazole, chloramphenicol and erythromycin significantly decrease Rb binding, while gentamicin and sisomicin are without effect. Antibiotics display their inhibitory effect by acting on peripheral blood lymphocytes likely by competing with lipopolysaccharide for receptor binding capacity on lymphocyte surface.     

Aridicins, novel glycopeptide antibiotics. III. Preparation, characterization, and biological activities of aglycone derivatives

The aglycone and two pseudoaglycones of aridicin A were prepared by selective hydrolysis and characterized, chemically and biologically. These new analogs demonstrate improved activities in vitro over the parent antibiotics against methicillin sensitive and resistant staphylococci. The major determinant of activity is the mannose substituent, the presence of which results in less potent compounds. The analogs have potent activity against enterococci.     

Antiproliferative potential of sarcophine and its semisynthetic sulfur-containing derivatives against human mammary carcinoma cell lines

The marine-derived cembranoid sarcophine (1) and its sulfur-containing semisynthetic derivatives (2–6) were evaluated for anticancer potential using cell cycle progression markers. No effect on MCF-7 cell viability or apoptosis was seen with these derivatives at concentrations of up to 100 μM after 72 h of incubation. At 100 μM, sarcophine and its derivatives 2–5 arrested the MCF-7 cells in G0/G1 phase, with concomitant decrease in the cell populations at S and G2+M phases. MDA-MB-231 cells were not responsive to any of the derivatives. Our preliminary results suggest that the sulfur-containing derivatives of sarcophine, especially 2 and 3, show potent and cell-specific antiproliferative activity.     

糖肽类抗生素N-甲基无糖万古霉素的分离、纯化和结构鉴定

目的 利用含N-甲基转移酶的粗酶液对无糖万古霉素进行催化,从得到的反应液中分离、纯化N-甲基无糖万古霉素,并进行结构鉴定。方法 利用大孔树脂吸附、中压反相制备色谱等方法进行分离纯化。利用光谱分析,进行结构解析。结果 分离到一个糖肽类化合物N-甲基无糖万古霉素。结论