Triterpenes from the roots of Lantana montevidensis with antiprotozoal activity

Bioassay guided fractionation of the roots of Lantana montevidensis (Verbenaceae) has resulted in the isolation and identification of three new triterpenoids; 13β-hydroxy-3-oxo-olean-11-en-28-oic acid (1), 12β,13β-dihydroxyolean-3-oxo-28-oic acid (2) and 12β,13β,22β-trihydroxyolean-3-oxo-28-oic acid (3) in addition to nine known compounds: oleanonic acid (4), oleanolic acid (5), 3β,25β-dihydroxy-olean-12-en-28-oic acid (6), lantadene A (7), 19α-hydroxy-3-oxo-olean-12-en-28-oic acid (8) pomolic acid (9), camaric acid (10) together with β-sitosterol (11) and β-sitosterol-3-O-β-d-glucoside (12). The structures of the isolated metabolites were elucidated based on comprehensive 1D and 2D NMR spectroscopic data as well as HR-ESI–MS. The extracts and the isolated metabolites were evaluated for their antiprotozoal and antimicrobial activities. Compound 2 showed antibacterial activity against Staphylococcus aureus and methicillin resistant S. aureus with IC₅₀ values against both organisms of 2.1 μM and compound 10 showed activity against same organisms with IC₅₀ values 8.74 and 8.09 μM, respectively, compared to the positive control ciprofloxacin (IC₅₀ = 0.3 μM against S. aureus and MRSA). Compounds 1, 4, 5, 6, and 10 showed moderate antileishmanial activity with IC₅₀ values ranging between (2.54–14.95 μM) and IC₉₀ values ranging between (11.90–19.47 μM), using pentamidine as a control (IC₅₀ values 2.09 ≥ 16.8 μM) and IC₉₀ values ranging between (4.72 ≥ 16.8 μM). These compounds also showed highly potent antitrypanosomal activity with IC₅₀ values ranging between (0.39–7.12 μM) and IC₉₀ values ranging between (1.91–10.51 μM), which are more efficient than the DFMO, the antitrypanosomal drug employed as positive control (IC₅₀ and IC₉₀values 11.82 and 30.82 μM).     

Dammarane-type saponins from Ziziphus jujube and their inhibitory effects against TNF-α release in LPS-induced RAW 246.7 macrophages

Four new dammarane-type saponins jujubosides F–J, together with six known compounds were isolated from the seeds of Ziziphus jujube. Their structures were elucidated on the basis of chemical and spectroscopic evidences. Compounds 1–10 showed moderate inhibitory effects against pro-inflammatory cytokine TNF-α release in LPS-induced RAW 246.7 macrophages.     

Beilschglabrines A and B: Two new bioactive phenanthrene alkaloids from the stem bark of Beilschmiedia glabra

Two new phenanthrene alkaloids, beilschglabrines A (1) and B (2) were isolated from the stem bark of Beilschmiedia glabra, together with lupeol, taraxerol, and 24-methylenelanosta-7,9-diene-3β-15α-diol. The structures of the isolated compounds were elucidated by extensive spectroscopic data analysis and comparison with respective literature data. The compounds were tested for DPPH radical scavenging, acetylcholinesterase and lipoxygenase inhibitory activities. Compound 1 displayed considerable activity in the acetylcholinesterase (IC₅₀ 50.4 μM), the DPPH radical scavenging (IC₅₀ 115.9 μM) and the lipoxygenase (IC₅₀ 32.8 μM) assays.     

Structure-antioxidant and anti-tumor activity of Teucrium polium phytochemicals

Chemical characterization as well as antioxidant and anti-tumor activity are reported for isolated metabolites from Teucrium polium L. (Lamiaceae). Structures were identified using standard MS and NMR spectroscopic methods. Sesquiterpene absolute stereochemistry was determined based on a modified Mosher’s reaction. Biological activity was evaluated by a cupric reducing antioxidant capacity (CUPRAC) assay and select compounds screened for anti-tumor activity. (1R,4S,10R) 10,11-dimethyl-dicyclohex-5(6)-en-1,4-diol-7-one and (R)-mandelonitrile-β-laminaribioside, together with ten previously reported compounds were identified. Antioxidant versus tumor-inhibition relationships was examined.     

Three new diterpenes with cytotoxic activity from the roots of Euphorbia ebracteolata Hayata

From the roots of Euphorbia ebracteolata Hayata, three new diterpenes, Ebracteolatas A–C, based on the rosane (1–2) and lathyrane (3) skeleton, were isolated together with four known ones (4–7). Their structures and relative configurations were elucidated on the basis of spectroscopic methods, especially 2D NMR techniques. Compounds 1, 6, and 7 exhibited moderate cytotoxic effects against five cancer cell lines.     

A bispecific antibody effectively neutralizes all four serotypes of dengue virus by simultaneous blocking virus attachment and fusion

Although dengue virus (DENV) infection severely threatens the health of humans, no specific antiviral drugs are currently approved for clinical use against DENV infection. Attachment and fusion are 2 critical steps for the flavivirus infection, and the corresponding functional epitopes are located at E protein domain III (E-DIII) and domain II (E-DII), respectively. Here, we constructed a bispecific antibody (DVD-1A1D-2A10) based on the 2 well-characterized anti-DENV monoclonal antibodies 1A1D-2 (1A1D) and 2A10G6 (2A10). The 1A1D antibody binds E-DIII and can block the virus attaching to the cell surface, while the 2A10 antibody binds E-DII and is able to prevent the virus from fusing with the endosomal membrane. Our data showed that DVD-1A1D-2A10 retained the antigen-binding activity of both parental antibodies. Importantly, it was demonstrated to be significantly more effective at neutralizing DENV than its parental antibodies both in vitro and in vivo, even better than the combination of them. To eliminate the potential antibody-dependent enhancement (ADE) effect, this bispecific antibody was successfully engineered to prevent Fc-γ-R interaction. Overall, we generated a bispecific anti-DENV antibody targeting both attachment and fusion stages, and this bispecific antibody broadly neutralized all 4 serotypes of DENV without risk of ADE, suggesting that it has great potential as a novel antiviral strategy against DENV.     

Comparative proteomic analysis of growth hormone secretagogue A233 treatment of murine macrophage cells J774A.2 indicates it has a role in antiviral innate response

BackgroundGrowth hormone secretagogues (GHS), among other factors, regulate the release of GH. The biological activity of the secretagogue peptide A233 as a promoter of growth and innate immunity in teleost fish has previously been demonstrated, but its role in the immune system of mammals is not well understood.MethodsThe effect of the peptide was investigated in J774A.2 macrophage cells using a comparative proteomics approach after 6 and 12 h of peptide stimulation.ResultsThe functional analysis of differentially modulated proteins showed that A233 peptide treatment appears to promote activation and ROS-dependent cytotoxic functions in macrophages and enhanced expression of antiviral protein complexes such as MAVS. In accordance with this hypothesis, we found that A233 treatment enhanced superoxide anion production and the IFN-γ level in J774A.2 cells and mouse splenocytes, respectively, and reduced viral load in a dengue virus mouse model of infection.ConclusionsThe growth hormone secretagogue A233 peptide promotes activation of ROS-dependent cytotoxic functions and exerts immunomodulatory effects that enable an antiviral state in a dengue virus mouse model.General SignificanceThe increase of IFN-γ level and the differential modulation of antiviral proteins by the A233 peptide suggest that the molecule could activate an innate immune response with a possible further impact in the treatment of acute and chronic diseases.     

羊毛硫肽类化合物(Lanthipeptide)生物合成新进展

羊毛硫肽化合物(Lanthipeptides)是由核糖体合成并经过翻译后修饰得到的一大类肽类天然产物。这类化合物广泛的产生于不同种类的细菌,具有丰富的结构和生物活性多样性,为活性药物研究和开发提供重要的来源。本文综述了近几年来羊毛硫肽化合物生物合成进展,从其合成酶结构,进化机制,区域和立体选择性控制等方面进行了简要的讨论,展示了羊毛硫肽类化合物生物合成中特殊而迷人的酶学机制。     

靶向铜绿假单胞菌(Pseudomonas aeruginosa)粘肽合成酶PBP3的抗菌先导化合物的虚拟筛选及活性研究

【目的】开发出与铜绿假单胞菌粘肽合成酶PBP3有高亲和力,具有全新结构的先导化合物。【方法】以铜绿假单胞菌粘肽合成酶PBP3为靶点,通过分子对接软件DOCK6.5,对含有104万个小分子化合物的数据库进行了大规模虚拟筛选,选取结构相对简单的中选化合物进行合成,得到先导化合物,并验证其抑菌活性。【结果】通过grid score进行第一轮初筛,筛选出grid score分值小于–30 kcal/mol的6万个化合物,接着以amber score进行第二轮筛选,筛出amber score分值小于–20 kcal/mol的化合物约200个。最终,经过观察分析,从中挑选出4种打分高并且结构新颖的小分子化合物作为先导化合物。合成出的先导化合物及其衍生物对铜绿假单胞菌等常见微生物的最小抑菌浓度(MIC)在175–275μg/m L之间,对革兰氏阴性菌和阳性菌均有效,MIC值比作为阳性对照的磺胺嘧啶更低,说明先导化合物具有较好的抗菌活性。【结论】这些先导化合物可以进一步开发为新型抗菌药物,用于解决铜绿假单胞菌的耐药性问题。