TXNL1-XRCC1 pathway regulates cisplatin-induced cell death and contributes to resistance in human gastric cancer

Cisplatin is a cytotoxic platinum compound that triggers DNA crosslinking induced cell death, and is one of the reference drugs used in the treatment of several types of human cancers including gastric cancer. However, intrinsic or acquired drug resistance to cisplatin is very common, and leading to treatment failure. We have recently shown that reduced expression of base excision repair protein XRCC1 (X-ray repair cross complementing group1) in gastric cancerous tissues correlates with a significant survival benefit from adjuvant first-line platinum-based chemotherapy. In this study, we demonstrated the role of XRCC1 in repair of cisplatin-induced DNA lesions and acquired cisplatin resistance in gastric cancer by using cisplatin-sensitive gastric cancer cell lines BGC823 and the cisplatin-resistant gastric cancer cell lines BGC823/cis-diamminedichloridoplatinum(II) (DDP). Our results indicated that the protein expression of XRCC1 was significantly increased in cisplatin-resistant cells and independently contributed to cisplatin resistance. Irinotecan, another chemotherapeutic agent to induce DNA damaging used to treat patients with advanced gastric cancer that progressed on cisplatin, was found to inhibit the expression of XRCC1 effectively, and leading to an increase in the sensitivity of resistant cells to cisplatin. Our proteomic studies further identified a cofactor of 26S proteasome, the thioredoxin-like protein 1 (TXNL1) that downregulated XRCC1 in BGC823/DDP cells via the ubiquitin-proteasome pathway. In conclusion, the TXNL1-XRCC1 is a novel regulatory pathway that has an independent role in cisplatin resistance, indicating a putative drug target for reversing cisplatin resistance in gastric cancer.     

De novo design of novel DNA–gyrase inhibitors based on 2D molecular fingerprints

As increasing drug-resistance poses an emerging threat to public health, the development of novel antibacterial agents is critical. We developed a workflow consisting of various methods for de novo design. In the workflow, 2D-QSAR model based on molecular fingerprints was constructed to extract the bioactive molecular fingerprints from a data set of DNA–gyrase inhibitors with new structure and mechanism. These fingerprints were converted into molecular fragments which were recombined to generate compound library. The new compound library was virtually screened by LigandFit and Gold docking, and the results were further investigated by pharmacophore validation and binding mode analysis. The workflow successfully achieved a potential DNA–gyrase inhibitor. It could be applied to design more novel potential DNA–gyrase inhibitors and provide theoretical basis for further optimization of the hit compounds.     

Study on the interactions between diketo-acid inhibitors and prototype foamy virus integrase-DNA complex via molecular docking and comparative molecular dynamics simulation methods

Human immunodeficiency virus type 1 (HIV-1) integrase (IN) is an important drug target for anti-acquired immune deficiency disease (AIDS) treatment and diketo-acid (DKA) inhibitors are potent and selective inhibitors of HIV-1 IN. Due to lack of three-dimensional structures including detail interactions between HIV-1 IN and its substrate viral DNA, the drug design and screening platform remains incompleteness and deficient. In addition, the action mechanism of DKA inhibitors with HIV-1 IN is not well understood. In view of the high homology between the structure of prototype foamy virus (PFV) IN and that of HIV-1 IN, we used PFV IN as a surrogate model for HIV-1 IN to investigate the inhibitory mechanism of raltegravir (RLV) and the binding modes with a series of DKA inhibitors. Firstly, molecular dynamics simulations of PFV IN, IN-RLV, IN-DNA, and IN-DNA-RLV systems were performed for 10?ns each. The interactions and inhibitory mechanism of RLV to PFV IN were explored through overall dynamics behaviors, catalytic loop conformation distribution, and hydrogen bond network analysis. The results show that the coordinated interactions of RLV with IN and viral DNA slightly reduce the flexibility of catalytic loop region of IN, and remarkably restrict the mobility of the CA end of viral DNA, which may lead to the partial loss of the inhibitory activity of IN. Then, we docked a series of DKA inhibitors into PFV IN-DNA receptor and obtained the IN-DNA-inhibitor complexes. The docking results between PFV IN-DNA and DKA inhibitors agree well with the corresponding complex of HIV-1 IN, which proves the dependability of PFV IN-DNA used for the anti-AIDS drug screening. Our study may help to make clear some theoretical questions and to design anti-AIDS drug based on the structure of IN.     

EGF类生长因子来源的新型靶向肽在抗肿瘤药物蛋白中的应用

许多肿瘤细胞表面表皮生长因子受体EGFR都存在过表达现象。考察了牛痘病毒生长因子(VGF)中的EGFR结合域(S3)与人的肝素样表皮生长因子(HB-EGF)来源的肝素结合域(命名为HE)重组后对肿瘤细胞的选择性。通过重组表达带有靶向和穿膜结构域的EGFP-S3-HE和EGFP-S3-HE-TATm两种融合蛋白与正常细胞和肿瘤细胞的共孵育实验来研究其对肿瘤细胞的特异性靶向吸附和穿膜效应。进一步将S3-HE-TATm靶向穿膜序列与苦瓜来源的核糖体失活蛋白MAP30融合,可显著提高MAP30对肿瘤细胞的抑杀作用,但这种抑杀作用却对正常细胞仍保持在较低水平。由此表明S3-HE-TATm是一种新型优异的肿瘤细胞靶向药物运输载体,可用于肿瘤治疗的进一步开发研究。     

GGIP: Structure and sequence‐based GPCR–GPCR interaction pair predictor

G Protein‐Coupled Receptors (GPCRs) are important pharmaceutical targets. More than 30% of currently marketed pharmaceutical medicines target GPCRs. Numerous studies have reported that GPCRs function not only as monomers but also as homo‐ or hetero‐dimers or higher‐order molecular complexes. Many GPCRs exert a wide variety of molecular functions by forming specific combinations of GPCR subtypes. In addition, some GPCRs are reportedly associated with diseases. GPCR oligomerization is now recognized as an important event in various biological phenomena, and many researchers are investigating this subject. We have developed a support vector machine (SVM)‐based method to predict interacting pairs for GPCR oligomerization, by integrating the structure and sequence information of GPCRs. The performance of our method was evaluated by the Receiver Operating Characteristic (ROC) curve. The corresponding area under the curve was 0.938. As far as we know, this is the only prediction method for interacting pairs among GPCRs. Our method could accelerate the analyses of these interactions, and contribute to the elucidation of the global structures of the GPCR networks in membranes. Proteins 2016; 84:1224–1233. © 2016 Wiley Periodicals, Inc.     

2015 年 11 月美国、欧盟和日本新批准药物概述

2015 年 11 月,美国、欧盟和日本共批准 36 个新药,包括新分子实体、新有效成分、新生物制品、新增适应证及新剂型药物。 对全球首次获得批准的新分子实体、新有效成分、新生物制品进行分析,重点介绍这些药物的临床研究结果和研发历史进程。     

从阿维菌素获得诺贝尔奖到中国创造

纵观世界历史,大国崛起无不伴随着科技的兴起和机制体制的突破。来自大自然的天然产物对于人类的健康起到非常重要的作用,从抗肿瘤明星分子紫杉醇到挽救了无数人生命的抗感染药物青霉素,从治疗代谢疾病到营养保健,都离不开天然产物。此外,还有大量天然产物资源没有被开发过。而随着阿维菌素的发现者Satoshiōmura教授和William C.Campbell博士,及青蒿素的发现者屠呦呦研究员因为这两种天然产物在治疗寄生虫感染病和疟疾上的应用而获得2015年诺贝尔生理与医学奖后,天然产物有望迎来其发展的第二个黄金时代。我国是世界工厂也是天然药物的资源大国,为了实现产业升级,弯道超车,实现大国崛起的中国梦,我国科学家在"十二五"期间围绕着天然产物的高产和创新两大主题开展了富有成效的合成生物学研究。阿维菌素是由阿维链霉菌产生的高效低毒生物杀虫剂,其原料产能占国际市场的100%。但我国原有生产菌株的单位发酵产量较低,高消耗、高污染、片面追求生产规模的粗放型发展模式已经成了阻碍低碳经济持续高速发展的瓶颈。如何从根本上解决问题,提高生产菌株的单位发酵产量和原料利用率,降低能耗和生产成本,减少环境污染,是促进我国从"发酵大国"向"发酵强国"转变的关键。本文以阿维菌素为例,综述其基础研究的技术发展,特别是中国科学院微生物研究所引入合成生物学技术,将阿维菌素的单位产量提高了1000倍,至9 g/L,在内蒙古新威远与阿维菌素产业联盟的公司应用,迫使默克公司全面退出阿维菌素历史舞台,从而引领产业迅速发展的过程,为我国其它天然产物生物制造品种的改良提供思路和方法。     

Compensatory effects in the PI3K/PTEN/AKT signaling network following receptor tyrosine kinase inhibition

Overcoming de novo and acquired resistance to anticancer drugs that target signaling networks is a formidable challenge for drug design and effective cancer therapy. Understanding the mechanisms by which this resistance arises may offer a route to addressing the insensitivity of signaling networks to drug intervention and restore the efficacy of anticancer therapy. Extending our recent work identifying PTEN as a key regulator of Herceptin sensitivity, we present an integrated theoretical and experimental approach to study the compensatory mechanisms within the PI3K/PTEN/AKT signaling network that afford resistance to receptor tyrosine kinase (RTK) inhibition by anti-HER2 monoclonal antibodies. In a computational model representing the dynamics of the signaling network, we define a single control parameter that encapsulates the balance of activities of the enzymes involved in the PI3K/PTEN/AKT cycle. By varying this control parameter we are able to demonstrate both distinct dynamic regimes of behavior of the signaling network and the transitions between those regimes. We demonstrate resistance, sensitivity, and suppression of RTK signals by the signaling network. Through model analysis we link the sensitivity-to-resistance transition to specific compensatory mechanisms within the signaling network. We study this transition in detail theoretically by variation of activities of PTEN, PI3K, AKT enzymes, and use the results to inform experiments that perturb the signaling network using combinatorial inhibition of RTK, PTEN, and PI3K enzymes in human ovarian carcinoma cell lines. We find good alignment between theoretical predictions and experimental results. We discuss the application of the results to the challenges of hypersensitivity of the signaling network to RTK signals, suppression of drug resistance, and efficacy of drug combinations in anticancer therapy.