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1. chinaXiv:201711.02414 [pdf]

基于骨架跃迁和药物拼接所确立的新型二肽基肽酶IV抑制剂

王善春; 曾丽丽; 丁宇洋; 曾少高; 宋宏锐; 胡文辉; 谢慧
分类: 生物学 >> 生态学

截至目前,已有7个二肽基肽酶IV(DPP-IV)抑制剂成为抗糖尿病新药,它们的结构差异和内在关联性为进一步的结构修饰提供了新的思路。本研究针对阿格列汀和利那列汀的结构特征,采用骨架跃迁及药物拼接的原理,快速得到了新型的DPP-IV抑制剂8g (IC50= 4.9 nM),其活性和选择性均接近于上市新药。因此,运用经典的药物化学策略,对基于同一靶标的上市药物实施分子操作,可以有效地产生新型的活性分子。

提交时间: 2017-11-17 点击量13, 下载量5

2. chinaXiv:201711.02415 [pdf]

Visualization and Quantification of Browning Using a Ucp1-2A-Luciferase Knock-in Mouse Model

Mao, LF; Nie, BM; Nie, T; Hui, XY; Gao, XF; Lin, XL; Liu, X; Xu, Y; Tang, XF; Yuan, R; Li, K; Li, P; Ding, K; Wang, Y; Xu, AM; Fei, J; Han, WP; Liu, PT; Madsen, L; Kristiansen, K
分类: 生物学 >> 生态学

Both mammals and adult humans possess classic brown adipocytes and beige adipocytes, and the amount and activity of these adipocytes are considered key factors in combating obesity and its associated metabolic diseases. Uncoupling protein 1 (Ucp1) is the functional marker of both brown and beige adipocytes. To facilitate a reliable, easy, and sensitive measurement of Ucp1 expression both in vivo and in vitro, we generated a Ucp1-2A-luciferase knock-in mouse by deleting the stop codon for the mouse Ucp1 gene and replacing it with a 2A peptide. This peptide was followed by the luciferase coding sequence to recapitulate the expression of the Ucp1 gene at the transcriptional and translational levels. With this mouse, we discovered a cold-sensitive brown/beige adipose depot underneath the skin of the ears, which we named uBAT. Because of the sensitivity and high dynamic range of luciferase activity, the Ucp1-2A-luciferase mouse is useful for both in vitro quantitative determination and in vivo visualization of nonshivering thermogenesis. With the use of this model, we identified and characterized axitinib, an oral small-molecule tyrosine kinase inhibitor, as an effective browning agent.

提交时间: 2017-11-17 点击量14, 下载量6

3. chinaXiv:201711.02416 [pdf]

Toll-like receptor 2 costimulation potentiates the antitumor efficacy of CAR T Cells.

Lai, Y; Weng, J; Wei, X; Qin, L; Lai, P; Zhao, R; Jiang, Z; Li, B; Lin, S; Wang, S; Wu, Q; Tang, Z; Liu, P; Pei, D; Yao, Y; Du, X; Li, P
分类: 生物学 >> 生态学

Chimeric antigen receptor (CAR) T-cell immunotherapies have shown unprecedented success in treating leukemia but limited clinical efficacy in solid tumors. Here, we generated 1928zT2 and m28zT2, targeting CD19 and mesothelin, respectively, by introducing the Toll/interleukin-1 receptor domain of Toll-like receptor 2 (TLR2) to 1928z and m28z. T cells expressing 1928zT2 or m28zT2 showed improved expansion, persistency and effector function against CD19+ leukemia or mesothelin+ solid tumors respectively in vitro and in vivo. In a patient with relapsed B-cell acute lymphoblastic leukemia, a single dose of 5 * 104/kg 1928zT2 T cells resulted in robust expansion and leukemia eradication and led to complete remission. Hence, our results demonstrate that TLR2 signaling can contribute to the efficacy of CAR T cells. Further clinical trials are warranted to establish the safety and efficacy of this approach.Leukemia advance online publication, 25 August 2017; doi:10.1038/leu.2017.249.

提交时间: 2017-11-17 点击量12, 下载量6

4. chinaXiv:201711.02417 [pdf]

Rapid Generation of a novel DPP-4 inhibitor with long-acting property SAR study and PKPD evaluation

Hui Xiea, Shaogao Zengb, Guicheng Zhangb, Lili Zeng b, Guifa Zhong b, Junling Zhaob, Xin Zhaoc, Hongjiang Xud, Ling Yangd, Xiquan Zhangd, Shanchun Wangd, Wenhui Huc
分类: 生物学 >> 生态学

Drug compliance is critical for the patients with chronic diseases like diabetes. In our continuous effort to find better glucose lowering agents, an exploration for long-acting DPP-4 inhibitor had been launched. Based on our previous reported compound 111 bearing a pyrrolopyrimidine scaffold, lead compound 114 (IC50 = 2.3 nM, t1/2(rat) = 5.46 h) was rapidly determined with the pharmacokinetic superiority. Further SAR study indicated that the pyrrole ring was generally tolerable for variation, in which the β-substitution gave a better DPP-4 affinity. In depth evaluation on β position of pyrrole ring brought up with highly potent compound 124 (IC50 = 0.76 nM, t1/2(rat) = 7.89 h). In vivo pharmacodynamics tests demonstrated a similar or even slightly better sustained DPP-4 inhibition of compound 114 and 124 compared with the first marketed once-weekly drug Trelagliptin in this category, indicating that improvement of DPP-4 inhibitory activity or pharmacokinetic profile might be both feasible ways to rapid generation of long-acting DPP-4 inhibitors.

提交时间: 2017-11-17 点击量12, 下载量6

5. chinaXiv:201711.02418 [pdf]

PSCA and MUC1 in Non-small-cell Lung Cancer as Targets of Chimeric Antigen Receptor T cells

Wei, XR [ 1,2,3 ]; Lai, YX [ 1,2,3 ]; Li, J [ 4 ]; Qin, L [ 1,2,3 ]; Xu, YD [ 1,2,3 ]; Zhao, RC [ 1,2,3 ]; Li, BH [ 1,2,3 ]; Lin, SM [ 1,2,3 ]; Wang, SN [ 1,2,3 ]; Wu, QT [ 1,2,3 ]; Liang, QB [ 5 ]; Peng, MY [ 6 ]; Yu, FL [ 6 ]; Li, YQ [ 7 ]; Zhang, XC [ 8 ]; Wu, YL [ 8 ]; Liu, PT [ 9 ]; Pei, DQ [ 1,2 ]; Yao, Y [ 1,2,3 ]; Li, P [ 1,2,3 ]
分类: 生物学 >> 生态学

In recent years, immunotherapies, such as those involving chimeric antigen receptor (CAR) T cells, have become increasingly promising approaches to non-small-cell lung cancer (NSCLC) treatment. In this study, we explored the antitumor potential of prostate stem cell antigen (PSCA)-redirected CAR T and mucin 1 (MUC1)-redirected CAR T cells in tumor models of NSCLC. First, we generated patient-derived xenograft (PDX) mouse models of human NSCLC that maintained the antigenic profiles of primary tumors. Next, we demonstrated the expression of PSCA and MUC1 in NSCLC, followed by the generation and confirmation of the specificity and efficacy of PSCA-and MUC1-targeting CAR T cells against NSCLC cell lines in vitro. Finally, we demonstrated that PSCA-targeting CAR T cellscould efficiently suppress NSCLC tumor growth in PDX mice and synergistically eliminate PSCA(+)MUC1(+) tumors when combined with MUC1-targeting CAR Tcells. Taken together, our studies demonstrate that PSCA and MUC1 are both promising CAR T cell targets in NSCLC and that the combinatorial targeting ofthese antigens could further enhance the antitumor efficacy of CAR T cells.

提交时间: 2017-11-17 点击量14, 下载量6

6. chinaXiv:201711.02419 [pdf]

Novel pyrrolopyrimidine analogues as potent dipeptidyl peptidase IV inhibitors based on pharmacokinetic property-driven optimization

Xie, H(Xie, Hui); Zeng, LL(Zeng, Lili); Zeng, SG(Zeng, Shaogao); Lu, X (Lu, Xin); Zhang, GC (Zhang, Guicheng); Zhao, X (Zhao, Xin); Cheng, N (Cheng, Na); Tu, ZC (Tu, Zhengchao); Li, ZY (Li, Zhiyuan); Xu, HJ (Xu, Hongjiang); Yang, L (Yang, Ling); Zhang, XQ (Zhang, Xiquan); Huang, M (Huang, Min); Zhao, JL (Zhao, Junling); Hu, WH (Hu, Wenhui)
分类: 生物学 >> 生态学

We previously reported a highly potent DPP-IV inhibitor 6 with low in vivo efficacy. While trying to maintain consistent in vitro and in vivo biological activity, we initiated a pharmacokinetic property-driven optimization to improve the metabolic stability and permeability of inhibitor 6. A simple scaffold replacement of thienopyrimidine with pyrrolopyrimidine (21a) led to significantly improved metabolic stability (4% vs. 65% remaining). Further modification of the pyrrolopyrimidine scaffold to produce compound 21j resulted in much better oral bioavailability than 6. Importantly, compound 21j exhibits greater in vivo efficacy than does 6 and Alogliptin and is worthy of further development. (C) 2012 Elsevier Masson SAS. All rights reserved.

提交时间: 2017-11-17 点击量13, 下载量7

7. chinaXiv:201711.02422 [pdf]

Fumarylacetoacetate Hydrolase Knock-out Rabbit Model for Hereditary Tyrosinemia Type 1

Li, L (Li, Li); Zhang, QJ (Zhang, Quanjun); Yang, HQ (Yang, Huaqiang); Zou, QJ (Zou, Qingjian); Lai, CD (Lai, Chengdan); Jiang, F (Jiang, Fei); Zhao, P (Zhao, Ping); Luo, ZW (Luo, Zhiwei); Yang, JY (Yang, Jiayin); Chen, Q (Chen, Qian); Wang, Y (Wang, Yan); Newsome, PN (Newsome, Philip N.); Frampton, J (Frampton, Jon); Maxwell, PH (Maxwell, Patrick H.); Li, WJ (Li, Wenjuan); Chen, SH (Chen, Shuhan); Wang, DY (Wang, Dongye); Siu, TS (Siu, Tak-Shing); Tam, S (Tam, Sidney); Tse, HF (Tse, Hung-Fat)
分类: 生物学 >> 生态学

From the (a)CAS Key Laboratory of Regenerative Biology, Joint School of Life Sciences, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China, and Guangzhou Medical University, Guangzhou 511436, China, (b)CAS Key Laboratory of Regenerative Biology and Guangdong Provincial Key Laboratory of Stem Cells and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China, (c)Laboratory of RNA, Chromatin, and Human Disease, CAS Key Laboratory of Regenerative Biology and Guangdong Provincial Key Laboratory of Stem Cells and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China, (d)Cardiology Division, Department of Medicine, Queen Mary Hospital, The University of Hong Kong, Hong Kong SAR, China, (e)Hong Kong-Guangdong Stem Cell and Regenerative Medicine Research Centre, The University of Hong Kong and Guangzhou Institutes of Biomedicine and Health, Hong Kong SAR, China, (f)Department of Ophthalmology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou 510630, China, (g)State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Guangdong Provincial Research Center for Liver Fibrosis, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital and (h)Biomedical Research Center, Southern Medical University, Guangzhou 510515, China, (i)Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, (j)National Institute for Health Research (NIHR) Birmingham Liver Biomedical Research Unit and Centre for Liver Research, and (k)Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, United Kingdom, (l)Cambridge Institute for Medical Research, Wellcome Trust/Medical Research Council (MRC) Building, Cambridge CB2 0XY, United Kingdom, mDepartment of Clinical Biochemistry Unit, Queen Mary Hospital, Hong Kong SAR, China, (n)Department of Medicine, University of Hong Kong-Shenzhen Hospital, Shenzhen 518053, Guangdong, China, and (o)Laboratory of Metabolism and Cell Fate, CAS Key Laboratory of Regenerative Biology and Guangdong Provincial Key Laboratory of Stem Cells and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, Guangdong, China

提交时间: 2017-11-17 点击量13, 下载量5

8. chinaXiv:201711.02423 [pdf]

Expression of human il-15 in Pichia pastoris final V

Wei Sun; Yunxin Lai; Hongbo Li; Tao Nie; Ye Kuang; Xiaofeng Tang; Kuai Li; P. Rod Dunbar; Aimin Xua; Peng Li; Donghai Wu
分类: 生物学 >> 生态学

Interleukin-15 (IL-15) is a pleiotropic cytokine and a member of the four α-helix bundle family of cytokines which include IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21. IL-15 exhibits a broad biological activity and induces the differentiation and proliferation of T, B and natural killer (NK) cells. In this study, a DNA fragment containing the mature human IL-15 sequence was cloned into pPICZaA vector, generating a fusion protein with the alpha factor signal sequence in the Nterminus and 6×His as well as c-Myc tags in the C-terminus. The resulting plasmid was integrated into the genome of Pichia pastoris strain X-33. Recombinant yeast transformants with high-level recombinant human IL-15 (rhIL-15) production were identified, which secrete as much as 75 mg/L rhIL-15 after 3 days of induction by methanol. The rhIL-15 was purified by Ni+-NTA affinity chromatography, followed by DEAE anion exchange, yielding over 95% highly purified rhIL-15. Mass spectrometry and MALDI-TOF-TOF analysis showed the purified rhIL-15 had larger molecular weights than expected, due to different degrees of N-linked glycosylation. The biological activity of the rhIL-15 proteins was measured by its ability to enhance cellular proliferation of CTLL-2 and NK cells. The results demonstrate that the experimental procedure we have reported here can produce a large amount of active recombinant human IL-15 from Pichia pastoris.

提交时间: 2017-11-17 点击量15, 下载量9

9. chinaXiv:201711.02424 [pdf]

Discovery of potent dipeptidyl peptidase IV inhibitors through pharmacophore hybridization and hit-to-lead optimization

Zeng, SG (Zeng, Shaogao); Xie, H (Xie, Hui); Zeng, LL (Zeng, Li-li); Lu, X (Lu, Xin); Zhao, X (Zhao, Xin); Zhang, GC (Zhang, Gui-cheng); Tu, ZC (Tu, Zheng-chao); Xu, HJ (Xu, Hong-jiang); Yang, L (Yang, Ling); Zhang, XQ (Zhang, Xi-quan); Hu, WH (Hu, Wenhui)
分类: 生物学 >> 生态学

A novel dipeptidyl peptidase IV inhibitor hit (5, IC50 = 0.86 mu M) was structurally derived from our recently disclosed preclinical candidate 4 by replacing the cyanobenzyl with a butynyl based on pharmacophore hybridization. A hit-to-lead optimization effort was then initiated to improve its potency. Most N-substituted analogs exhibited good in vitro activity, and compound 180 (IC50 = 1.55 nM) was identified to be a potent dipeptidyl peptidase IV inhibitor with a significantly improved pharmacokinetic properties (bioavailablity: 41% vs 82.9%; T-1/2: 2 h vs 4.9 h). (C) 2013 Elsevier Ltd. All rights reserved.

提交时间: 2017-11-17 点击量12, 下载量6

10. chinaXiv:201711.02425 [pdf]

Discovery of novel pyrrolopyrimidine analogues as potent dipeptidyl peptidase IV inhibitors based on a pharmacokinetic property-driven optimization

Hui Xie; Saogao Zeng; Lili Zeng; Xiaobing Lan; Guicheng Zhang; Li Liu; Xin Lu; Na Chen; Zhiyuan Li; Zengzhao Tu; Hongjiang Xu; Ling Yang; Xiquan Zhang; Wenhui Hu
分类: 生物学 >> 生态学

Followed pharmacological evaluation exposed an extensive hepatic first pass effect within our recently disclosed DPP-IV inhibitors bearing thienopyrimidine scaffold. Through scaffold replacement with pyrrolopyrimidine, compound 1a had substantially improved the metabolic stability (from 6.6% to 65.07%), yet with severely poor absorptive property. Further modification by incorporation with varied substituents and structure conversion yielded both permeable and metabolic stable compounds. The whole pharmacokinetic- property based optimization had succeeded in balancing overall properties and resulted in the compound 1j, that with excellent efficacy to be a potential anti-diabetic candidate.

提交时间: 2017-11-17 点击量13, 下载量6

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