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1. chinaXiv:202002.00062 [pdf]

Furin, a potential therapeutic target for COVID-19

Hua Li; Canrong Wu; Yueying Yang; Yang Liu; Peng Zhang; Yali Wang; Qiqi Wang; Yang Xu; Mingxue Li; Mengzhu Zheng; Lixia Chen
Subjects: Medicine, Pharmacy >> Pharmacology

A novel coronavirus (SARS-CoV-2) infectious disease has broken out in Wuhan, Hubei Province since December 2019, and spread rapidly from Wuhan to other areas, which has been listed as an international concerning public health emergency. We compared the Spike proteins from four sources, SARS-CoV-2, SARS-CoV, MERS-CoV and Bat-CoVRaTG13, and found that the SARS-CoV-2 virus sequence had redundant PRRA sequences. Through a series of analyses, we propose the reason why SARS-CoV-2is more infectious than other coronaviruses. And through structure based virtual ligand screening, we foundpotentialfurin inhibitors, which might be used in the treatment of new coronary pneumonia.

submitted time 2020-02-23 Hits157679Downloads22918 Comment 0

2. 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
Subjects: Biology >> Ecology

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.

submitted time 2017-11-17 Hits1545Downloads940 Comment 0

3. chinaXiv:201711.02428 [pdf]

Discovery of Multiple Lead Compounds as M2 Inhibitors through the Focused Screening of a Small Primary Amine Library

Wenhui Hu; Shaogao Zeng; Chufang Li; Yanling Jie; Zhiyuan L; Ling Chen
Subjects: Biology >> Ecology

The discovery of new anti-influenza drugs is urgent, particularly considering the recent threat of swine flu. Although amantadine derivatives are the only M2 drugs for influenza virus A, their use is limited in the US due to drug resistance. Here we report the discovery of multiple M2 inhibitor lead compounds that were rapidly generated through focused screening of a small primary amine library which was designed using a scaffold-hopping strategy based on amantadine.

submitted time 2017-11-17 Hits1609Downloads899 Comment 0

4. chinaXiv:201605.01735 [pdf]

PTEN deficiency reprogrammes human neural stem cells towards a glioblastoma stem cell-like phenotype

Duan, Shunlei; Yuan, Guohong; Ren, Ruotong; Xu, Xiuling; Fu, Lina; Li, Ying; Yang, Jiping; Zhang, Weiqi; Liu, Guang-Hui; Liu, Xiaomeng; Li, Jingyi; Tang, Fuchou; Ren, Ruotong; Bai, Ruijun; Liu, Guang-Hui; Ren, Ruotong; Bai, Ruijun; Qu, Jing; Zhang, Weizhou; Wu, Jun
Subjects: Biology >> Biophysics

PTEN is a tumour suppressor frequently mutated in many types of cancers. Here we show that targeted disruption of PTEN leads to neoplastic transformation of human neural stem cells (NSCs), but not mesenchymal stem cells. PTEN-deficient NSCs display neoplasm-associated metabolic and gene expression profiles and generate intracranial tumours in immunodeficientmice. PTEN is localized to the nucleus in NSCs, binds to the PAX7 promoter through association with cAMP responsive element binding protein 1 (CREB)/CREB binding protein (CBP) and inhibits PAX7 transcription. PTEN deficiency leads to the upregulation of PAX7, which in turn promotes oncogenic transformation of NSCs and instates 'aggressiveness' in human glioblastoma stem cells. In a large clinical database, we find increased PAX7 levels in PTEN-deficient glioblastoma. Furthermore, we identify that mitomycin C selectively triggers apoptosis in NSCs with PTEN deficiency. Together, we uncover a potential mechanism of how PTEN safeguards NSCs, and establish a cellular platform to identify factors involved in NSC transformation, potentially permitting personalized treatment of glioblastoma.

submitted time 2016-05-15 Hits3988Downloads1785 Comment 0

5. chinaXiv:201605.01512 [pdf]

Baicalin Inhibits the Lethality of Ricin in Mice by Inducing Protein Oligomerization

Dong, Jing; Zhang, Yong; Zhang, Yu; Li, Rui; Deng, Xuming; Dong, Jing; Chen, Yutao; Wang, Quan; Li, Xuemei; Niu, Xiaodi; Yang, Cheng
Subjects: Biology >> Biophysics >> Biochemistry & Molecular Biology

Toxic ribosome-inactivating proteins abolish cell viability by inhibiting protein synthesis. Ricin, a member of these lethal proteins, is a potential bioterrorism agent. Despite the grave challenge posed by these toxins to public health, post-exposure treatment for intoxication caused by these agents currently is unavailable. In this study, we report the identification of baicalin extracted from Chinese herbal medicine as a compound capable of inhibiting the activity of ricin. More importantly, post-exposure treatment with baicalin significantly increased the survival of mice poisoned by ricin. We determined the mechanism of action of baicalin by solving the crystal structure of its complex with the A chain of ricin (RTA) at 2.2 angstrom resolution, which revealed that baicalin interacts with two RTA molecules at a novel binding site by hydrogen bond networks and electrostatic force interactions, suggesting its role as molecular glue of the RTA. Further biochemical and biophysical analyses validated the amino acids directly involved in binding the inhibitor, which is consistent with the hypothesis that baicalin exerts its inhibitory effects by inducing RTA to form oligomers in solution, a mechanism that is distinctly different from previously reported inhibitors. This work offers promising leads for the development of therapeutics against ricin and probably other ribosome-inactivating proteins.

submitted time 2016-05-12 Hits2389Downloads1287 Comment 0

6. chinaXiv:201605.01502 [pdf]

Uncovering the Molecular Mechanism of Actions between Pharmaceuticals and Proteins on the AD Network

Cao, Shujuan; Yu, Liang; Ruan, Jishou; Cao, Shujuan; Yu, Liang; Ruan, Jishou; Mao, Jingyuan; Wang, Quan; Wang, Quan; Ruan, Jishou
Subjects: Biology >> Biophysics

This study begins with constructing the mini metabolic networks (MMNs) of beta amyloid (A beta) and acetylcholine (ACh) which stimulate the Alzheimer's Disease (AD). Then we generate the AD network by incorporating MMNs of A beta and ACh, and other MMNs of stimuli of AD. The panel of proteins contains 49 enzymes/receptors on the AD network which have the 3D-structure in PDB. The panel of drugs is formed by 5 AD drugs and 5 AD nutraceutical drugs, and 20 non-AD drugs. All of these complexes formed by these 30 drugs and 49 proteins are transformed into dyadic arrays. Utilizing the prior knowledge learned from the drug panel, we propose a statistical classification (dry-lab). According to the wet-lab for the complex of amiloride and insulin degrading enzyme, and the complex of amiloride and neutral endopeptidase, we are confident that this dry-lab is reliable. As the consequences of the dry-lab, we discover many interesting implications. Especially, we show that possible causes of Tacrine, donepezil, galantamine and huperzine A cannot improve the level of ACh which is against to their original design purpose but they still prevent AD to be worse as A beta deposition appeared. On the other hand, we recommend Miglitol and Atenolol as the safe and potent drugs to improve the level of ACh before A beta deposition appearing. Moreover, some nutrients such as NADH and Vitamin E should be controlled because they may harm health if being used in wrong way and wrong time. Anyway, the insights shown in this study are valuable to be developed further.

submitted time 2016-05-12 Hits1759Downloads1023 Comment 0

7. chinaXiv:201605.01492 [pdf]

Structure Elucidation of Coxsackievirus A16 in Complex with GPP3 Informs a Systematic Review of Highly Potent Capsid Binders to Enteroviruses

De Colibus, Luigi; Spyrou, John A. B.; Ren, Jingshan; Grimes, Jonathan M.; Stuart, David I.; Wang, Xiangxi; Rao, Zihe; Tijsma, Aloys; Neyts, Johan; Leyssen, Pieter; Grimes, Jonathan M.; Stuart, David I.; Puerstinger, Gerhard; Rao, Zihe
Subjects: Biology >> Biophysics

The replication of enterovirus 71 (EV71) and coxsackievirus A16 (CVA16), which are the major cause of hand, foot and mouth disease (HFMD) in children, can be inhibited by the capsid binder GPP3. Here, we present the crystal structure of CVA16 in complex with GPP3, which clarifies the role of the key residues involved in interactions with the inhibitor. Based on this model, in silico docking was performed to investigate the interactions with the two next-generation capsid binders NLD and ALD, which we show to be potent inhibitors of a panel of enteroviruses with potentially interesting pharmacological properties. A meta-analysis was performed using the available structural information to obtain a deeper insight into those structural features required for capsid binders to interact effectively and also those that confer broad-spectrum anti-enterovirus activity.

submitted time 2016-05-12 Hits1776Downloads1037 Comment 0

8. chinaXiv:201605.01454 [pdf]

Expression, purification and crystallization of the (3R)-hydroxyacyl-ACP dehydratase HadAB complex from Mycobacterium tuberculosis

Dong, Yu; Li, Jun; Qiu, Xiaodi; Yan, Chuanqiang; Li, Xuemei; Dong, Yu; Qiu, Xiaodi; Yan, Chuanqiang
Subjects: Biology >> Biophysics

The (3R)-hydroxyacyl-ACP dehydratase HadAB, involved in the biosynthetic pathway for mycolic acid (MA) of Mycobacterium tuberculosis, catalyzes the third step in the fatty acid (FA) elongation cycle, which is an ideal and actual target for anti-tubercular agent. Though HadAB is predicted to be a member of the hotdog superfamily, it shares no sequence identity with typical hotdog fold isoenzyme FabZ. To characterize the significance of HadAB from the perspective of structural biology, large amount of pure HadAB complex is required for biochemical characterization and crystallization. Here, we used a unique expression and purification method. HadA and HadB were cloned separately and co-expressed in Escherichia coli. After GST affinity chromatography, two steps of anion exchange chromatography and gel filtration, the purity of the protein as estimated by SDS-PAGE was >95%. Using hanging-drop vapor-diffusion method, crystals were obtained and diffracted X-rays to 1.75 angstrom resolution. The crystal belongs to space group P4(1)2(1)2, with unit-cell parameters a = b = 82.0 angstrom, c = 139.8 angstrom, alpha = beta = gamma = 90.0 degrees. (C) 2015 The Authors. Published by Elsevier Inc.

submitted time 2016-05-12 Hits1903Downloads966 Comment 0

9. chinaXiv:201605.01364 [pdf]

Novel near-infrared BiFC systems from a bacterial phytochrome for imaging protein interactions and drug evaluation under physiological conditions

Chen, Minghai; Li, Wei; Zhang, Zhiping; Liu, Sanying; Zhang, Xiaowei; Zhang, Xian-En; Cui, Zongqiang; Zhang, Xian-En; Chen, Minghai; Liu, Sanying
Subjects: Biology >> Biophysics >> Imaging Medicine and Biomedical Engineering

Monitoring protein protein interactions (PPIs) in live subjects is critical for understanding these fundamental biological processes. Bimolecular fluorescence complementation (BiFC) provides a good technique for imaging PPIs; however, a BiFC system with a long wavelength remains to be pursued for in vivo imaging. Here, we conducted systematic screening of split reporters from a bacterial phytochrome-based, near-infrared fluorescent protein (iRFP). Several new near-infrared phytochrome BiFC systems were built based on selected split sites including the amino acids residues 97/98, 99/100,122/123, and 123/124. These new near-infrared BiFC systems from a bacterial phytochrome were verified as powerful tools for imaging PPIs under physiological conditions in live cells and in live mice. The interaction between HIV-1 integrase (IN) and cellular cofactor protein Lens epithelium-derived growth factor (LEDGF/p75) was visualized in live cells using the newly constructed iRFP BiFC system because of its important roles in HIV-1 integration and replication. Because the HIV IN-LEDGF/p75 interaction is an attractive anti-HIV target, drug evaluation assays to inhibit the HIV IN-LEDGF/p75 interaction were also performed using the newly constructed BiFC system. The results showed that compound 6 and carbidopa inhibit the HIV IN-LEDGF/p75 interaction in a dose-dependent manner under physiological conditions in the BiFC assays. This study provides novel near-infrared BiFC systems for imaging protein interactions under physiological conditions and provides guidance for splitting other bacterial phytochrome-like proteins to construct BiFC systems. The study also provides a new method for drug evaluation in live cells based on iRFP BiFC systems and supplies some new information regarding candidate drugs for anti-HIV therapies. (C) 2015 Elsevier Ltd. All rights reserved.

submitted time 2016-05-12 Hits3002Downloads1708 Comment 0

10. chinaXiv:201605.01279 [pdf]

Peptidyl Aldehyde NK-1.8k Suppresses Enterovirus 71 and Enterovirus 68 Infection by Targeting Protease 3C

Wang, Yaxin; Sun, Yuna; Rao, Zihe; Yang, Ben; Zhai, Yangyang; Yin, Zheng; Rao, Zihe; Zhai, Yangyang; Yin, Zheng; Rao, Zihe; Zhai, Yangyang; Yin, Zheng; Rao, Zihe; Wang, Yaxin; Rao, Zihe; Rao, Zihe
Subjects: Biology >> Biophysics

Enterovirus (EV) is one of the major causative agents of hand, foot, and mouth disease in the Pacific-Asia region. In particular, EV71 causes severe central nervous system infections, and the fatality rates from EV71 infection are high. Moreover, an outbreak of respiratory illnesses caused by an emerging EV, EV68, recently occurred among over 1,000 young children in the United States and was also associated with neurological infections. Although enterovirus has emerged as a considerable global public health threat, no antiviral drug for clinical use is available. In the present work, we screened our compound library for agents targeting viral protease and identified a peptidyl aldehyde, NK-1.8k, that inhibits the proliferation of different EV71 strains and one EV68 strain and that had a 50% effective concentration of 90 nM. Low cytotoxicity (50% cytotoxic concentration, >200 mu M) indicated a high selective index of over 2,000. We further characterized a single amino acid substitution inside protease 3C (3C(pro)), N69S, which conferred EV71 resistance to NK-1.8k, possibly by increasing the flexibility of the substrate binding pocket of 3C(pro). The combination of NK-1.8k and an EV71 RNA-dependent RNA polymerase inhibitor or entry inhibitor exhibited a strong synergistic anti-EV71 effect. Our findings suggest that NK-1.8k could potentially be developed for anti-EV therapy.

submitted time 2016-05-11 Hits1857Downloads1155 Comment 0

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