Publications by authors named "Lingling Geng"

23 Publications

  • Page 1 of 1

Large-scale chemical screen identifies Gallic acid as a geroprotector for human stem cells.

Protein Cell 2021 Sep 20. Epub 2021 Sep 20.

State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.

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http://dx.doi.org/10.1007/s13238-021-00872-5DOI Listing
September 2021

Effectiveness of Selenium on Chondrocyte Glycoprotein Glycosylation Which Play Important Roles in the Pathogenesis of an Endemic Osteoarthritis, Kashin-Beck Disease.

Biol Trace Elem Res 2021 Jun 24. Epub 2021 Jun 24.

School of Public Health, Health Science Center, Xi'an Jiaotong University, Key Laboratory of Trace Elements and Endemic Diseases, National Health Commission, Xi'an, Shaanxi, China.

In this study, we aimed to explore the effectiveness of selenium on the chondrocyte glycoprotein glycosylation which plays important roles in the pathogenesis of Kashin-Beck disease (KBD). Cartilage samples were collected from KBD patients after total knee replacement surgery. Chondrocytes were cultured with sodium selenium. The group of chondrocytes which were cultured without adding sodium selenium was considered as control group. Lectin microarray was used to screen the differences in lectin levels between KBD and KBD with selenium groups. Stronger signals for Bandeiraea simplicifolia (BS-I), Hippeastrum hybrid lectin (HHL), Pisum sativum agglutinin (PSA), Psophocarpus tetragonolobus lectin I (PTL-I), Psophocarpus tetragonolobus lectin II (PTL-II), Sophora japonica agglutinin (SJA), Lotus tetragonolobus lectin (LTL), and Triticum vulgaris (WGA) were observed in the KBD group. Meanwhile, Aleuria aurantia lectin (AAL), Lens culinaris agglutinin (LCA), Lycopersicon esculentum (tomato) lectin (LEL), Peanut agglutinin (PNA), and Sambucus nigra lectin (SNA) signals were lower in the KBD group. Selenium may have the function of influence the expression levels of carbohydrate chains Galα1,3-Gal, high mannose, and GlcNAc.
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http://dx.doi.org/10.1007/s12011-021-02778-zDOI Listing
June 2021

Meningoencephalitis, coronary artery and keratitis as an onset of brucellosis: a case report.

BMC Infect Dis 2020 Sep 7;20(1):654. Epub 2020 Sep 7.

Department of Rheumatology and Immunology, Xi'an Children's Hospital Affiliated to Xi'an Jiaotong University, Xi'an, 710003, People's Republic of China.

Background: Brucellosis is a zoonotic disease caused by brucella. It has been an increasing trend in recent years (Wang H, Xu WM, Zhu KJ, Zhu SJ, Zhang HF, Wang J, Yang Y, Shao FY, Jiang NM, Tao ZY, Jin HY, Tang Y, Huo LL, Dong F, Li ZJ, Ding H, Liu ZG, Emerg Microbes Infect 9:889-99, 2020). Brucellosis is capable to invade multiple systems throughout the body, lacking in typical clinical manifestations, and easily misdiagnosed and mistreated.

Case Presentation: We report a case of a male, 5-year-and-11-month old child without relevant medical history, who was admitted to hospital for 20 days of fever. When admitted to the hospital, we found that he was enervated, irritable and sleepy, accompanied with red eyes phenomenon. After anti-infection treatment with meropenem, no improvement observed. Lumbar puncture revealed normal CSF protein, normal cells, and negative culture. Later, doppler echocardiography suggested coronary aneurysms, and incomplete Kawasaki Disease with coronary aneurysms was proposed. The next day, brucellosis agglutination test was positive. Metagenomic next-generation sequencing (mNGS) of cerebrospinal fluid suggested B.melitensis, which was confirmed again by blood culture. The child was finally diagnosed as brucellosis with meningocephalitis, coronary aneurysm and keratitis. According to our preliminary research and review, such case has never been reported in detail before. After diagnosis confirmation, the child was treated with rifampicin, compound sulfamethoxazole, and ceftriaxone for cocktail anti-infection therapy. Aspirin and dipyridamole were also applied for anticoagulant therapy. After medical treatment, body temperature of the child has reached normal level, eye symptoms alleviated, and mental condition gradually turned normal. Re-examination of the doppler echocardiographic indicated that the coronary aneurysm was aggravated, so warfarin was added for amplification of anticoagulation treatment. At present, 3 months of follow-up, the coronary artery dilatation gradually assuaged, and the condition is continued to alleviate.

Conclusion: Brucellosis can invade nervous system, coronary artery, and cornea. Brucellosis lacks specific signs for clinical diagnosis. The traditional agglutination test and the new mNGS are convenient and effective, which can provide the reference for clinical diagnosis.
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http://dx.doi.org/10.1186/s12879-020-05358-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7487788PMC
September 2020

Caloric Restriction Reprograms the Single-Cell Transcriptional Landscape of Rattus Norvegicus Aging.

Cell 2020 03 27;180(5):984-1001.e22. Epub 2020 Feb 27.

State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; Advanced Innovation Center for Human Brain Protection, and National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing 100053, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China; University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address:

Aging causes a functional decline in tissues throughout the body that may be delayed by caloric restriction (CR). However, the cellular profiles and signatures of aging, as well as those ameliorated by CR, remain unclear. Here, we built comprehensive single-cell and single-nucleus transcriptomic atlases across various rat tissues undergoing aging and CR. CR attenuated aging-related changes in cell type composition, gene expression, and core transcriptional regulatory networks. Immune cells were increased during aging, and CR favorably reversed the aging-disturbed immune ecosystem. Computational prediction revealed that the abnormal cell-cell communication patterns observed during aging, including the excessive proinflammatory ligand-receptor interplay, were reversed by CR. Our work provides multi-tissue single-cell transcriptional landscapes associated with aging and CR in a mammal, enhances our understanding of the robustness of CR as a geroprotective intervention, and uncovers how metabolic intervention can act upon the immune system to modify the process of aging.
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http://dx.doi.org/10.1016/j.cell.2020.02.008DOI Listing
March 2020

Low-dose quercetin positively regulates mouse healthspan.

Protein Cell 2019 10;10(10):770-775

State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China.

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http://dx.doi.org/10.1007/s13238-019-0646-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6776572PMC
October 2019

Rescue of premature aging defects in Cockayne syndrome stem cells by CRISPR/Cas9-mediated gene correction.

Protein Cell 2020 01 30;11(1):1-22. Epub 2019 Apr 30.

Department of Obstetrics and Gynecology, Center for Reproductive Medicine, Peking University Third Hospital, Beijing, 100191, China.

Cockayne syndrome (CS) is a rare autosomal recessive inherited disorder characterized by a variety of clinical features, including increased sensitivity to sunlight, progressive neurological abnormalities, and the appearance of premature aging. However, the pathogenesis of CS remains unclear due to the limitations of current disease models. Here, we generate integration-free induced pluripotent stem cells (iPSCs) from fibroblasts from a CS patient bearing mutations in CSB/ERCC6 gene and further derive isogenic gene-corrected CS-iPSCs (GC-iPSCs) using the CRISPR/Cas9 system. CS-associated phenotypic defects are recapitulated in CS-iPSC-derived mesenchymal stem cells (MSCs) and neural stem cells (NSCs), both of which display increased susceptibility to DNA damage stress. Premature aging defects in CS-MSCs are rescued by the targeted correction of mutant ERCC6. We next map the transcriptomic landscapes in CS-iPSCs and GC-iPSCs and their somatic stem cell derivatives (MSCs and NSCs) in the absence or presence of ultraviolet (UV) and replicative stresses, revealing that defects in DNA repair account for CS pathologies. Moreover, we generate autologous GC-MSCs free of pathogenic mutation under a cGMP (Current Good Manufacturing Practice)-compliant condition, which hold potential for use as improved biomaterials for future stem cell replacement therapy for CS. Collectively, our models demonstrate novel disease features and molecular mechanisms and lay a foundation for the development of novel therapeutic strategies to treat CS.
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http://dx.doi.org/10.1007/s13238-019-0623-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6949206PMC
January 2020

Chemical screen identifies a geroprotective role of quercetin in premature aging.

Protein Cell 2019 06 1;10(6):417-435. Epub 2018 Aug 1.

Advanced Innovation Center for Human Brain Protection, National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital of Capital Medical University, Beijing, 100053, China.

Aging increases the risk of various diseases. The main goal of aging research is to find therapies that attenuate aging and alleviate aging-related diseases. In this study, we screened a natural product library for geroprotective compounds using Werner syndrome (WS) human mesenchymal stem cells (hMSCs), a premature aging model that we recently established. Ten candidate compounds were identified and quercetin was investigated in detail due to its leading effects. Mechanistic studies revealed that quercetin alleviated senescence via the enhancement of cell proliferation and restoration of heterochromatin architecture in WS hMSCs. RNA-sequencing analysis revealed the transcriptional commonalities and differences in the geroprotective effects by quercetin and Vitamin C. Besides WS hMSCs, quercetin also attenuated cellular senescence in Hutchinson-Gilford progeria syndrome (HGPS) and physiological-aging hMSCs. Taken together, our study identifies quercetin as a geroprotective agent against accelerated and natural aging in hMSCs, providing a potential therapeutic intervention for treating age-associated disorders.
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http://dx.doi.org/10.1007/s13238-018-0567-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6538594PMC
June 2019

Peptide probes derived from pertuzumab by molecular dynamics modeling for HER2 positive tumor imaging.

PLoS Comput Biol 2017 Apr 13;13(4):e1005441. Epub 2017 Apr 13.

CAS Key Laboratory for Biological Effects of Nanomaterials & Nanosafety, National Center for Nanoscience and Technology, Beijing, China.

A high level of HER2 expression in breast cancer correlates with a higher tumor growth rate, high metastatic potential, and a poor long-term patient survival rate. Pertuzumab, a human monoclonal antibody, can reduce the effect of HER2 overexpression by preventing HER2 dimerization. In this study, a combination protocol of molecular dynamics modeling and MM/GBSA binding free energy calculations was applied to design peptides that interact with HER2 based on the HER2/pertuzumab crystal structure. Based on a β hairpin in pertuzumab from Glu46 to Lys65-which plays a key role in interacting with HER2-mutations were carried out in silico to improve the binding free energy of the hairpin that interacts with the Phe256-Lys314 of the HER2 protein. Combined the use of one-bead-one-compound library screening, among all the mutations, a peptide (58F63Y) with the lowest binding free energy was confirmed experimentally to have the highest affinity, and it may be used as a new probe in diagnosing and treating HER2-positive breast cancer.
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http://dx.doi.org/10.1371/journal.pcbi.1005441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5390981PMC
April 2017

Corrigendum to "MiR-146a modulates macrophage polarization in systemic juvenile idiopathic arthritis by targeting INHBA" [Mol. Immunol. 77 (2016) 205-212].

Mol Immunol 2017 07 31;87:329-330. Epub 2017 Mar 31.

Department of Internal Hematology, the Second Affiliated Hospital of Xi'an Jiaotong University, 157 West Fifth Road, Xi'an, Shaanxi Province 710004, China. Electronic address:

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http://dx.doi.org/10.1016/j.molimm.2017.03.016DOI Listing
July 2017

Visualization of aging-associated chromatin alterations with an engineered TALE system.

Cell Res 2017 Apr 31;27(4):483-504. Epub 2017 Jan 31.

National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China.

Visualization of specific genomic loci in live cells is a prerequisite for the investigation of dynamic changes in chromatin architecture during diverse biological processes, such as cellular aging. However, current precision genomic imaging methods are hampered by the lack of fluorescent probes with high specificity and signal-to-noise contrast. We find that conventional transcription activator-like effectors (TALEs) tend to form protein aggregates, thereby compromising their performance in imaging applications. Through screening, we found that fusing thioredoxin with TALEs prevented aggregate formation, unlocking the full power of TALE-based genomic imaging. Using thioredoxin-fused TALEs (TTALEs), we achieved high-quality imaging at various genomic loci and observed aging-associated (epi) genomic alterations at telomeres and centromeres in human and mouse premature aging models. Importantly, we identified attrition of ribosomal DNA repeats as a molecular marker for human aging. Our study establishes a simple and robust imaging method for precisely monitoring chromatin dynamics in vitro and in vivo.
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http://dx.doi.org/10.1038/cr.2017.18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5385610PMC
April 2017

Chiral Nanoparticle as a New Efficient Antimicrobial Nanoagent.

Adv Healthc Mater 2017 Feb 27;6(4). Epub 2016 Dec 27.

CAS Center of Excellence for Nanoscience, CAS Key Laboratory for Nanosystem and Hierarchical Fabrication, National Center for Nanoscience and Technology, 11 Beiyitiao Zhongguancun, Beijing, 100190, P. R. China.

d-type functionalized nanoparticles (NPs) can bind to MurD ligase with high affinity and inhibit its peptidoglycan synthetic enzyme activity, and finally cause bacterial killing. In contrast, its L-type counterpart displays a negligible effect, indicating that the chiral structure of the functionalized NPs plays an essential role in their binding interaction with MurD and therefore the antibacterial activity.
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http://dx.doi.org/10.1002/adhm.201601011DOI Listing
February 2017

Tumor detection using magnetosome nanoparticles functionalized with a newly screened EGFR/HER2 targeting peptide.

Biomaterials 2017 01 16;115:53-64. Epub 2016 Nov 16.

CAS Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety, National Center for Nanoscience and Technology, Beijing 100190, China; CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing 100190, China. Electronic address:

A novel peptide (P75) targeting EGFR and HER2 is successfully screened from a one-bead-one-compound (OBOC) library containing approximately 2 × 10 peptides built with the aid of computational simulation. In vitro and in vivo analyses show that P75 binds to human epithelial growth factor receptor (EGFR) with nanomolar affinity and to epithelial growth factor receptor-2 (HER2) with a lower affinity but comparable to other reported peptides. The peptide is used to modify the surface of magnetosome nanoparticles (NPs) for targeted magnetic resonance imaging (MRI). In vitro and in vivo fluorescence imaging results suggest peptide P75 modified magnetosomes (Mag-P75) specifically bind to MDA-MB-468 and SKBR3 cells as well as xenograft tumors with surprisingly low accumulation in other organs including liver and kidney. In vivo T-weighted MR imaging studies of the xenograft tumors from SKBR3 and MDA-MB-468 cells show obviously negative contrast enhancement. The high affinity and specificity of P75 to EGFR and HER2 positive tumors, together with the success of peptide functionalized magnetosome NPs for targeted MRI demonstrate the potential of this peptide being used in the EGFR and HER2 positive tumors diagnosis and therapy.
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http://dx.doi.org/10.1016/j.biomaterials.2016.11.022DOI Listing
January 2017

MiR-146a modulates macrophage polarization in systemic juvenile idiopathic arthritis by targeting INHBA.

Mol Immunol 2016 09 16;77:205-12. Epub 2016 Aug 16.

Department of Internal Hematology, the Second Affiliated Hospital of Xi'an Jiaotong University, 157 West Fifth Road, Xi'an, Shaanxi Province 710004, China. Electronic address:

Monocytes from patients with systemic juvenile idiopathic arthritis (SJIA) have both features of classical activated M1 and alternatively activated M2 macrophages. An increasing number of studies have indicated that microRNAs (miRNAs) are critical regulators of monocyte polarization. Here, we focused on miR-146a expression in SJIA and investigated the function of miR-146a in monocyte polarization. We found that miR-146a expression was highly up-regulated in SJIA monocytes and correlated with the systemic features. miR-146a was expressed at a higher level in monocytes polarized with M2 conditions than those polarized with M1 conditions. miR-146a overexpression significantly decreased the production of M1 phenotype markers such as IL-6, IL-12, TNF-α, CD86 and iNOS in M1 macrophages, but increased the production of M2 marker genes such as Arg1, CCL17, CCL22 and CD206 in M2 macrophages. Conversely, knockdown of miR-146a promoted M1 macrophage polarization but diminished M2 macrophage polarization. We subsequently demonstrated that miR-146a targeted the 3'-untranslated region (UTR) of INHBA to inhibit its expression. Additionally, INHBA overexpression rescued the reduced IL-6, IL-12, and TNF-α levels induced by miR-146a overexpression in M1 macrophages, and rescued the increased Arg1, CCL17, and CCL22 levels induced by miR-146a overexpression in M2 macrophages. Similarly, the effects of miR-146a inhibition in monocyte polarization were all partly reversed by INHBA inhibition. Taken together, the data suggest that miR-146a serves as a molecular regulator in monocyte polarization and might play an important role in monocytes from patients with SJIA.
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http://dx.doi.org/10.1016/j.molimm.2016.08.007DOI Listing
September 2016

HER2 Targeting Peptides Screening and Applications in Tumor Imaging and Drug Delivery.

Theranostics 2016 28;6(8):1261-73. Epub 2016 May 28.

1. CAS Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety, National Center for Nanoscience and Technology, Beijing 100190, China;; 2. CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing 100190, China;

Herein, computational-aided one-bead-one-compound (OBOC) peptide library design combined with in situ single-bead sequencing microarray methods were successfully applied in screening peptides targeting at human epidermal growth factor receptor-2 (HER2), a biomarker of human breast cancer. As a result, 72 novel peptides clustered into three sequence motifs which are PYL***NP, YYL***NP and PPL***NP were acquired. Particularly one of the peptides, P51, has nanomolar affinity and high specificity for HER2 in ex vivo and in vivo tests. Moreover, doxorubicin (DOX)-loaded liposome nanoparticles were modified with peptide P51 or P25 and demonstrated to improve the targeted delivery against HER2 positive cells. Our study provides an efficient peptide screening method with a combination of techniques and the novel screened peptides with a clear binding site on HER2 can be used as probes for tumor imaging and targeted drug delivery.
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http://dx.doi.org/10.7150/thno.14302DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4893650PMC
October 2017

Function projective synchronization between integer-order and stochastic fractional-order nonlinear systems.

ISA Trans 2016 Sep 4;64:34-46. Epub 2016 May 4.

Department of Mathematics, Beijing Jiaotong University, Beijing 100044, PR China. Electronic address:

In this paper, the function projective synchronization between integer-order and stochastic fractional-order nonlinear systems is investigated. Firstly, according to the stability theory of fractional-order systems and tracking control, a controller is designed. At the same time, based on the orthogonal polynomial approximation, the method of transforming stochastic error system into an equivalent deterministic system is given. Thus, the stability of the stochastic error system can be analyzed through its equivalent deterministic one. Finally, to demonstrate the effectiveness of the proposed scheme, the function projective synchronization between integer-order Lorenz system and stochastic fractional-order Chen system is studied.
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http://dx.doi.org/10.1016/j.isatra.2016.04.018DOI Listing
September 2016

Distinguishing of tumor cell-targeting peptide ligands through a color-encoding microarray.

Lab Chip 2015 Dec 4;15(24):4512-6. Epub 2015 Nov 4.

CAS Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety, National Center for Nanoscience and Technology of China, Beijing 100190, China.

A silicon-based microarray system was constructed to discover the affinity peptides and to distinguish the specific peptides from a high throughput library. Using a color-encoding strategy, in situ peptide distinguishing between HER1 ligands and HER2 ligands was achieved. Novel affinity peptide sequences H1P (HER1 ligand) and H2P (HER2 ligand) were determined with nmol affinity.
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http://dx.doi.org/10.1039/c5lc01010aDOI Listing
December 2015

Structure-based Design of Peptides with High Affinity and Specificity to HER2 Positive Tumors.

Theranostics 2015 1;5(10):1154-65. Epub 2015 Aug 1.

CAS Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety, National Center for Nanoscience and Technology, Beijing 100190, China.

To identify peptides with high affinity and specificity against human epidermal growth factor receptor 2 (HER2), a series of peptides were designed based on the structure of HER2 and its Z(HER2:342) affibody. By using a combination protocol of molecular dynamics modeling, MM/GBSA binding free energy calculations, and binding free energy decomposition analysis, two novel peptides with 27 residues, pep27 and pep27-24M, were successfully obtained. Immunocytochemistry and flow cytometry analysis verified that both peptides can specifically bind to the extracellular domain of HER2 protein at cellular level. The Surface Plasmon Resonance imaging (SPRi) analysis showed that dissociation constants (K D) of these two peptides were around 300 nmol/L. Furthermore, fluorescence imaging of peptides against nude mice xenografted with SKBR3 cells indicated that both peptides have strong affinity and high specificity to HER2 positive tumors.
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http://dx.doi.org/10.7150/thno.12398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4533098PMC
April 2016

Microarray based screening of peptide nano probes for HER2 positive tumor.

Anal Chem 2015 Aug 6;87(16):8367-72. Epub 2015 Aug 6.

§Institute for Systems Biology, 401 Terry Avenue North, Seattle, Washington 98109, United States.

Peptides are excellent biointerface molecules and diagnostic probes with many advantages such as good penetration, short turnover time, and low cost. We report here an efficient peptide screening strategy based on in situ single bead sequencing on a microarray. Two novel peptides YLFFVFER (H6) and KLRLEWNR (H10) specifically binding to the tumor biomarker human epidermal growth factor receptor 2 (HER2) with aKD of 10(-8) M were obtained from a 10(5) library. Conjugated to nanoparticles, both the H6 and H10 probes showed specific accumulation in HER2-positive tumor tissues in xenografted mice by in vivo imaging.
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http://dx.doi.org/10.1021/acs.analchem.5b01588DOI Listing
August 2015

Rapid screening of peptide probes through in situ single-bead sequencing microarray.

Anal Chem 2014 Dec 14;86(23):11854-9. Epub 2014 Nov 14.

CAS Key Laboratory for Biomedical Effects of Nanomaterials & Nanosafety, National Center for Nanoscience and Technology of China , Beijing 100190, China.

Peptide ligands as targeting probes for in vivo imaging and drug delivery have attracted great interest in the biomedical community. However, high affinity and specificity screening of large peptide libraries remains a tedious process. Here, we report a continuous-flow microfluidic method for one-bead-one-compound (OBOC) combinatorial peptide library screening. We screened a library with 2 × 10(5) peptide beads within 4 h and discovered 140 noncanonical peptide hits targeting the tumor marker, aminopeptidase N (APN). Using the Clustal algorithm, we identified the conserved sequence Tyr-XX-Tyr in the N terminal. We demonstrated that the novel sequence YVEYHLC peptides have both nanomolar affinity and high specificity for APN in ex vivo and in vivo models. We envision that the successful demonstration of this integrated novel nanotechnology for peptide screening and identification open a new avenue for rapid discovery of new peptide-based reagents for disease diagnostics and therapeutics.
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http://dx.doi.org/10.1021/ac503454zDOI Listing
December 2014

Computational study on the molecular mechanisms of drug resistance of Narlaprevir due to V36M, R155K, V36M+R155K, T54A, and A156T mutations of HCV NS3/4A protease.

Biochem Cell Biol 2014 Oct 23;92(5):357-69. Epub 2014 Jul 23.

School of Chemistry and Chemical Engineering, University of Chinese Academy of Sciences, Yuquan Road 19A, 100049 Beijing, P.R. China.

Narlaprevir is a novel NS3/4A protease inhibitor of hepatitis C virus (HCV), and it has been tested in a phase II clinical trial recently. However, distinct drug-resistance of Narlaprevir has been discovered. In our study, the molecular mechanisms of drug-resistance of Narlaprevir due to the mutations V36M, R155K, V36M+R155K, T54A, and A156T of NS3/4A protease have been investigated by molecular dynamics (MD) simulations, free energy calculations, and free energy decomposition analysis. The predicted binding free energies of Narlaprevir towards the wild-type and five mutants show that the mutations V36M, R155K, and T54A lead to low-level drug resistance and the mutations V36M+R155K and A156T lead to high-level drug resistance, which is consistent with the experimental data. The analysis of the individual energy terms indicates that the van der Waals contribution is important for distinguishing the binding affinities of these six complexes. These findings again show that the combination of different molecular modeling techniques is an efficient way to interpret the molecular mechanism of drug-resistance. Our work mainly elaborates the molecular mechanism of drug-resistance of Narlaprevir and further provides valuable information for developing novel, safer, and more potent HCV antiviral drugs in the near future.
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http://dx.doi.org/10.1139/bcb-2014-0039DOI Listing
October 2014

Computational insights into the selectivity mechanism of APP-IP over matrix metalloproteinases.

J Comput Aided Mol Des 2012 Dec 9;26(12):1327-42. Epub 2012 Dec 9.

School of Chemistry and Chemical Engineering, Graduate University of Chinese Academy of Sciences, Beijing 100049, People's Republic of China.

In this work, selectivity mechanism of APP-IP inhibitor (β-amyloid precursor protein-derived inhibitory peptide) over matrix metalloproteinases (MMPs including MMP-2, MMP-7, MMP-9 and MMP-14) was investigated by molecular modeling methods. Among MMPs, MMP-2 is the most favorable one for APP-IP interacting based on our calculations. The predicted binding affinities can give a good explanation of the activity difference of inhibitor APP-IP. In Comparison with MMP-2/APP-IP complex, the side chain of Tyr214(MMP-7) makes the binding pocket so shallow that the whole side chain of Tyr3(APP-IP) can not be fully embraced, thus unfavorable for the N-terminal of APP-IP binding to MMP-7. The poor selectivity of APP-IP toward MMP-9 is mainly related with the decrease of interaction between the APP-IP C-terminal and MMP-9 due to the bulky side chains of Pro193 and Gln199, which is in agreement with experiment. The mutations at residues P193A and Q199G of MMP-9 alternate the binding pattern of the C-terminal of APP-IP by forming two new hydrogen bonds and hydrophobic interactions with MMP-9. The mutants favor the binding affinity of MMP-9 largely. For MMP-14/APP-IP, the large steric effect of Phe204(MMP-14) and the weak contributions of the polar residues Asn231(MMP-14) and Thr190(MMP-14) could explain why MMP-14 is non-selective for APP-IP interacting. Here, the molecular modeling methods were successfully employed to explore the selective inhibitor of MMPs, and our work gives valuable information for future rational design of selective peptide inhibitors toward individual MMP.
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http://dx.doi.org/10.1007/s10822-012-9617-3DOI Listing
December 2012

Molecular dynamics and free energy studies of chirality specificity effects on aminobenzo[a]quinolizine inhibitors binding to DPP-IV.

J Mol Model 2013 Mar 15;19(3):1167-77. Epub 2012 Nov 15.

College of Chemistry and Chemical Engineering, Graduate University of the Chinese Academy of Sciences, Beijing 100049, People's Republic of China.

The aminobenzo[a]quinolizines were investigated as a novel class of DPP-IV inhibitors. The stereochemistry of this class plays an important role in the bioactivity. In this study, the mechanisms of how different configuration of three chiral centers of this class influences the binding affinity were investigated by molecular dynamics simulations, free energy decomposition analysis. The S configuration for chiral center 3* is decisive for isomers to maintain high bioactivity; the chirality effect of chiral center 2* on the binding affinity is largely dependent, while the S configuration for chiral center 2* is preferable to R configuration for the bioactivity gain; the effect of chiral center 11b* on the binding affinity is insignificant. The chirality specificity for three chiral centers is responsible for distinction of two van der Waals contacts with Tyr547 and Phe357, and of H-bonding interactions with Arg125 and Glu206. Particularly, the Arg125 to act as a bridge in the H-bonding network contributes to stable H-bonding interactions of isomer in DPP-IV active site.
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http://dx.doi.org/10.1007/s00894-012-1653-3DOI Listing
March 2013

Structure-based design of peptides against G3BP with cytotoxicity on tumor cells.

J Chem Inf Model 2010 Mar;50(3):380-7

Department of Chemistry, Graduate University of Chinese Academy of Sciences, Beijing, People's Republic of China.

Herein, we report a successful application of molecular modeling techniques to design two novel peptides with cytotoxicity on tumor cells. First, the interactions between the nuclear transport factor 2 (NTF2)-like domain of G3BP and the SH3 domain of RasGAP were studied by a well-designed protocol, which combines homology modeling, protein/protein docking, molecular dynamics simulations, molecular mechanics/generalized born surface area (MM/GBSA) free energy calculations, and MM/GBSA free energy decomposition analysis together. Then, based on the theoretical predictions, two novel peptides were designed and synthesized for biological assays, and they showed an obvious sensitizing effect on cis-platin. Furthermore, the designed peptides had no significant effects on normal cells, while cis-platin did. Our results demonstrate that it is feasible to use the peptides to enhance the efficacy of clinical drugs and to kill cancer cells selectively. We believe that our work should be very useful for finding new therapies for cancers.
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http://dx.doi.org/10.1021/ci900404pDOI Listing
March 2010
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