Yong-Tang Zheng

Kunming Institute of Zoology CAS, Yün-nan, Yunnan, China

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Publications (207)550.75 Total impact

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    ABSTRACT: Chinese rhesus macaques (CRMs) are ideal experimental animals for studying the pathogenesis of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) and for vaccine research. SHIV89.6 has been reported to be an attenuated virus because, in most cases, SHIV89.6 infection only causes limited alteration of immune cells and tissues, and it has been used commonly for vaccine research. After two serial passages in vivo, SHIV (SHIV-89.6P) induces CD4 lymphopenia and an AIDS-like disease with wasting and opportunistic infections. However, the pathogenic ability of SHIV89.6 is not well understood. In this study, we found that 6 of 14 SHIV89.6-infected CRMs died within 127 weeks after infection. We found especially high immune activation, low IFN-α expression, and distinctive cytokine expression profiles in the infected and dead (ID) group of monkeys, while there was only few change in the CD4(+) T counts and distribution of T cell subsets in the ID group monkeys. Also, there was a similar dynamic of viral load between infected and surviving (IS) and ID group monkeys. Furthermore, we found various correlations among immune activation, IFN-α expression, and frequencies of cytokine-secreting cells. These results suggest that SHIV89.6 infections have pathogenic potential in CRMs and that high immune activation and abnormal expression of cytokines contribute to death of SHIV89.6-infected CRMs. This also implies that high immune activation may be relevant to dysfunction of immune cells. It is proposed that high immune activation and dysfunction of immune cells may be good predictors for disease progression and markers for therapy.
    Archives of Virology 06/2015; DOI:10.1007/s00705-015-2455-6 · 2.28 Impact Factor
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    ABSTRACT: The Myanmar-China border region appears to be the "hot spot" region for HIV-1 recombination occurrence. Majority of previous analyses on HIV-1 recombination were based on partial genomic sequences, which obviously cannot well reflect the reality of HIV-1 genetic diversity in this area. Here, we presented a near full-length characterization of a novel HIV-1 CRF01_AE/B/C recombinant isolated from a long-distance truck driver in Northern Myanmar. It is the first release of a near full-length genomic sequence in Myanmar since 2003, and might be one of the most complicated HIV-1 chimeras ever detected in Myanmar, containing 4 CRF01_AE, 6 B and 5 C segments separated by 14 breakpoints throughout its genome. The discovery and characterization of this new CRF01_AE/B/C recombinant illustrates that inter-subtype recombination is ongoing in Myanmar, continuously generating new forms of HIV. More works based on near full-length sequence analyses are urgently needed to better understand the genetic diversity of HIV-1 in these regions.
    AIDS research and human retroviruses 05/2015; DOI:10.1089/AID.2015.0021 · 2.46 Impact Factor
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    ABSTRACT: Human mitochondrial antiviral signaling protein (hMAVS, also known as IPS-1, VISA, or Cardif) is essential for antiviral innate immunity. The Chinese tree shrew (Tupaia belangeri chinenses), a close relative of primates, is emerging as a potential animal model for investigating viral infection. However, there is a lack of biological knowledge about the antiviral innate immunity of the tree shrew. In this study, we identified and characterized the function of the Chinese tree shrew MAVS gene (tMAVS). The cDNA of tMAVS was 2771 bp in length and encoded a polypeptide of 501 amino acids. Phylogenetic analyses based on the amino acid sequences revealed a closer affinity of tMAVS with those of primates. Quantitative real-time PCR analysis indicated that tMAVS mRNA was constitutively expressed in all seven tissues analyzed in this study. The tMAVS mRNA expression was rapidly and significantly increased after RNA virus infections. Ectopic-expression of tMAVS significantly potentiated the virus-triggered activation of IRF3, NF-κB and interferon-β (IFN-β), whereas knockdown of tMAVS displayed the opposite effect. Furthermore, tMAVS mutants lacking the caspase activation and recruitment (CARD) domains or the transmembrane (TM) domain were unable to induce IFN-β. Similar with hMAVS, mitochondrial localization of tMAVS was dependent on its domain. Collectively, this study revealed evolutionary conservation of the MAVS antiviral signaling pathway in the Chinese tree shrew. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Developmental and comparative immunology 04/2015; 52(1). DOI:10.1016/j.dci.2015.04.014 · 3.71 Impact Factor
  • Yi-Qun Kuang, Hong-Liang Liu, Yong-Tang Zheng
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    ABSTRACT: During the long-term evolutionary history, the interaction between virus and host has driven the first-line barrier, innate immunity, to invading pathogens. Innate immune factor TRIM5α and host peptidyl-prolyl cis-trans isomerase Cyclophilin A are two key players in the interaction between HIV-1 and host. Interestingly, Cyclophilin A is retrotransposed into the critical host gene, TRIM5, locus via LINE-1 element in some primate species including New World monkeys and Old World monkeys. This review aims to comprehensively discuss the sensing and immune activation procedures of TRIM5α innate signaling pathway through Cyclophilin A. It will then present the production of TRIMCyp chimeric gene and the different fusion patterns in primates. Finally, it will summarize the distinct restriction activity of TRIMCyp from different primates and explain the current understanding on the innate immune mechanisms involved in the early phase of the viral life cycle during HIV-1 replication.
    Medical Microbiology and Immunology 04/2015; DOI:10.1007/s00430-015-0417-y · 2.43 Impact Factor
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    ABSTRACT: Searching for more safe and effective agents for HIV treatments is still an urgent topic worldwide. Based on our continuous modifications on the benzophenone derivatives as HIV-1 reverse transcriptase (RT) inhibitors, a new template bearing N-phenylbenzenesulfonamide (PBSA) structure was designed to enhance the interactions with HIV-1 RT. In this manuscript, a series of PBSA derivatives were synthesized and evaluated for their anti-HIV-1 activity. The preliminary test showed that these compounds were potent to inhibit wild-type HIV-1 with EC50 values ranging of 0.105–14.531 μmol/L. In particular, compound 13f not only has high anti-HIV-1 activity (0.108 μmol/L), but also possesses low toxicity with a TI value of 1816.6. Furthermore, the major interactions of the inhibitor 13f with HIV-1 RT were also investigated using the molecular modelling. Our discovered structure-activity relationships (SARs) of these analogues may serve as an important clue for further optimizations.
    Chinese Chemical Letters 02/2015; 26(2). DOI:10.1016/j.cclet.2014.11.004 · 1.18 Impact Factor
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    ABSTRACT: Ribosome inactivating proteins (RIPs) inhibit protein synthesis by depurinating the large ribosomal RNA and some are found to possess anti-human immunodeficiency virus (HIV) activity. Maize ribosome inactivating protein (RIP) has an internal inactivation loop which is proteolytically removed for full catalytic activity. Here, we showed that the recombinant active maize RIP protected chimeric simian-human immunodeficiency virus (SHIV) 89.6-infected macaque peripheral blood mononuclear cells from lysis ex vivo and transiently reduced plasma viral load in SHIV89.6-infected rhesus macaque model. No evidence of immune dysregulation and other obvious side-effects was found in the treated macaques. Our work demonstrates the potential development of maize RIP as an anti-HIV agent without impeding systemic immune functions.
    Toxins 01/2015; 7(1):156-69. DOI:10.3390/toxins7010156 · 2.48 Impact Factor
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    ABSTRACT: Pig-tailed macaques (Macaca nemistrina group) have been extensively used as non-human primate animal models for various human diseases in recent years, notably for AIDS research due to their sensitivity to HIV-1. Northern pig-tailed macaques (M. leonina) are distributed in China and other surrounding Southeast Asia countries. Although northern pig-tailed macaques have been bred on a large scale as experimental animals since 2012, the reference value of normal levels of leukocytes is not available. To obtain such information, 62 blood samples from male and female healthy northern pig-tailed macaques at different ages were collected. The normal range of major leukocyte subpopulations, such as T lymphocytes, B lymphocytes, natural killer (NK) cells, monocytes, and the expression levels of activation or differentiation related molecules (CD38, HLA-DR, CCR5, CD21, IgD, CD80 and CD86) on lymphocytes were analyzed by flow cytometry. The counts of B cells decreased with age, but those of CD8(+) T cells and NK cells and the frequency of CD38(+)HLA-DR(+)CD4(+) T cells were positively correlated with age. The counts of leukocyte subpopulations were higher in males than those in females except for CD4(+) T cells. Males also showed higher expression levels of IgD and CD21 within B cells. This study provides basic data about the leukocyte subpopulations of northern pig-tailed macaques and compares this species with commonly used Chinese rhesus macaques (M. mulatta), which is meaningful for the biomedical application of northern pig-tailed macaques.
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    ABSTRACT: Non-human primates (NHPs) are phylogenetically close to humans, with many similarities in terms of physiology, anatomy, immunology, as well as neurology, all of which make them excellent experimental models for biomedical research. Compared with developed countries in America and Europe, China has relatively rich primate resources and has continually aimed to develop NHPs resources. Currently, China is a leading producer and a major supplier of NHPs on the international market. However, there are some deficiencies in feeding and management that have hampered China's growth in NHP research and materials. Nonetheless, China has recently established a number of primate animal models for human diseases and achieved marked scientific progress on infectious diseases, cardiovascular diseases, endocrine diseases, reproductive diseases, neurological diseases, and ophthalmic diseases, etc. Advances in these fields via NHP models will undoubtedly further promote the development of China's life sciences and pharmaceutical industry, and enhance China's position as a leader in NHP research. This review covers the current status of NHPs in China and other areas, highlighting the latest developments in disease models using NHPs, as well as outlining basic problems and proposing effective countermeasures to better utilize NHP resources and further foster NHP research in China.
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    ABSTRACT: A novel series of 1-(thiophen-2-yl)-9H-pyrido [3,4-b]indole derivatives were synthesized using DL-tryptophan as starting material. All the compounds were characterized by spectral analysis such as (1) H NMR, Mass, IR, elemental analysis and evaluated for inhibitory potency against HIV-1 replication. Among the reported analogues, compound 7g exhibited significant anti-HIV activity with EC50 0.53 μM and selectivity index 483; compounds 7e, 7i and 7o displayed moderate activity with EC50 3.8, 3.8 and 2.8 μM and selectivity index >105, >105 and 3.85 respectively. Interestingly compound 7g inhibited p24 antigen expression in acute HIV-1IIIB infected cell line C8166 with EC50 1.1 μM. In this study, we also reported the Lipinski rule of 5 parameters, predicted toxicity profile, drug likeness and drug score of the synthesized analogues. This article is protected by copyright. All rights reserved.
    Chemical Biology &amp Drug Design 10/2014; 85(6). DOI:10.1111/cbdd.12456 · 2.51 Impact Factor
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    ABSTRACT: The China-Myanmar border is a particularly interesting region that has very high prevalence of and considerable diversity of HIV-1 recombinants. Due to the transient nature of their work, long-distance truck drivers (LDTDs) have a comparatively high potential to become infected with HIV-1 and further spread virus to other individuals in the area they travel within. In this study, we hypothesized that Burmese LDTDs crossing the China-Myanmar border frequently may potentially be involved in the cross-border transmission of HIV, and contribute to the extremely high prevalence of HIV-1 inter-subtype recombinants in this border region.
    BMC Infectious Diseases 08/2014; 14(1):463. DOI:10.1186/1471-2334-14-463 · 2.56 Impact Factor
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    ABSTRACT: Azvudine is a novel nucleoside reverse transcriptase inhibitor with antiviral activity on human immunodeficiency virus, hepatitis B virus and hepatitis C virus. Here we reported the in vitro activity of azvudine against HIV-1 and HIV-2 when used alone or in combination with other antiretroviral drugs and its drug resistance features. Azvudine exerted highly potent inhibition on HIV-1 (EC50s ranging from 0.03 to 6.92 nM) and HIV-2 (EC50s ranging from 0.018 to 0.025 nM). It also showed synergism in combination with six approved anti-HIV drugs on both C8166 and PBMC. In combination assay, the concentrations of azvudine used were 1000 or 500 fold lower than other drugs. Azvudine also showed potent inhibition on NRTI-resistant strains (L74V and T69N). Although M184V caused 250 fold reduction in susceptibility, azvudine remained active at nanomolar range. In in vitro induced resistant assay, the frequency of M184I mutation increased with induction time which suggests M184I as the key mutation in azvudine treatment. As control, lamivudine treatment resulted in a higher frequency of M184I/V given the same induction time and higher occurrence of M184V was found. Molecular modeling analysis suggests that steric hindrance is more pronounced in mutant M184I than M184V due to the azido group of azvudine. The present data demonstrates the potential of azvudine as a complementary drug to current anti-HIV drugs. M184I should be the key mutation, however, azvudine still remains active on HIV-1LAI-M184V at nanomolar range.
    PLoS ONE 08/2014; 9(8):e105617. DOI:10.1371/journal.pone.0105617 · 3.53 Impact Factor
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    ABSTRACT: The origin of novel genes and their evolutionary fates are long-standing questions in evolutionary biology. These questions become more complicated for genes conserved across various lineages, such as TRIM5, an antiretroviral restriction factor and a retrovirus capsid sensor in immune signalling. TRIM5 has been subjected to numerous pathogenic challenges and undergone dynamic evolution, making it an excellent example for studying gene diversification. Previous studies among several species showed that TRIM5 gained genetic and functional novelty in a lineage-specific manner, either via gene duplication or a cyclophilin A (CypA) retrotransposing into the TRIM5 locus, creating the gene fusion known as TRIM5-Cyclophilin A (TRIMCyp). To date, the general pattern of TRIM5 across the mammalian lineage remains elusive. In this study, we surveyed 36 mammalian genomes to verify a potentially novel TRIM5 pattern that uniquely seems to have occurred in tree shrews (Tupaia belangeri), and found that both gene duplication and retrotransposition worked jointly to form a specific TRIM5/TRIMCyp cluster not found among other mammals. Evolutionary analyses showed that the tree shrew TRIMCyp (tsTRIMCyp) originated independently in comparison with previously reported TRIMCyp and underwent strong positive selection, while no signal of positive selection was detected for other tree shrew TRIM5 (tsTRIM5) genes. Functional assay results suggest a functional divergence between tsTRIMCyp and its closest paralog TRIM5-4, likely reflecting different fates under diverse evolutionary forces. These findings present a rare example of novel gene origination resulting from a combination of gene duplication, retrotransposition and exon shuffling processes, providing a new paradigm to study genetic innovations and evolutionary fates of duplicated genes.
    Molecular Biology and Evolution 08/2014; 31(11). DOI:10.1093/molbev/msu238 · 14.31 Impact Factor
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    ABSTRACT: The interaction between HIV-1 integrase and LEDGF/P75 has been validated as a target for anti-HIV drug development. Based on the crystal structure of integrase in complex with LEDGF/P75, a library containing 80 thousand natural compounds was filtered with virtual screening. 11 hits were selected for cell based assays. One compound, 3-(1,3-benzothiazol-2-yl)-8-{[bis(2-hydroxyethyl)amino]methyl}-7-hydroxy-2H-chromen-2-one) (D719) inhibited integrase nuclear translocation in cell imaging. The binding mode of D719 was analyzed with molecular simulation. The anti-HIV activity of D719 was assayed by measuring the p24 antigen production in acute infection. The structure characteristics of D719 may provide valuable information for integrase inhibitor design.
    FEBS Letters 08/2014; 588(18). DOI:10.1016/j.febslet.2014.08.004 · 3.34 Impact Factor
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    ABSTRACT: Three tigliane-type diterpenoids named excoecafolins A-C and two daphnane-type diterpenoids named excoecafolins D and E, together with 13 known compounds, were isolated from the EtOAc extract of Excoecaria acerifolia Didr.. Their structures were elucidated through the analysis of the spectroscopic data. The anti-HIV-1 activity evaluation five of these compounds showed that four possessed moderate anti-HIV-1 activities with EC50 0.258, 0.036, 0.046, and 0.978 μM, SI >1,836.9, 431.1, 298.7, and >503.7, respectively. Additionally, the chemotaxonomic issue of the affinity correlation between Thymelaeceae and Euphorbiaceae is discussed based on the isolates.
    Fitoterapia 06/2014; 95. DOI:10.1016/j.fitote.2014.02.018 · 2.22 Impact Factor
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    ABSTRACT: The northern pig-tailed macaque (Macaca leonina) has been identified as an independent species of Old World monkey, and we previously found that PBMCs from M. leonina were susceptible to human immunodeficiency virus type 1 (HIV-1), which may be due to the absence of a TRIM5 protein restricting HIV-1 replication. Here we investigated the infection potentials of six laboratory adapted HIV-1 strains and three primary HIV-1 isolates in PBMCs from M. leonina. The results indicate that these strains are characterized by various but low replication levels, and among which, HIV-1NL4-3 shows the highest replication ability. Based on the abundant evidence of species-specific interactions between restriction factors APOBEC3 and HIV/SIV-derived Vif protein, we subsequently examined the replication potentials of vif-substituted HIV-1 (HSIV) in M. leonina PBMCs. Notably, HSIV-vifmac and stHIV-1SV chimeras, two HIV-1NL4-3-derived viruses encoding the viral infectivity factor (Vif) protein from SIVmac239, replicated robustly in cells from M. leonina, which suggests that HSIV could effectively antagonize the antiviral activity of APOBEC3 proteins expressed in cells of M. leonina. Therefore, our data demonstrate that M. leonina has the potential to be developed into a promising animal model for human AIDS.
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    ABSTRACT: The northern pig-tailed macaque (NPM,Macaca leonina) has become a widely used animal model in biomedical research. In this study, we measured serum immunoglobulin IgG, IgM, IgA, complement C3, C4 and CRP levels in 3-11 year old captive northern pig-tailed macaques using HITACHI 7600-20 automated chemistry analyzer in order to determine the influences of age and gender on these items. The results showed that serum IgA, IgM, C3 and C4 levels were not correlated with age (P>0.05), while serum IgG levels increased progressively with age (r=0.202;P=0.045). Serum IgG, IgA, IgM and C3 levels were higher in females than in males (P<0.05). Moreover, serum C3 concentration was both positively and strongly correlated with that of C4 (r=0.700; P<0.0001). This study provides basic serum immunoglobulin and complement data of captive northern pig-tailed macaques, which may prove useful for future breeding efforts and biomedical research.
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    ABSTRACT: HIV integrase (IN) is an essential enzyme for the viral replication. Currently, three IN inhibitors have been approved for treating HIV-1 infection. All three drugs selectively inhibit the strand transfer reaction by chelating a divalent metal ion in the enzyme active site. Flavonoids are a well-known class of natural products endowed with versatile biological activities. Their β-ketoenol or catechol structures can serve as a metal chelation motif and be exploited for the design of novel IN inhibitors. Using the metal chelation as a common pharmacophore, we introduced appropriate hydrophobic moieties into the flavonol core to design natural product-based novel IN inhibitors. We developed selective and efficient syntheses to generate a series of mono 3/5/7/3'/4'-substituted flavonoid derivatives. Most of these new compounds showed excellent HIV-1 IN inhibitory activity in enzyme-based assays and protected against HIV-1 infection in cell-based assays. The 7-morpholino substituted 7c showed effective antiviral activity (EC50=0.826μg/mL) and high therapeutic index (TI>242). More significantly, these hydroxyflavones block the IN-LEDGF/p75 interaction with low- to sub-micromolar IC50 values and represent a novel scaffold to design new generation of drugs simultaneously targeting the catalytic site as well as protein-protein interaction domains.
    Bioorganic & medicinal chemistry 04/2014; 22(12). DOI:10.1016/j.bmc.2014.04.016 · 2.95 Impact Factor
  • Hong-Yi Zheng, Ming-Xu Zhang, Wei Pang, Yong-Tang Zheng
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    ABSTRACT: The elderly usually suffer from increased morbidity and mortality due to infectious diseases, and this way may be attributed to diminishing immune protection with age. This phenomenon is commonly referred to as immunosenescence. However, this theory is still not well defined. Non-human primates serve as a favorable model to facilitate the studying aging of the immune system. Here, we investigated phenotypic features of T and B-cell aging in peripheral blood from Chinese rhesus macaques, included (1) a decrease of CD4/CD8 ratio; (2) a loss of naïve T cells accompanied with elevated proliferation and expansion of effector memory subset; (3) a reduction in B cell numbers and a shift from naïve B cells towards memory phenotype; and (4) increased levels of PD-1 expression in T cells and CD95 expression in B cells. Moreover, an accelerated decline in CD4(+) T cells and naïve T cells was found in male macaques, giving them a more severe immune risk profile. These data indicated Chinese rhesus macaques share a significant homology with humans in phenotypic aging of adaptive immunity, and may be an appropriate animal model for human aging research.
    Experimental gerontology 04/2014; 55. DOI:10.1016/j.exger.2014.04.004 · 3.53 Impact Factor
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    ABSTRACT: Aim To evaluate the anti-HIV activity and mechanism of action of wikstroelide M, a daphnane diterpene from Daphne acutiloba Rehder (Thymelaeaceae). Methods The anti-HIV activities of wikstroelide M against different HIV strains were evaluated by cytopathic effect assay and p24 quantification assay with ELISA. The inhibitory effect of wikstroelide M on HIV reverse transcription was analyzed by real-time PCR and ELISA. The effect of wikstroelide M on HIV-1 integrase nuclear translocation was observed with a cell-based imaging assay. The effect of wikstroelide M on LEDGF/p75-IN interaction was assayed by molecular docking. Results Wikstroelide M potently inhibited different HIV-1 strains, including HIV-1IIIB, HIV-1A17, and HIV-19495, induced a cytopathic effect, with EC50 values ranging from 3.81 to 15.65 ng·mL−1. Wikstroelide M also had high inhibitory activities against HIV-2ROD and HIV-2CBL-20-induced cytopathic effects with EC50 values of 18.88 and 31.90 ng·mL−1. The inhibitory activities of wikstroelide M on the three HIV-1 strains were further confirmed by p24 quantification assay, with EC50 values ranging from 15.16 to 35.57 ng·mL−1. Wikstroelide M also potently inhibited HIV-1IIIB induced cytolysis in MT-4 cells, with an EC50 value of 9.60 ng·mL−1. The mechanistic assay showed that wikstroelide M targeted HIV-1 reverse transcriptase and nuclear translocation of integrase through disrupting the interaction between integrase and LEDGF/p75. Conclusion Wikstroelide M may be a potent HIV-1 and HIV-2 inhibitor, the mechanisms of action may include inhibition of reverse trascriptase activity and inhibition of integrase nuclear translocation through disrupting the interaction between integrase and LEDGF/p75.
    Chinese Journal of Natural Medicines 03/2014; 12(3):186–193. DOI:10.1016/S1875-5364(14)60031-5
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    ABSTRACT: Translocation of viral integrase (IN) into the nucleus is a critical precondition of integration during the life cycle of HIV, a causative agent of Acquired Immunodeficiency Syndromes (AIDS). As the first discovered cellular factor to interact with IN, Lens epithelium-derived growth factor (LEDGF/p75) plays an important role in the process of integration. Disruption of the LEDGF/p75-IN interaction has provided a great interest for anti-HIV agent discovery. In this work, we reported that one small molecular compound, 1,4-bis(5-(naphthalen-1-yl)thiophen-2-yl)naphthalene(Compound 15), potently inhibit the IN- LEDGF/p75 interaction and affect the HIV-1 IN nuclear distribution at 1μM. The putative binding mode of Compound 15 was constructed by a molecular docking simulation to provide structural insights into the ligand-binding mechanism. Compound 15 suppressed viral replication by measuring p24 antigen production in HIV-1IIIB acute infected C8166 cells with EC50 value of 11.19μM. Compound 15 might supply useful structural information for further anti-HIV agent discovery.
    Chemico-biological interactions 01/2014; DOI:10.1016/j.cbi.2014.01.011 · 2.98 Impact Factor

Publication Stats

2k Citations
550.75 Total Impact Points

Institutions

  • 2003–2015
    • Kunming Institute of Zoology CAS
      • State Key Laboratory of Genetic Resources and Evolution
      Yün-nan, Yunnan, China
  • 2014
    • University of Science and Technology of China
      • School of Life Sciences
      Luchow, Anhui Sheng, China
  • 2006–2013
    • Chinese Academy of Sciences
      • Key Laboratory of Animal Models and Human Disease Mechanisms
      Peping, Beijing, China
    • Fudan University
      Shanghai, Shanghai Shi, China
  • 2005–2013
    • Kunming University of Science and Technology
      Yün-nan, Yunnan, China
  • 2008–2010
    • Northwest A & F University
      • College of Science
      Yang-ling-chen, Shaanxi, China
  • 2009
    • Hebei University
      Pao-ting-shih, Hebei, China
    • Birla Institute of Technology and Science Pilani
      Pilāni, Rajasthan, India
  • 2007
    • Yunnan University
      Yün-nan, Yunnan, China