Li Wu

Publications (3)19.58 Total impact

• Article: Multimode, cooperative mechanism of action of allosteric HIV-1 integrase inhibitors.

  Jacques J Kessl, Nivedita Jena, Yasuhiro Koh, Humeyra Taskent-Sezgin, Alison Slaughter, Lei Feng, Suresh de Silva, Li Wu, Stuart F J Le Grice, Alan Engelman, James R Fuchs, Mamuka Kvaratskhelia
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  ABSTRACT: The multifunctional HIV-1 enzyme integrase interacts with viral DNA and its key cellular cofactor LEDGF to effectively integrate the reverse transcript into a host cell chromosome. These interactions are crucial for HIV-1 replication and present attractive targets for antiviral therapy. Recently, 2-(quinolin-3-yl) acetic acid derivatives were reported to selectively inhibit the integrase-LEDGF interaction in vitro and impair HIV-1 replication in infected cells. Here, we show that this class of compounds impairs both integrase-LEDGF binding and LEDGF-independent integrase catalytic activities with similar IC(50) values, defining them as bona fide allosteric inhibitors of integrase function. Furthermore, we show that 2-(quinolin-3-yl) acetic acid derivatives block the formation of the stable synaptic complex between integrase and viral DNA by allosterically stabilizing an inactive multimeric form of integrase. In addition, these compounds inhibit LEDGF binding to the stable synaptic complex. This multimode mechanism of action concordantly results in cooperative inhibition of the concerted integration of viral DNA ends in vitro and HIV-1 replication in cell culture. Our findings, coupled with the fact that high cooperativity of antiviral inhibitors correlates with their increased instantaneous inhibitory potential, an important clinical parameter, argue strongly that improved 2-(quinolin-3-yl) acetic acid derivatives could exhibit desirable clinical properties.
  Journal of Biological Chemistry 03/2012; 287(20):16801-11. · 4.77 Impact Factor
• Article: The differential effects of aligned electrospun PHBHHx fibers on adipogenic and osteogenic potential of MSCs through the regulation of PPARγ signaling.

  Yang Wang, Rui Gao, Pei-Pei Wang, Jia Jian, Xian-Li Jiang, Chao Yan, Xiao Lin, Li Wu, Guo-Qiang Chen, Qiong Wu
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  ABSTRACT: Cell-substrate interaction was functionally essential for phenotypic maintenance and multipotency remodeling of stem cells. For bone tissue engineering, electrospinning techniques are useful to create fibrous scaffolds mimicking natural mineralized collagen fibrous structure in bone. In this study, influence of electrospun fiber alignment on MSCs differentiation potential was investigated on PHBHHx electrospun meshes. Compared with randomly-oriented ones, the aligned fiber orientation increased elastic modulus and tension stress of the PHBHHx meshes. Most of the attached MSCs elongated along the aligned fibers. From the transcriptome microarray results, there were a total of 67 differentially expressed genes between aligned and random groups, and most of them were involved in cell adhesion and actin cytoskeleton regulation. In addition, PPAR signaling pathway was reduced on the aligned fibers, which might contribute to the impaired adipogenesis and enhanced osteogenesis. It was further confirmed by RT-PCR and western blotting. The PPARγ downregulation on the aligned fibers was related to phosphorylated activation of ERK, with no effect on total ERK expression. However, the induction of osteogenic by PHBHHx fiber alignment was relatively less significant that it could only support initial adipo-osteogenic switch and would be partially covered up by osteogenic or adipogenic inductive chemicals.
  Biomaterials 01/2012; 33(2):485-93. · 7.40 Impact Factor
• Article: MicroRNAs in the regulation of interfacial behaviors of MSCs cultured on microgrooved surface pattern.

  Yang Wang, Xian-Li Jiang, Shih-Chi Yang, Xiao Lin, Yu He, Chao Yan, Li Wu, Guo-Qiang Chen, Zhe-Yao Wang, Qiong Wu
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  ABSTRACT: Cell-substrate interaction is one of the most important aspects of tissue engineering. Changes of MSCs interfacial behaviors were found to be triggered by 10 μm wide grooved pattern on poly(3-hydroxybutyrate-co-3-hydroxyhexanoate) (PHBHHx). Global marker genes expression and miRNAs profiling analysis provided insights into the regulation network of the topography induced MSCs' cell responses including adhesion, proliferation, differentiation and apoptosis. Compared to MSCs cultured on the smooth substrates, MSCs incubated on microgrooved PHBHHx substrates showed increased expression of osteogenesis-related marker genes including cbfa1, col1a1 and bmp2, and decreased expression of vcl, vinculin encoding gene, adipogenesis-related genes including lpl, des and acta2, as well as myogenesis-related genes of myh11 and nse. The miRNA microarrays revealed that 18 differentially-expressed miRNAs on microgrooved pattern had multiple target genes, contributing comprehensively to the cellular regulation process. Similar to the topography-triggered ostegenenesis, co-transfection of the osteogenic miRNAs combination (miR-140, miR-214, miR-320, miR-351 and miR-674-5p) was able to stimulate the expression of osteogenic marker genes. This study elucidated the important roles of miRNAs in the regulation processes of the microenvironment triggered cell behaviors, and provided clues for the PHA biomedical materials development.
  Biomaterials 09/2011; 32(35):9207-17. · 7.40 Impact Factor