查找使用阿拉丁产品的科研文献

Syntheses of CF2H-containing spirocyclopropyloxindoles from in situ generated CF2HCHN2 and 3-ylideneoxindoles

Wen-Yong Han,Jia Zhao,Jian-Shu Wang,Bao-Dong Cui,Nan-Wei Wan,Yong-Zheng Chen

A facile and practical [3+2] cycloaddition/ring contraction for the construction of structurally diverse CF 2 H-containing spirocyclopropyloxindoles was developed. Starting from isatin-derived 3-ylideneoxindoles and in situ generated CF 2 HCHN 2 , the desired products were obtained in good to excellent results (up to 99% yield and >99:1 trans/cis ) in the absence of metal catalyst . The potential application of the protocol was also demonstrated by the synthesis of the CF 2 H-substituted analog of HIV-1 NNRTI inhibitor.

Synthesis of piscidinol A derivatives and their ability to inhibit HIV-1 protease

Ying Wei,Chao-Mei Ma,Tai-Bai Jiang,Jiang Du,Xing Zhou,Guo-Qing Liu,Masao Hattori

Decreased MIP-3α Production from Antigen-Activated PBMCs in Symptomatic HIV-Infected Subjects

Fuchun Zhang,Lingling Sun,Mark K. Lafferty,Joseph B. Margolick,Alfredo Garzino-Demo

CD4+CCR6+T cells are highly susceptible to HIV infection, and a high cytokine producing CCR6+T cell subset is selectively lost during HIV infection. The CCR6 chemokine MIP-3α (CCL20) is produced at sites of infection in SIV animal models. Recently, we have shown that MIP-3α inhibits HIV replication. This inhibition of HIV infection is mediated by CCR6 signaling and eventuates in increased APOBEC3G expression. Since there are few existing reports on the role of MIP-3α in health or disease, we studied its production by PBMCs from HIV-seronegative and HIV+ subjects. We evaluated the ability of PBMCs to produce MIP-3α in response to antigen stimulation using cells obtained from two groups: one composed of HIV-seronegative subjects (n = 16) and the other composed of HIV+ subjects (n = 58), some asymptomatic and some with clinically defined AIDS. Antigens included fragment C of the tetanus toxin,Candida albicans, whole-inactivated HIV, and HIV p24. MIP-3α was detected by ELISA in tissue culture supernatants of antigen-stimulated PBMCs. MIP-3α production by antigen-stimulated PBMCs was readily measured for HIV-negative subjects and for HIV-seropositive asymptomatic subjects, but not for patients with AIDS. These results suggest that subversion of the MIP-3α-CCR6 axis by HIV during the course of infection contributes to the loss of immune function that eventually leads to AIDS.Keywords:CCR6;MIP-3α;immune response;antigen stimulation;Th17

Adenoviral vectors coated with cationic PEG derivatives for intravaginal vaccination against HIV-1

Zhaolu Xie,Zhonghua Ji,Zhirong Zhang,Tao Gong,Xun Sun

Mucus layer coating the vaginal epithelium represents a barrier for intravaginally delivered recombined adenoviral (rAd) vectors, but it could be overcome by proper polyethylene glycol (PEG) modification. Here we synthesized two cationic PEG derivatives, amino-(EO) n /(AGE) m -Cyss (APCs). The polymers contained neutral linear PEG (2–5 kDa) to provide a hydrophilic surface and amine pendants to provide positive charge for coating negatively charged rAd by physical adsorption. Given proper molecular composition, the polymer (5k-APC) could coat rAd without causing aggregation, facilitating its mucus penetrating ability and enhancing gene expression both in vitro and in vivo . With HIVgag as the model antigen, the polymer-rAd complexes were administered intravaginally to elicit both systemic and mucosal immune responses. 5k-APC-rAd immunization elicited robust HIVgag-specific cellular responses and also induced higher antigen-specific serum IgG. More importantly, mice immunized with 5k-APC-rAd showed higher level of IgA in vaginal lavage fluid. These findings suggest that 5k-APC-rAd is a promising system for intravaginal immunization against infectious diseases such as HIV within the vaginal tract.

Anti-HIV Effects of Baculiferins Are Regulated by the Potential Target Protein DARS

Jianrong Liu,Ling Ma,Chang Song,Hui Xing,Shan Cen,Wenhan Lin

Baculiferins are a group of marine sponge-derived polycyclic alkaloids with anti-HIV (human immunodeficiency virus) activities. To identify additional baculiferin-based congeners for SAR analysis and to investigate the mode of action, a total of 18 new baculiferin-type derivatives were synthesized. The inhibitory activities of the congeners against the HIV-1 virus were evaluated in vitro, and the relevant SAR was discussed. Compound 18 exerted the most potent activity toward VSV-G-pseudotyped HIV-1 (IC50 of 3.44 μM) and HIV-1 strain SF33 (IC50 of 2.80 μM) in vitro. To identify the cellular targets, three photoaffinity baculiferin probes were simultaneously synthesized. Photoaffinity labeling experiments together with LC-MS/MS data identified aspartate-tRNA ligase (DARS) as a putative target protein of 18. The overexpression and knockdown of DARS in HEK293T cells provided additional data to demonstrate that DARS is a potential target protein in the regulation of HIV virus infection. The modes of antiviral baculiferins 13 and 18 binding to DARS were determined by a molecular docking simulation. Thus, baculiferin 18 is considered a promising lead as a new molecular target for the development of anti-HIV agents.

Highly Potent Phosphinic HIV-1 Protease Inhibitors: Synthesis, In Vitro Evaluation, and Docking Studies

Komal Hayat,Danwen Qiu,Yuanyuan Wang,Palmer Sivoko Imbenzi,Faez Iqbal Khan,Magdalini Matziari

In the search for effective HIV-1 protease inhibitors, the design of symmetrical phosphinic pseudopeptides derived from a dual addition of hypophosphorous acid to acrylates (PACs) has emerged as a promising strategy due to their nonhydrolyzable nature and high affinity for this protease. In this study, we report the synthesis, in vitro evaluation, and docking studies of a series of new symmetrical phosphinic inhibitors, synthesized via simple and cost-effective procedures. This approach overcomes the complexities of previous methods and utilizes commercially or readily available reagents. The synthesized PACs, featuring various P2 and P2’ substituents, have been evaluated for their inhibitory activity against the HIV-1 protease. Among them, the PAC-Phe-Val derivative (9c) demonstrated potent inhibition, with an IC50 value of 33 nM, comparable to the FDA-approved Darunavir. Resolution of the isomers of 9c revealed the most potent candidate, with an IC50 value of 1 nM. Molecular docking studies revealed strong hydrogen bonding interactions between PAC-Phe-Val and key active site residues, suggesting a stable and effective binding profile. The compound’s structure–activity relationship (SAR) was explored, identifying crucial features for its inhibitory potency. This work highlights the potential of symmetrical phosphinic pseudopeptides as HIV-1 protease inhibitors and provides a foundation for further development of these compounds as novel antiretroviral therapies. Future research will focus on optimizing the pharmacokinetic properties and evaluating resistance profiles, aiming to advance the next generation of HIV treatments.

Self-assembled fluorescent Ce(Ⅲ) coordination polymer as ratiometric probe for HIV antigen detection

Mingyuan Du,Ningxing Li,Guobin Mao,Yucheng Liu,Xinxin Wang,Songbai Tian,Qinxue Hu,Xinghu Ji,Yalan Liu,Zhike He

The viral capsid protein p24 of human immunodeficiency virus is expressed at different level during viral invasion. Detection of p24 is of great importance in acquired immunodeficiency syndrome monitoring and therapy. A ratiometric probe that is easily-synthesized was constructed based on self-assembled fluorescent Ce(Ⅲ) and fluorescein . Fluorescein was used as reference. Hydrogen peroxide quenches the fluorescence of the Ce(III) easily but does not quench the fluorescence of fluorescein. The mechanism of reaction was discussed. Benefiting from the sensitive response to hydrogen peroxide, this probe was applied for p24 detection in enzyme linked immunoassay . The fluorescence ratio was in a good linear relationship with the concentration of p24, and the detection limit was 1.1 pg mL −1 . This proposed method has shown potential in virus detection with easy operation.

Metabolite Identification of HIV-1 Capsid Modulators PF74 and 11L in Human Liver Microsomes

Shujing Xu,Lin Sun,Dang Ding,Xujie Zhang,Xinyong Liu,Peng Zhan

PF74and11L, as potent modulators of the HIV-1 capsid protein, have been demonstrated to act at both early and late stages in the HIV-1 life cycle. However, their clearance is high in human liver microsomes (HLMs). The main goal of this study was to clarify the metabolism ofPF74and11Lin HLMs, and provide guidance for future structural optimization. To accomplish this, the phase-I metabolites ofPF74and11L, resulting from in vitro incubation with HLMs, were investigated via ultra-performance liquid chromatography–ultraviolet–high-resolution mass spectrometry (UPLC–UV–HRMS). The results show that 17 phase-I metabolites were putatively annotated forPF74, whereas 16 phase-I metabolites were found for11L. The main metabolic pathways ofPF74in HLMs were oxidation and demethylation, and the secondary metabolic pathway was hydrolysis; thus, the di-oxidation and demethylation products (M7,M9,M11, andM14) were found to be major metabolites ofPF74in HLMs. In comparison, the main metabolic pathways of11Lin HLMs were oxidation, demethylation, dehydrogenation, and oxidative deamination, withM6′,M11′,M15′, andM16′as the main metabolites. We suggest that the indole ring andN-methyl group ofPF74, and the aniline group, benzene ring R1′,N-methyl, and methoxy group of11L, were the main metabolic soft spots. Therefore, our research illuminates structural optimization options in seeking improved HIV-1 CA modulators.Keywords:PF74;11L;capsid modulators;human liver microsomes;UPLC–UV–HRMS;metabolite identification

Point-of-Care Multiplexed Assays of Nucleic Acids Using Microcapillary-based Loop-Mediated Isothermal Amplification

Yi Zhang,Lu Zhang,Jiashu Sun,Yulei Liu,Xingjie Ma,Shangjin Cui,Liying Ma,Jianzhong Jeff Xi,Xingyu Jiang

This report demonstrates a straightforward, robust, multiplexed and point-of-care microcapillary-based loop-mediated isothermal amplification (cLAMP) for assaying nucleic acids. This assay integrates capillaries (glass or plastic) to introduce and house sample/reagents, segments of water droplets to prevent contamination, pocket warmers to provide heat, and a hand-held flashlight for a visual readout of the fluorescent signal. The cLAMP system allows the simultaneous detection of two RNA targets of human immunodeficiency virus (HIV) from multiple plasma samples, and achieves a high sensitivity of two copies of standard plasmid. As few nucleic acid detection methods can be wholly independent of external power supply and equipment, our cLAMP holds great promise for point-of-care applications in resource-poor settings.

A Thioflavin T-induced G-Quadruplex Fluorescent Biosensor for Target DNA Detection

Xiao Fang ZHANG,Hong Mei XU,Lei HAN,Nian Bing LI,Hong Qun LUO

The detection of disease-related DNA is of great significance for early and accurate diagnosis and therapy. In this work, we successfully achieved the sensitive detection of target DNA based on a thioflavin T (ThT)-induced G-quadruplex fluorescent biosensor. ThT, a water-soluble fluorescent dye, can induce G-rich sequences to form G-quadruplexes and obtain an obviously enhanced fluorescence. In this work, it was employed to construct a biosensor for the detection of HIV. When the target HIV existed, the hairpin DNA probes would be opened in succession and release the completely exposed G-rich sequence to combine with ThT. The simple and rapid biosensor performed satisfactory selectivity; it also exhibited sensitivity with a detection limit of 2.4 nM. With good performance in human serum, we believe that this optical biosensor has the potential to be applied to the practical detection of target DNA.

Highly efficient preparation of active S-phenyl-L-cysteine with tryptophan synthase using a chemoenzymatic method

Xu Lisheng,Zhang Xingtao,Gao Guizhen,Yue Sun

Background S-Phenyl-L-cysteine is regarded as having potential applicability as an antiretroviral/protease inhibitor for human immunodeficiency virus (HIV). In the present study, optically active S -phenyl-L-cysteine was prepared in a highly efficient manner from inexpensive bromobenzene using tryptophan synthase through a chemoenzymatic method. Results The chemoenzymatic method used a four-step reaction sequence. The process started with the reaction of magnesium and bromobenzene, followed by a Grignard reaction, and then hydrolysis and enzymatic synthesis using tryptophan synthase. Through this approach, S -phenyl-L-cysteine was chemoenzymatically synthesized using tryptophan synthase from thiophenol and L-serine as the starting material. Conclusions High-purity, optically active S -phenyl-L-cysteine was efficiently and inexpensively obtained in a total yield of 81.3% (> 99.9% purity).

Anti-HIV agent azidothymidine decreases Tet(X)-mediated bacterial resistance to tigecycline in Escherichia coli

Liu Yuan,Jia Yuqian,Yang Kangni,Li Ruichao,Xiao Xia,Wang Zhiqiang

Recent emergence of high-level tigecycline resistance mediated by Tet(X3/X4) in Enterobacteriaceae undoubtably constitutes a serious threat for public health worldwide. Antibiotic adjuvant strategy makes antibiotic more effective against these resistant pathogens through interfering intrinsic resistance mechanisms or enhancing antibiotic actions. Herein, we screened a collection of drugs to identify compounds that are able to restore tigecycline activity against resistant pathogens. Encouragingly, we discovered that anti-HIV agent azidothymidine dramatically potentiates tigecycline activity against clinically resistant bacteria. Meanwhile, addition of azidothymidine prevents the evolution of tigecycline resistance in E. coli and the naturally occurring horizontal transfer of tet (X4). Evidence demonstrated that azidothymidine specifically inhibits DNA synthesis and suppresses resistance enzyme activity. Moreover, in in vivo infection models by Tet(X4)-expression E. coli , the combination of azidothymidine and tigecycline achieved remarkable treatment benefits including increased survival and decreased bacterial burden. These findings provide an effective regimen to treat infections caused by tigecycline-resistant Escherichia coli .