ACS Omega
·
2024
·
IF 3.7
Komal Hayat,Gemma Nixon,Qian Zhang,Magdalini Matziari
A highly efficient method to synthesize diverse symmetrical phosphinic acids with the potential to act as pivotal candidates in the design of HIV-1 protease inhibitors has been developed. Such compounds have been designed based on the enzyme–substrate specificity, and their elongated analogues are expected to demonstrate significant inhibition against the HIV-1 protease with IC50 values in the low nanomolar range. Moreover, a highly efficient esterification protocol with carbohydrates and flavonoids has been devised to address the inherent absorption challenges associated with phosphinic-based drugs. These esters not only exhibit low toxicity but also have the potential to generate flavonoid moieties in situ, which are associated with hepatoprotective effects, or naturally occurring carbohydrate metabolites. The methodology utilizes effective peptide coupling reagents, such as aminium-based TBTU and carbodiimide-based DIC, and affords the target products in excellent to quantitative yields. This research represents a promising avenue for the development of novel HIV-1 protease inhibitors with significant therapeutic benefits.
研究领域:
药物化学
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生物化学
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抗病毒研究
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DOI
PubMed
高影响因子
Journal of Chemistry
·
2025
·Vol. 2025
·期 1
·7113993
·
IF 2.6
Danwen Qiu,Komal Hayat,Yuanyuan Wang,Konstantinos Douroudis,Md. Imtaiyaz Hassan,Faez Iqbal Khan,Magdalini Matziari
Human immunodeficiency virus (HIV) remains a significant health issue with no vaccine available. Targeting the HIV-1 protease (HIV-1 PR) is essential in treatment, with inhibitors like lopinavir being historically an important component. However, lopinavir alone has low bioavailability and causes side effects when combined with ritonavir, leading to efforts to develop improved analogs. In this study, we designed and synthesized a phosphinic analog of lopinavir, PL1, by replacing its hydroxyethylene moiety with a phosphinic group. The inhibitory evaluation demonstrated a promising inhibition potency of PL1 against HIV-1 PR, supported by molecular dynamics simulations predicting its favorable interactions. Integrating AI-based docking tools confirmed PL1’s strong potential, with an IC 50 /EC 50 of 1.32 × 10 −8 mol/L and a binding affinity of 6.142, surpassing lopinavir’s 5.928. PL1’s binding efficacy index of 0.0119, comparable to lopinavir’s 0.0132, indicates efficient inhibition. Importantly, PL1 is less toxic than lopinavir, making it a promising lead molecule for HIV-1 PR targeting.
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DOI
高影响因子
Journal of Pharmaceutical Analysis
·
2022
·
IF 14.026
Liang Qi,Jiayun Zhang,Ying Gao,Pin Gong,Chengyuan Liang,Yao Su,Qiao Zeng,Yafeng Zhang
The regulator of expression of virion (Rev) protein binds specifically to the Rev-responsive element (RRE) RNA in order to regulate the expression of the human immunodeficiency virus (HIV)-1 genes. Fluorescence indicator displacement assays have been used to identify ligands that can inhibit the Rev–RRE interaction; however, the small fluorescence indicators cannot fully replace the Rev peptide or protein. As a result, a single rhodamine B labeled Rev (RB-Rev) model peptide was utilized in this study to develop a direct and efficient Rev–RRE inhibitor screening model. Due to photon-induced electron transfer quenching of the tryptophan residue on the RB fluorophore, the fluorescence of RB in Rev was weakened and could be dramatically reactivated by interaction with RRE RNA in ammonium acetate buffer (approximately six times). The interaction could reduce the electron transfer between tryptophan and RB, and RRE could also increase RB fluorescence. The inhibitor screening model was evaluated using three known positive Rev–RRE inhibitors, namely, proflavin, 6-chloro-9-[3-(2-chloroethylamino)propylamino]-2-methoxyacridine (ICR 191), and neomycin, as well as a negative drug, arginine. With the addition of the positive drugs, the fluorescence of the Rev–RRE decreased, indicating the displacement of RB-Rev. This was confirmed using atomic force microscopy (AFM) and the fluorescence was essentially unaffected by the addition of arginine. The results demonstrated that RB-Rev can be used as a fluorescent probe for recognizing small ligands that target RRE RNA. The Rev–RRE inhibitor screening model offers a novel approach to evaluating and identifying long-acting Rev inhibitors.
研究领域:
病毒学
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生物化学
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分子生物学
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药学
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DOI
PubMed
高影响因子
ANALYTICAL CHEMISTRY
·
2023
·
IF 7.4
Jialin Sai,Lu Zhou,Lin Jiang,Dongguo Xue,Renjun Pei,Aihua Liu,Lijun Xu
Signal amplification techniques are highly desirable for the analysis of low-level targets that are closely related with diseases and the monitoring of important biological processes. However, it is still challenging to achieve this goal in a facile and economical way. Herein, we developed a novel dual signal amplification strategy by combining urease catalysis with the release of Ag+ from silver nanoparticles (AgNPs). This strategy was used for quantifying a DNA sequence (HIV-1) related with human immunodeficiency virus (HIV). DNA target HIV-1 hybridizes with the capture DNA probe on magnetic beads and the reporter DNA probe on AgNPs, forming a sandwich complex. The captured AgNPs are then transformed into numerous Ag+ ions that inactivate numerous ureases. Without catalytic production of ammonia from urea, the substrate solution shows a low pH 5.8 that will increase otherwise. The pH change is monitored by a pH indicator (phenol red), which allows for colorimetric detection. The proposed approach is sensitive, easy to use, economic, and universal, exhibiting a low detection limit of 9.7 fM (i.e., 1.94 attomoles) and a dynamic linear range of 4 orders for HIV-1 sequence detection.
研究领域:
分析化学
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生物化学
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纳米技术
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病毒学
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DOI
PubMed
高影响因子
Frontiers in Immunology
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2012
·
IF 0
Slyker Jennifer Ann,Lohman-Payne Barbara Louise,John-Stewart Grace,Dong Tao,Mbori-Ngacha Dorothy,Tapia Kenneth,Atzberger Ann,Taylor Stephen,Rowland-Jones Sarah,Blish Catherine A
Natural killer (NK) cells play an important role in the containment of HIV replication during primary infection, though their functions are impaired during chronic HIV infection. Infants experience more rapid HIV disease progression than adults, but contributions of infant NK cells to containing HIV infection are unknown. The aim of this study was to determine the impact of HIV infection on infant NK cell phenotype by evaluating samples and data from a cohort study of women and their infants, conducted in Nairobi, Kenya between 1999 and 2003. The percentage and phenotype of NK cells was evaluated longitudinally by multi-parameter flow cytometry over the first year of life in HIV-infected (HIV+, = 16), HIV-exposed uninfected (HIV-EU, n = 6), and healthy unexposed controls (HIV–, n = 4). At birth, NK subset distributions based on expression of CD56 and CD16 did not differ between HIV+, HIV-EU, or HIV– infants. However, HIV infection was associated with a subsequent decline in NK cells as a percentage of total lymphocytes (p < 0.001), and an expanding proportion of CD56-CD16+ NK cells (p < 0.001). Activated CD38brightCD69+ NK cells were more frequent in the HIV+ infants, followed by HIV-EU and HIV- infants, in both CD56dim (p = 0.005) and CD56bright compartments (p = 0.03). HIV infection and exposure was also associated with a significant decline in the percentage of perforin-expressing NK cells in the CD56dim compartment over the first year of life, with HIV+ infants losing approximately 2.5% (p < 0.001) and HIV-EU infants losing 3.0% (p = 0.01) of perforin+ cells per month. Thus, infant HIV infection is associated with alterations in NK cell subsets, activation, and cytolytic potential that could contribute to their poor control over HIV infection. Furthermore, exposure to HIV infection in infants who escaped infection is also associated with alterations in NK cells that may contribute to the reduced ability to fight infections that is observed in HIV-EU infants.
研究领域:
免疫学
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传染病学
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儿科
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DOI
PubMed
ANALYTICAL CHEMISTRY
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2017
·
IF 6.32
Shanglin Li,Yin Gu,Yi Lyu,Yan Jiang,Peng Liu
An integrated graphene oxide purification-lateral flow test strip (iGOP-LFTS) was developed for on-strip purifying and visually detecting polymerase chain reaction (PCR) products with an improved sensitivity as well as a more stringent specificity. PCR products amplified with a pair of biotin- and digoxin-labeled primers were directly pipetted onto GO pads, on which graphene oxide selectively adsorbed residual primers and primer-dimers with the aid of a running buffer containing MgCl2 and Tween 20. By stacking up three GO pads to increase the surface area for adsorption, 83.4% of double-stranded DNA with a length of 30 bp and 98.6% of 20-nt primers could be removed from a 10-μL DNA mixture. Since no primers interfered with detection, the increase of the sample loading volume from 5 to 20 μL could improve the signal-to-noise ratio of the test line 1.6 fold using the iGOP-LFTS while no changes were observed using the conventional LFTS. The limit of detection of the iGOP-LFTS was determined to be 30 copies of bacteriophage λ-DNA with naked eyes and this limit could be further decreased to 3 copies by loading 20 μL of the sample, which corresponded to a 1000-fold improvement compared to that of the LFTS detected by naked eyes. When the ImageJ analysis was employed, a 100-fold decrease of the detection limit can be obtained. In addition, due to the removal of the primer-dimers, the dim test line observed in the negative control of the LFTS was eliminated using the iGOP-LFTS. A mock clinical specimen spiked with defective HIV-1 (human immunodeficiency virus) viruses was successfully analyzed using a two-step reverse transcription-PCR with 30 amplification cycles followed by the iGOP-LFTS detection. These significant improvements were achieved without introducing any additional hands-on operations and instrumentations.
研究领域:
分子生物学
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分析化学
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生物医学工程
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病毒学
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产品关联
DOI
PubMed
高影响因子
BIOMACROMOLECULES
·
2016
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IF 5.583
Nan Wang,Xin Jin,Dongbo Guo,Gangsheng Tong,Xinyuan Zhu
Iron accumulation in substantia nigra pars compacta (SNpc) has been proved to be a prominent pathophysiological feature of Parkinson’s diseases (PD), which can induce the death of dopaminergic (DA) neurons, up-regulation of reactive oxygen species (ROS), and further loss of motor control. In recent years, iron chelation therapy has been demonstrated to be an effective treatment for PD, which has shown significant improvements in clinical trials. However, the current iron chelators are suboptimal due to their short circulation time, side effects, and lack of proper protection from chelation with ions in blood circulation. In this work, we designed and constructed iron chelation therapeutic nanoparticles protected by a zwitterionic poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC) to delay the saturation of iron chelators in blood circulation and prolong the in vivo lifetime, with HIV-1 trans-activating transcriptor (TAT) served as a shuttle to enhance the blood-brain barrier (BBB) permeability. We explored and investigated whether the Parkinsonian neurodegeneration and the corresponding symptoms in behaviors and physiologies could be prevented or reversed both in vitro and in vivo. The results demonstrated that iron chelator loaded therapeutic nanoparticles could reverse functional deficits in Parkinsonian mice not only physiologically but also behaviorally. On the contrary, both untreated PD mice and non-TAT anchored nanoparticle treated PD mice showed similar loss in DA neurons and difficulties in behaviors. Therefore, with protection of zwitterionic polymer and prolonged in vivo lifetime, iron chelator loaded nanoparticles with delayed saturation provide a PD phenotype reversion therapy and significantly improve the living quality of the Parkinsonian mice.
研究领域:
神经科学
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药学
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纳米技术
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分子生物学
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产品关联
DOI
PubMed
高影响因子
BIOCHIMIE
·
2016
·
IF 3.017
Xiaoqiu He,Huayan Zhang,Yuhua Shi,Xin Gong,Shanshan Guan,He Yin,Lan Yang,Yongjiao Yu,Ziyu Kuai,Dongni Liu,Rui Hua,Song Wang,Yaming Shan
With increasing microbial drug resistance worldwide, antimicrobial peptides (AMPs) are considered promising alternatives to addressing this problem. In this study, a series of synthetic peptides were designed based on the membrane-disrupting properties of the membrane-proximal external region (MPER) of human immunodeficiency virus type 1 (HIV-1) envelope protein. The peptide AP16-A was found to exhibit the most effective antimicrobial activities against both Gram-negative and Gram-positive bacteria. The minimal bactericidal concentration (MBC) of AP16-A ranged from 2 μg/ml to 16 μg/ml. AP16-A had no detectable cytotoxicity in various tissue cultures and a mouse model. Furthermore, results of confocal fluorescence microscopy and the SYTOX Green uptake assay indicated that AP16-A killed Gram-negative bacteria by the combined effects of relatively slow membrane permeabilization and interaction with an intracellular target, while it killed Gram-positive bacteria by a fast membrane permeabilization process, which achieved relatively more rapid bacterial killing kinetics. The results of this study support the potential use of AP16-A as an AMP.
研究领域:
微生物学
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病毒学
·
药学
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产品关联
DOI
PubMed
高影响因子
ANALYTICAL CHEMISTRY
·
2022
·
IF 8.008
Jun Li,Yao-Yao Fan,Jie Wen,Jing Zhang,Zhi-Qi Zhang
The HIV-Ι trans-activation responsive (TAR) RNA–trans-activator of transcription (Tat) protein complex is crucial for the efficient transcription of the integrated human immunodeficiency virus-I genome and is an established therapeutic target for AIDS diagnosis and treatment. Developing a sensitive strategy for the TAR RNA-binding ligand assay could provide antiviral leads with a radically new mechanism for the treatment of AIDS. Herein, a new TAR RNA-binding ligand assay platform was established using a signal amplification strategy that combines aggregation-induced emission (AIE) with a metal-enhanced fluorescence (MEF) concept. The tetraphenylethylene (TPE) derivative was labeled on the Tat peptide as a fluorescent molecule, while the TAR RNA was immobilized on the surface of the Fe3O4@Au@Ag@SiO2 nanoparticles (NPs) to specifically bind the TPE-Tat peptide. The TPE-Tat peptide was weakly emissive itself while emitting strongly in the NP–TAR–TPE-Tat complex by the AIE and MEF signal amplification effect. It was confirmed by known Tat peptide competitors that this system could be applied to the screening and detection of TAR RNA-binding ligands because they could replace the TPE-Tat peptide from the complex and make the system fluorescence decrease. When this system was adopted to test four candidate ligands, it was found that bisantrene had a favorable TAR RNA-binding ability. The proposed AIE–MEF strategy not only provides a sensitive and reliable method for the TAR RNA-binding ligand assay but also can avoid the influence of ligands on fluorescent detection in the conventional displacement assay.
研究领域:
病毒学
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分子生物学
·
生物医学工程
·
化学生物学
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DOI
PubMed
高影响因子
Proteomics Clinical Applications
·
2022
·Vol. 16
·期 6
·2100099
·
IF 3.603
Ting Li,Hong Qu,Haibo Ding,Haiteng Deng,Yuling Chen
Purpose Antiretroviral therapy (ART) prevents human immunodeficiency virus (HIV)-1 onward transmission and disease progression, leading to excellent prognosis in people living with HIV-1 (PWH). However, side effects, complications, and impaired immune reconstitution persist in some patients treated with ART. We aimed to profile proteome changes in plasma before and after ART to identify the molecular pathways altered by ART. Experimental Design Quantitative proteomics analysis based on tandem mass tag (TMT) labeling was used to profile proteome changes of paired plasma samples from HIV-1 patients before receiving ART and after ART treatment. Results A total of 1398 protein groups (PGs) were identified, in which 18 proteins were downregulated and 50 were upregulated in plasma from ART treated patients. Based on Ingenuity Pathway analysis (IPA), gap junction signaling and actin cytoskeleton signaling were enriched among upregulated proteins, while downregulated proteins were mainly participated in IL-15 signaling pathway. Patients with the low level of CSF1R and the high levels of MINPP1 and TGM3 showed better CD4 + T-cell recovery. Conclusions The present study provided plasma proteome changes after ART to elucidate the underlying mechanistic pathways in response to ART, and also identified potential targets to prompt immune reconstitution.
研究领域:
免疫学
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蛋白质组学
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病毒学
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临床研究
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产品关联
DOI
PubMed
高影响因子
RSC Advances
·
2017
·Vol. 7
·期 34
·20766-20778
·
IF 3.108
Nan Wang,Xin Jin,Xinyuan Zhu
The effective treatments for central nervous system (CNS) diseases are impeded mostly by the existence of the blood–brain barrier (BBB). The accumulation of therapeutic drugs inside the brain is far from the therapy threshold, which is closely related to the transient circulation time of drugs and their carriers. Herein, a core–shell protein-based long-circulation delivery platform was constructed. Through in situ free radical polymerization, a zwitterionic polymer poly(2-methacryloyloxyethyl phosphorylcholine) (PMPC) was modified on the surface to prolong the circulation lifetime with a biomimetic structure induced by a phosphorylcholine (PC) head-group similar to the lipids in the outer membrane of living cells. A cell-penetrating peptide, HIV-1 trans-activating transcriptor (TAT) was conjugated on the surface of the protein-based nanoparticles, endowing the delivery platform with BBB-crossing ability. The BBB-permeability of the nanoparticles was investigated both in vitro and in vivo. Encapsulated with zwitterionic polymer PMPC, the nanoparticles showed a long circulation lifetime due to strong resistance to nonspecific adsorption and provided a better chance for BBB penetration. The delivery platform had enhanced permeability for BBB and a longer retention time inside the brain in a healthy mouse model. Overall, the surface modification with zwitterionic polymer PMPC and cell-penetrating peptide TAT changes the circulation modality of the nanoparticles in vivo, and provides a promising pathway for BBB crossing as a potential drug delivery platform for CNS related disease therapy.
研究领域:
药学
·
纳米技术
·
神经科学
·
药物递送系统
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产品关联
DOI
高影响因子
危险品化学品经营许可证（带存储）