FUNDAMENTAL & CLINICAL PHARMACOLOGY
·
2023
·
IF 2.9
Yanting Li,Zhenwei Xie,Liming Chen,Xiangxing Liu,Shuang Li,Shichun Ye,Hongyan Tang,Chongyou Lee,Qun Gu,Fang Men,Jiaojiao Zhang,Dingyuan Hu,Yuanli Jiang,Xiaochun Wang,Qian Wang,Yufei Feng,Suping Niu,Yan Liu,Yi Fang
Background It was evidenced that cetylpyridinium-chloride (CPC) mouthwash could inhibit SARS-COV-2 activity and reduce salivary viral load, thus reducing SARS-CoV-2 transmission. However, due to insufficient residence time in the oral cavity, CPC-containing mouthwashes have no prolonged antiviral effect. The duration of action of the CPC buccal tablet is expected to be longer than that of the mouthwash. However, there are currently no reports on the salivary drug concentration of CPC buccal tablets. Objective The study aimed to investigate the salivary drug concentration of CPC buccal tablets and the antiviral effect of CPC on SARS-CoV-2 in vitro. Trial design This is a single-dose, single-arm clinical trial, involving 10 Chinese healthy subjects who received 2-mg CPC buccal tablet to collect saliva samples and to detect saliva concentration at different timepoints within 2 h (Clinical Trial Registration Number: NCT05802628, Registration Date: April 6, 2023). Materials and methods CPC concentration in saliva was detected by liquid chromatography tandem mass spectrometry (LC–MS/MS), and pharmacokinetic parameters were calculated based on the non-compartmental model. With an in vitro antiviral experiment, the activity of CPC buccal tablets against SARS-CoV-2 and its cellular toxicity was tested. Results Drug concentrations in saliva at 15 min, 30 min, 1 h, 1.5 h, and 2 h after administration were 8008.33 (1042.25, 41081.11), 2093.34 (373.15, 5759.83), 1016.58 (378.66, 3480.68), 891.77 (375.66, 6322.07), and 717.43 (197.87, 2152.71) ng/mL. PK parameters of saliva concentration: C max = 8008.33 (1042.25, 41081.11) ng/mL, AUC 0-t = 4172.37 (904.42, 13912.61) ng/mL * h, AUC 0-∞ = 6712.85 (1856.77, 19971.12) ng/mL * h, T 1/2 = 1.22 (0.59, 2.83) h, T max = 0.25 (0.25, 0.25) h. As determined in in vitro experiment, CPC was active on SARS-CoV-2 with cytotoxic and inhibitory activity of CC50 = 35.75 μM (≈12155 ng/mL) and EC50 = 7.39 μM (≈2512.6 ng/mL). Conclusions The comparison between the salivary CPC concentration and EC50/CC50 values from in vitro antiviral experiments suggests that CPC buccal tablets may inhibit SARS-CoV-2 activity, and the inhibition may last for approximately 30 min without cytotoxicity.
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MICROCHIMICA ACTA
·
2023
·Vol. 190
·期 10
·1-10
·
IF 5.7
Liang Zhanwei,Lu Xin,Jiao Xueshima,He Yi,Meng Bo,Xie Jie,Qu Ziyu,Zhu Manman,Gong Xiaoyun,Zhao Yang,Peng Tao,Fang Xiang,Dai Xinhua
A highly purified and bioactive immunoglobulin G monoclonal antibody against receptor-binding domain of SARS-CoV-2 (RBD-IgG-MAb) has been accurately quantified by amino acid determination using isotope dilution liquid chromatography–mass spectrometry. Absolute quantification of RBD-IgG-MAb was achieved by averaging 4 amino acid certified reference materials, which allows the quantitative value (66.1 ± 5.8 μg/L) to be traced to SI unit (mol). Afterwards, the RBD-IgG-MAb was employed as control and calibration compound for the development of a point-of-care testing (POCT) system based on colloidal gold lateral flow immunoassay, which aimed to rapidly and accurately detect the level of protective RBD-IgG after vaccination. Under the detection parameters, a sigmoidal curve has been plotted between signal intensity and the logarithmic concentration for quantitative detection with the limit of detection of about 0.39 μg/mL. The relative standard deviations of intra-assay and inter-assay were lower than 2.3% and 14%, and the recoveries ranged from 87 to 100%, respectively. Fingertip blood samples from 37 volunteers after vaccination were analyzed by the POCT system; results showed that levels of RBD-IgG in 33 out of 37 samples ranged from 0.45 to 2.46 μg/mL with the average level of 0.91 μg/mL. The developed POCT system has been successfully established with the quantity-traceability RBD-IgG-MAb as control and calibration compound, and the scientific contribution of this work can be promoted to other areas. Graphical Abstract
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BIOELECTROCHEMISTRY
·
2023
·
IF 5
Zheng-Zhi Yin,Zixuan Liu,Min Zhou,Xu Yang,Guojun Zheng,Hongyu Zhang,Yong Kong
Sensitive detection of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) spike protein (S protein) is of significant clinical importance in the diagnosis of COVID-19 pandemic. In this work, a surface molecularly imprinted (SMI) electrochemical biosensor is fabricated for the detection of SARS-CoV-2 S protein. Cu 7 S 4 -Au is used as the built-in probe and modified on the surface of a screen-printed carbon electrode (SPCE). 4-Mercaptophenylboric acid (4-MPBA) is anchored to the surface of the Cu 7 S 4 -Au through Au–SH bonds, which can be used for the immobilization of the SARS-CoV-2 S protein template through boronate ester bonds. After that, 3-aminophenylboronic acid (3-APBA) is electropolymerized on the electrode surface and used as the molecularly imprinted polymers (MIPs). The SMI electrochemical biosensor is obtained after the elution of the SARS-CoV-2 S protein template with an acidic solution by the dissociation of the boronate ester bonds, which can be utilized for sensitive detection of the SARS-CoV-2 S protein. The developed SMI electrochemical biosensor displays high specificity, reproducibility and stability, which might be a potential and promising candidate for the clinical diagnosis of COVID-19.
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JOURNAL OF ETHNOPHARMACOLOGY
·
2024
·
IF 4.8
Yun-Lu Xu,Xue-Jian Li,Wei Cai,Wen-Ying Yu,Jing Chen,Qin Lee,Yong-Jun Choi,Fang Wu,Ying-Jun Lou,Hua-Zhong Ying,Chen-Huan Yu,Qiao-Feng Wu
Ethnopharmacological relevance Viral pneumonia is the leading cause of death after SARS-CoV-2 infection. Despite effective at early stage, long-term treatment with glucocorticoids can lead to a variety of adverse effects and limited benefits. The Chinese traditional herb Pogostemonis Herba is the aerial part of Pogostemon Cablin (Blanco) Benth., which has potent antiviral, antibacterial, anti-inflammatory, and anticancer effects. It was used widely for treating various throat and respiratory diseases, including COVID-19, viral infection, cough, allergic asthma, acute lung injury and lung cancer. Aim of the study To investigate the antiviral and anti-inflammatory effects of chemical compounds from Pogostemonis Herba in SARS-CoV-2-infected hACE2-overexpressing mouse macrophage RAW264.7 cells and hACE2 transgenic mice. Materials and methods The hACE2-overexpressing RAW264.7 cells were exposed with SARS-CoV-2. The cell viability was detected by CCK8 assay and cell apoptotic rate was by flow cytometric assay. The expressions of macrophage M1 phenotype markers (TNF-α and IL-6) and M2 markers (IL-10 and Arg-1) as well as the viral loads were detected by qPCR. The mice were inoculated intranasally with SARS-CoV-2 omicron variant to induce viral pneumonia. The levels of macrophages, neutrophils, and T cells in the lung tissues of infected mice were analyzed by full spectrum flow cytometry. The expressions of key proteins were detected by western blot assay. Results Diosmetin-7-O-β-D-glucopyranoside (DG) presented the strongest anti-SARS-CoV-2 activity. Intervention with DG at the concentrations of 1.25-50 μM not only reduced the viral replication, cell apoptosis, and the productions of inflammatory cytokines (IL-6 and TNF-α) in SARS-CoV-2-infected RAW264.7 cells, but also reversed macrophage polarity from M1 to M2 phenotype. Furthermore, treatment with DG (25-100 mg/kg) alleviated acute lung injury, and reduced macrophage infiltration in SARS-COV-2-infected mice. Mechanistically, DG inhibited SARS-COV-2 gene expression and HK3 translation via targeting YTHDF1, resulting in the inactivation of glycolysis-mediated NF-κB pathway. Conclusions DG exerted the potent antiviral and anti-inflammatory activities. It reduced pneumonia in SARS-COV-2-infected mice via inhibiting the viral replication and accelerating M2 macrophage polarization via targeting YTHDF1, indicating its potential for COVID-19 treatment.
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Algal Research-Biomass Biofuels and Bioproducts
·
2025
·
IF 4.5
Qiao-Hui Zeng,Zhi-En Yao,Xian-Min Zhou,Ping Qi,Xin-An Zeng
Inhibition of the biological activity of SARS-CoV-2 main protease (Mpro) effectively prevents viral replication, thereby presenting a promising therapeutic target for Corona Virus Disease 2019 (COVID-19) intervention. This study aims to screen the Mpro inhibitory peptides from the natural nutritional supplement Spirulina platensis ( S. platensis ). Firstly, Mpro was successfully prepared by heterologous expression in E. coli and Mpro's activity was detected. Meanwhile, four distinct peptides derived from S. platensis were obtained through enzymatic hydrolysis of protein. Subsequently, highly active peptides were synthesized and their inhibition effects on Mpro were verified by in vitro experiment and computer simulations. Results showed that the extraction rate of the protein from S. platensis was 96.11 %, the activity of Mpro was 845.90 U mg −1 , the peptide MQGPNY could inhibit the activity of Mpro at the inhibition rate of 20.21 % ± 3.8 % at the concentration of 2 mmol L −1 . Furthermore, results from computer Simulation showed that the peptide MQGPNY forms four pairs of hydrogen bonds with Mpro, which are Gln189, Ser46, Thr26 and Glu166. In addition, there were ten free residues involved in hydrophobic contacts, including His164, His41, Thr24, Met49, Thr45, Thr25, Gly143, Asn142, Cys145 and Met165. The foundings could provide theoretical support for the use of protein and its hydrolysates from S. platensis in functional food and supplement formulations in the post-epidemic era.
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Journal of Materials Chemistry B
·
2022
·Vol. 10
·期 32
·6107-6117
·
IF 7.571
Siying Xie,Cheng Qin,Furong Zhao,Zhaoyang Shang,Pei Wang,Muhammad Sohail,Xing Zhang,Bingzhi Li
CRISPR-driven biosensing is developing rapidly, but current studies mostly adopt dye-labeled ssDNA as the signal reporter, which is costly and unstable. Herein, we developed a label-free and low-background reporter for CRISPR/Cas12a signaling by integrating DNA-templated copper nanoclusters (DNA–CuNCs) and exonuclease I (EXO I). The template of the DNA–CuNCs was rationally designed as a ds-/ss-DNA hybrid, ensuring that after a quick and nonpersistent cut of Cas12a, a majority of the template can be digested by EXO I. Based on this novel reporter, a biosensor termed CRISPR-CNS (cost-effective, nimble, and sensitive copper nanocluster sensor integrating CRISPR) was developed. Due to the high signal-to-background ratio of our proposed reporter, CRISPR-CNS shows excellent performances for nucleic acid detection, yielding a detection limit of 20 copies for SARS-CoV-2 RNA. Considering its facile synthesis, robust fluorescence, effective cost, and good sensitivity, this combination shall serve as a highly potential output for CRISPR-based point-of-care testing.
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MOLECULES
·
2023
·Vol. 28
·期 15
·5634
·
IF 4.6
Chen Sun,Bo Liu,Fengzhi Zhou,Qianqian Zheng,Chunmei Dai,Wei Wei,Guochao Liao,Yuqi Sun
SARS-CoV-2 is a highly contagious and pathogenic virus that first appeared in late December 2019 and caused a global pandemic in a short period. The virus is a single-stranded RNA virus belonging to the Coronaviridae family. Numerous treatments have been developed and tested in response to the pandemic, particularly antiviral drugs. Among them, GS441524 (GS441), a nucleoside antiviral drug, has demonstrated promising results in inhibiting SARS-CoV-2. Nevertheless, the limited oral bioavailability of GS441 restricts its application to patients with the virus. In this study, a novel prodrug of GS441 (NGP-1) with an isobutyl ester and cyclic carbonate structure was designed and synthesized. Its purity and the stability in different artificial digestive juices of NGP-1 was determined with HPLC-DAD methods. The pharmacokinetics of NGP-1 and GS441 were studied in rats via gavage administration. A new LC-MS/MS method was developed to quantitatively analyze GS441 in plasma samples. The results showed that the ka, Cmax, and MRT of converted GS441 from NGP-1 were 5.9, 3, and 2.5 times greater than those of GS441 alone. The Frelof NGP-1 was approximately four-fold that of GS441, with an AUC0–∞of 9716.3 h·ng mL−1. As a prodrug of GS441, NGP-1 increased its lipophilicity, absorption, and bioavailability, indicating that it holds promise in improving the clinical efficacy of anti-SARS-CoV-2 medications.Keywords:anti-SARS-CoV-2;prodrug of GS441524;purity;stability and pharmacokinetics;oral bioavailability;LC-MS/MS
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Biomolecules
·
2024
·Vol. 14
·期 12
·1568
·
IF 4.8
Rui Wang,Junping Xue,Guo Wei,Yimeng Zhang,Chuanliang Wang,Jinhua Li,Xuhui Geng,Abbas Ostovan,Lingxin Chen,Zhihua Song
The development of a novel strategy for the measurement of SARS-CoV-2 IgG antibodies is of vital significance forCOVID-19diagnosis and effect of vaccination evaluation. In this investigation, an SiO2@Au@CDs nanoparticle (NP)-based lateral flow immunoassay (LFIA) strip was fabricated and coupled with a miniaturized fluorimeter. The morphology features and particle sizes of the SiO2@Au@CDs NPs were characterized carefully, and the results indicated that the materials possess monodisperse, uniform, and spherical structures. Finally, this system was employed for SARS-CoV-2 IgG antibody test. In this work, the strategy for the SARS-CoV-2 IgG antibody test possesses several merits, such as speed (less than 15 min), high sensitivity (1.2 × 10−7mg/mL), broad linearity range (7.4 × 10−7~7.4 × 10−4mg/mL), accurate results, high selectivity, good stability, and low cost. Additionally, future trends in LFAs using quantum dot-based diagnostics are envisioned.
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EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
·
2025
·
IF 5.9
Yan-Yun Liu,Zheng-Ao Li,Yu-Zheng Zhou,Sen-Lin Wang,Zong-Peng Chen,Si-Xu Liu,Peng Zhan,Ying-Jun Zhou,Zan-Xian Xia,Xu Deng
The global COVID-19 pandemic caused by SARS-CoV-2 has underscored the urgent need for the development of new broad-spectrum antivirals to combat its high mutation rate and the emerging variants. Host ER α-glucosidases I/II are promising host-targeted therapeutic targets for the development of broad-spectrum antivirals against viral strains that depend on ERQC for infectivity. Herein, we designed and synthesized a series of TCM theory-inspired DNJ-flavonoid conjugates as novel α-glucosidase inhibitors, which were screened against their in vitro antiviral activities in non-replicative SARS-CoV-2 pseudovirus (PsV) assay. Remarkably, DNJ-20 not only demonstrated remarkable inhibition activity against α-glucosidase and viral entry process, but also exerted potent and broad-spectrum anti-coronaviral activity against SARS-CoV-2 pseudovirus (PsV), several SARS-CoV-2 variants, as well as HCoV-229E and HCoV-OC43, with EC 50 values up to 1.49 μM, which is more potent than the benchmark α-glucosidase inhibitor UV-4 ( DNJ-3 ). Besides, it had no observable cytotoxicity in HeLa-ACE2, HEK-293T and Beas-2B cells. Therefore, TCM theory-inspired DNJ-flavonoid conjugates can be served as promising drug leads for pan-coronavirus therapeutic development to combat current and future coronavirus pandemics.
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MOLECULAR PHARMACEUTICS
·
2025
·
IF 4.5
Hongyu Zhu,Sen Yang,Jingyang Zhao,Liuyang Wang,Chenghao Gao,Yanan Sheng,Xuan Lin,Zhiguo Su,Kiichi Sato,Zhongyu Hu,Songping Zhang
All-trans retinoic acid (Ra) has been demonstrated to enhance the establishment of systemic and intestinal immunity for codelivered antigens; however, the extremely poor water solubility of Ra significantly limits its application in vaccines. Herein, leveraging the advantages of ionic liquids in modifying the physicochemical properties of small-molecule drugs, we synthesized a novel ionic liquid composed of choline and retinoic acid ([Cho][Ra]). Compared to Ra, [Cho][Ra] exhibited an 18165-fold increase in solubility at pH 7.4 and an acid-responsive Ra release behavior. The [Cho][Ra] was then formulated with the SARS-CoV-2 RBD antigen, and its adjuvant effects were comprehensively evaluated. The in vitro cellular studies indicated that at 50 μg Ra equivalent dose, the [Cho][Ra]@RBD showed significantly higher than RBD along in activation of BMDC and the expression of gut homing molecules, including C–C motif chemokine receptor 9 (CCR9, 10.55 folds), α4β7 integrin (13.29 folds), and lymph node migration molecule CCR7 (82.68 folds). Animal experiments showed that compared to RBD alone, [Cho][Ra]@RBD promoted the establishment of mucosal immunity in the intestines in mice at the early stage following subcutaneous immunization and elicited higher serum antibody levels. Furthermore, compared to RBD and Alum@RBD, [Cho][Ra]@RBD enhanced the formation of CD4+ TCM and CD8+ TCM cells, indicating stronger cellular immune responses. In summary, [Cho][Ra] showed potential adjuvant effects in enhancing the humoral and cellular immune responses, as well as in the establishment of intestinal mucosal immunity for RBD antigen without the need for delivery system, thereby offering promising prospects for applying Ra in vaccines.
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ACS Nano
·
2025
·
IF 16
Chendong Yang,Entao Li,Xiaoping Guo,Wenyu Xie,Yuanzhan Wang,Xuefei Huang,Sandra Chiu,Xuanjun Wu
Over the past 3 years, SARS-CoV-2 Omicron has been circulating globally with the emergence of multiple subvariants, including BA.5, BA.5.2, XBB, XBB.1, EG.5.1, HK.3, BA.2.86, JN.1, and KP.2. To combat these Omicron subvariants, several vaccines based on receptor-binding domain (RBD) dimers have been developed; however, RBD dimer vaccines require frequent updates to cope with the emergence of new variants. In contrast, the development of a safe, effective, and broad-spectrum vaccine against multiple Omicron subvariants, including the latest JN.1 and KP.2, would be a one-size-fits-all solution. Here, we designed BA.4/5 RBD-PC7A conjugate micelles by displaying the BA.4/5 RBD in PC7A micelles. Remarkably, the micelles elicited potent neutralizing antibodies (NAbs) in rabbits, effectively neutralizing BA.5.2, XBB.1.18, and HK.3 infections. Moreover, the micelles alone were able to induce NAbs in mice against the BA.5 variant. When a cytosine-phosphate-guanine (CpG) adjuvant was added and electrostatically adsorbed to the micelles, there was a significant increase in the antibody titers of IgG1, IgG2b, and IgG2c. This enhancement facilitated the broad neutralization of various strains, including BA.5.2, XBB.1.18, HK.3, JN.1, and KP.2. Furthermore, the micelles adsorbed with CpG protected golden hamsters from infection with the BA.5.2 strain. This study presents a potent and broadly neutralizing nanovaccine that includes the BA.4/5 RBD antigen and a CpG adjuvant. It demonstrates efficacy against multiple Omicron subvariants, including BA.5, BA.5.2, XBB.1.18, HK.3, JN.1, and KP.2, highlighting its potential for clinical translation.
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INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2025
·
IF 8.5
Lei huang,Siyuan Tang,Jiachen Guo,Yixing Tu,Sian Li,Xianchao Dai,Taihua Yang,Dong Zhao,Chao Wang
The development of tumor-retained and minimally invasive mRNA and photothermal therapies for superficial malignant tumors, such as breast cancer, remains a significant challenge. In this study, we present a novel tumor-retained lipid nanoparticle-microneedle (LNP-MN) patch for localized co-delivery of mRNA and the photothermal agent indocyanine green (ICG). By optimizing LNP formulations, ICG loading methodology, mRNA-to-ICG ratio, and MN matrix composition, we achieved a balanced platform ensuring high mRNA transfection efficiency and robust ICG photothermal performance. This LNP-MN platform enabled efficient intratumoral deposition, demonstrating a 15.6-fold increase in tumor accumulation compared to intravenous administration. For the first time, SARS-CoV-2 spike mRNA was combined with ICG-mediated photothermal therapy (PTT) within a single system for superficial tumor treatment. In a 4 T1 breast cancer model, this combinatorial strategy achieved significant tumor growth inhibition (75.1 %), enhanced CD8+ T-cell infiltration, and minimized systemic toxicity, outperforming monotherapies. This study pioneers the integration of PTT and mRNA-based tumor-labeling immunotherapy in a minimally invasive MN platform, offering a promising strategy for enhanced superficial cancer therapy.
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