Publications by authors named "Yuhuan Li"

134 Publications

A Framework of Paracellular Transport via Nanoparticles-Induced Endothelial Leakiness.

Adv Sci (Weinh) 2021 Sep 8:e2102519. Epub 2021 Sep 8.

Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC, 3052, Australia.

Nanomaterial-induced endothelial leakiness (NanoEL) is an interfacial phenomenon denoting the paracellular transport of nanoparticles that is pertinent to nanotoxicology, nanomedicine and biomedical engineering. While the NanoEL phenomenon is complementary to the enhanced permeability and retention effect in terms of their common applicability to delineating the permeability and behavior of nanoparticles in tumoral environments, these two effects significantly differ in scope, origin, and manifestation. In the current study, the descriptors are fully examined of the NanoEL phenomenon elicited by generic citrate-coated gold nanoparticles (AuNPs) of changing size and concentration, from microscopic gap formation and actin reorganization down to molecular signaling pathways and nanoscale interactions of AuNPs with VE-cadherin and its intra/extracellular cofactors. Employing synergistic in silico methodologies, for the first time the molecular and statistical mechanics of cadherin pair disruption, especially in response to AuNPs of the smallest size and highest concentration are revealed. This study marks a major advancement toward establishing a comprehensive NanoEL framework for complementing the understanding of the transcytotic pathway and for guiding the design and application of future nanomedicines harnessing the myriad functions of the mammalian vasculature.
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http://dx.doi.org/10.1002/advs.202102519DOI Listing
September 2021

Validation of the Chinese Version of KIDSCREEN-10 Quality of Life Questionnaire: A Rasch Model Estimation.

Front Psychol 2021 16;12:647692. Epub 2021 Aug 16.

School of Government, Central University of Finance and Economics, Beijing, China.

The KIDSCREEN-10 was deemed as a cross-national instrument for measuring Health-Related Quality of Life (HRQoL). However, no empirical endeavor has explored its reliability and validity in the context of China. This study aims to translate and validate the Chinese version of the KIDSCREEN-10 questionnaire. The KIDSCREEN-10 was translated into Chinese (Mandarin) using a blindly bilingual forward-backward-forward technique. A cross-sectional survey, including 1,830 students aged from 8 to 18 years, was conducted in a county located in Gansu province, China. Psychometric properties were evaluated using the Rasch partial credit model, ANOVA, and the correlation analysis. Results indicated that the KIDSCREEN-10 performed good internal consistency, known-group validity, and concurrent validity, but there were still some deficiencies in psychometrics: first, disordered response categories were found between category 2 (seldom) and category 3 (sometimes); second, item 3 ("Have you felt sad?"), item 4 ("Have you felt lonely?"), and item 5 ("Have enough time for self?") demonstrated misfit to the Rasch model; third, items 3 and 4 exhibited differential item functioning. After collapsing the disordered response categories and removing the three misfit items, the seven-item questionnaire performed good psychometric properties. However, the seven-item version does not cover the psychological well-being dimension of HRQoL, and that may lead to inappropriate measures of HRQoL. Therefore, this paper suggested to use classical test theory to investigate the psychological properties of the KIDSCREEN-10.
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http://dx.doi.org/10.3389/fpsyg.2021.647692DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8415151PMC
August 2021

Associations between endocrine-disrupting heavy metals in maternal hair and gestational diabetes mellitus: A nested case-control study in China.

Environ Int 2021 Jul 24;157:106770. Epub 2021 Jul 24.

Institute of Reproductive and Child Health, Peking University/ Key Laboratory of Reproductive Health, National Health Commission of the People's Republic of China, Beijing 100191, PR China; Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing 100191, PR China.

Background: Exposure to environmental endocrine disruptors (EDCs) may lead to abnormal glucose metabolism and, potentially, gestational diabetes mellitus (GDM).

Objective: We investigated the association between five endocrine-disrupting heavy metals (EDHMs), i.e., arsenic (As), cadmium (Cd), lead (Pb), mercury (Hg), and tin (Sn), in maternal hair and the risk of GDM.

Methods: We conducted a nested case-control study including 335 GDM cases and 343 controls without GDM based on a prospective birth cohort established in Beijing, China. Concentrations of EDHMs were analyzed in maternal hair. Log-binomial regression and multiple linear regression were used to estimate the associations between the hair concentrations of single metals and the risk of GDM, while weighted quantile sum (WQS) regression for their mixed effects.

Results: The median concentrations of Hg (0.442 vs. 0.403 μg/g) and Sn (0.171 vs. 0.140 μg/g) in the case group were significantly higher than those in the control group. No differences were found between the two groups for the other three metals. After adjusting for confounders, the prevalence ratio (PR; highest vs. lowest tertile) of GDM risk for Hg was 1.27 (95% confidence interval [CI]: 1.05-1.54), while that for Sn was 1.26 (95% CI: 1.04-1.53). Among women with a body mass index < 24 kg/m, the PR (highest vs. lowest tertile) of GDM for Sn was 1.38 (95% CI: 1.09-1.75). The effect of exposure to the five EDHMs on the risk of GDM was estimated by WQS regression: Sn and Hg made the largest contributions to the WQS index (40.9% and 40.3%, respectively).

Conclusion: High maternal levels of EDHMs, particularly Sn and Hg, may promote the development of GDM.
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http://dx.doi.org/10.1016/j.envint.2021.106770DOI Listing
July 2021

Cyberbullying Involvement, Resilient Coping, and Loneliness of Adolescents During Covid-19 in Rural China.

Front Psychol 2021 16;12:664612. Epub 2021 Jun 16.

School of Government, Central University of Finance and Economics, Beijing, China.

Cyberbullying involvement can lead to internal health issues, especially mental health problems. Different coping strategies may reduce or enhance the strengths between cyberbullying experience and mental health problems. In this study, we examined the correlations between cyberbullying involvement and loneliness among a group of children and adolescents during the Covid-19 pandemic in China, focusing on investigating the protecting effect of the resilient coping strategy. The results demonstrated that 86.68% of the students were not involved in cyberbullying activities, 8.19% were victims only, 1.89% was perpetrators only, and 3.24% were both victims and perpetrators. Compared with the non-involved, the victims-only group had a significantly higher degree of reported loneliness and a lower score of resilient coping, while the differences of the other groups were not significant. Resilient coping strategy can significantly reduce loneliness and play a mediating role between cyberbullying victimization and loneliness, but such mitigating effect was relatively weak. Besides, peer relations were the primary protective factors, and age was the primary risk factor of loneliness among the controlled variables. This study can enrich current knowledge of cyberbullying involvement and the psychological health among children and adolescents, especially in the context of the pandemic.
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http://dx.doi.org/10.3389/fpsyg.2021.664612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8242172PMC
June 2021

Tailoring Unsymmetrical-Coordinated Atomic Site in Oxide-Supported Pt Catalysts for Enhanced Surface Activity and Stability.

Small 2021 07 21;17(30):e2101008. Epub 2021 Jun 21.

Hefei National Laboratory for Physical Sciences at the Microscale, Collaborative Innovation Center of Chemistry for Energy Materials (iChEM), School of Chemistry and Materials Science, and National Synchrotron Radiation Laboratory, University of Science and Technology of China, Hefei, 230026, China.

The catalytic properties of supported metal heterostructures critically depend on the design of metal sites. Although it is well-known that the supports can influence the catalytic activities of metals, precisely regulating the metal-support interactions to achieve highly active and durable catalysts still remain challenging. Here, the authors develop a support effect in the oxide-supported metal monomers (involving Pt, Cu, and Ni) catalysts by means of engineering nitrogen-assisted nanopocket sites. It is found that the nitrogen-permeating process can induce the reconstitution of vacancy interface, resulting in an unsymmetrical atomic arrangement around the vacancy center. The resultant vacancy framework is more beneficial to stabilize Pt monomers and prevent diffusion, which can be further verified by the density functional theory calculations. The final Pt-N/SnO catalysts exhibit superior activity and stability for HCHO response (26.5 to 15 ppm). This higher activity allows the reaction to proceed at a lower operating temperature (100 °C). Incorporated with wireless intelligent-sensing system, the Pt-N/SnO catalysts can further achieve continuous monitoring of HCHO levels and cloud-based terminal data storage.
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http://dx.doi.org/10.1002/smll.202101008DOI Listing
July 2021

Ultrasmall Molybdenum Disulfide Quantum Dots Cage Alzheimer's Amyloid Beta to Restore Membrane Fluidity.

ACS Appl Mater Interfaces 2021 Jun 18;13(25):29936-29948. Epub 2021 Jun 18.

Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.

Alzheimer's disease (AD) is a major cause of dementia characterized by the overexpression of transmembrane amyloid precursor protein and its neurotoxic byproduct amyloid beta (Aβ). A small peptide of considerable hydrophobicity, Aβ is aggregation prone catalyzed by the presence of cell membranes, among other environmental factors. Accordingly, current AD mitigation strategies often aim at breaking down the Aβ-membrane communication, yet no data is available concerning the cohesive interplay of the three key entities of the cell membrane, Aβ, and its inhibitor. Using a lipophilic Laurdan dye and confocal fluorescence microscopy, we observed cell membrane perturbation and actin reorganization induced by Aβ oligomers but not by Aβ monomers or amyloid fibrils. We further revealed recovery of membrane fluidity by ultrasmall MoS quantum dots, also shown in this study as a potent inhibitor of Aβ amyloid aggregation. Using discrete molecular dynamics simulations, we uncovered the binding of MoS and Aβ monomers as mediated by hydrophilic interactions between the quantum dots and the peptide N-terminus. In contrast, Aβ oligomers and fibrils were surface-coated by the ultrasmall quantum dots in distinct testudo-like, reverse protein-corona formations to prevent their further association with the cell membrane and adverse effects downstream. This study offers a crucial new insight and a viable strategy for regulating the amyloid aggregation and membrane-axis of AD pathology with multifunctional nanomedicine.
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http://dx.doi.org/10.1021/acsami.1c06478DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8251662PMC
June 2021

A Fully Automated and Integrated Microfluidic System for Efficient CTC Detection and Its Application in Hepatocellular Carcinoma Screening and Prognosis.

ACS Appl Mater Interfaces 2021 Jun 18;13(25):30174-30186. Epub 2021 Jun 18.

Department of General Surgery, Department of Pathology, Department of Ultrasound, Xiang'an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361101, China.

Analysis of circulating tumor cells (CTCs) is regarded as a useful diagnostic index to monitor tumor development and guide precision medicine. Although the immunoassay is a common strategy for CTC identification and heterogeneity characterization, it is challenged by poor reaction efficiency and laborious manipulations in microdevices, which hinder the sensitivity, throughput, simplification, and applicability. To meet the need for rapid, sensitive, and simple CTC analysis, we developed an efficient CTC detection system by integrating a 3D printed off-chip multisource reagent platform, a bubble retainer, and a single CTC capture microchip, which can achieve CTC capture and identification within 90 min. Compared with traditional CTC identification methods, this system decreases immunostaining time and antibody consumption by 90% and performs the on-chip immunoassay in a fully automated manner. Using this system, CTCs from the peripheral blood of 19 patients with various cancers were captured, detected, and compared with clinical data. The system shows great potential for early screening, real-time monitoring, and precision medicine for hepatocellular carcinoma (HCC). With the advantages of automation, stability, economy, and user-friendly operation, the proposed system is promising for clinical scenarios.
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http://dx.doi.org/10.1021/acsami.1c06337DOI Listing
June 2021

Optimization and SAR research at the piperazine and phenyl rings of JNJ4796 as new anti-influenza A virus agents, part 1.

Eur J Med Chem 2021 Oct 5;222:113591. Epub 2021 Jun 5.

CAMS Key Laboratory of Antiviral Drug Research, Beijing Key Laboratory of Antimicrobial Agents, NHC Key Laboratory of Biotechnology of Antibiotics, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100050, China. Electronic address:

JNJ4796, a small molecule fuse inhibitor targeting the conserved stem region of hemagglutinin, effectively neutralized a broad spectrum of group 1 influenza A virus (IAV), and protected mice against lethal and sublethal influenza challenge after oral administration. In this study, we reported the modification and structure-activity relationship (SAR) of C (piperazine ring) and E (phenyl ring) rings of JNJ4796. Compound (R)-2c was identified to show excellent in vitro activity against IAV H1N1 and Oseltamivir-resistant IAV H1N1 stains (IC: 0.03-0.06 μM), low cytotoxicity (CC > 200 μM), accepted oral PK profiles and low inhibition rate of hERG (13.2%, at 10 μM). Evaluation for the in vivo anti-IAV efficacy of (R)-2c will begin soon.
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http://dx.doi.org/10.1016/j.ejmech.2021.113591DOI Listing
October 2021

Research on estimation models of the spectral characteristics of soil organic matter based on the soil particle size.

Spectrochim Acta A Mol Biomol Spectrosc 2021 Nov 18;260:119963. Epub 2021 May 18.

College of Resources and Environment, Shandong Agricultural University, Taian 271018, China; National Engineering Laboratory for Efficient Utilization of Soil and Fertilizer Resources, Shandong Agricultural University, Taian 271018, China.

Soil organic matter (SOM) is an important part of soil fertility and the main nutrient source for crop growth. The establishment of an effective SOM content estimation model can provide technical support for the improvement of saline soil and the implementation of precision agriculture. In this paper, a laboratory spectrometer was used to measure the spectral reflectance of saline soils with particle sizes of 1 mm, 0.50 mm, 0.25 mm and 0.15 mm collected from Kenli County. After spectral preprocessing and spectral transformation, the characteristic bands of the SOM spectrum were extracted by the successive projections algorithm (SPA). Finally, stepwise multiple linear regression (SMLR), principal component regression (PCR) and partial least squares regression (PLSR) were used to establish SOM content estimation models based on soil particle size. The results showed the following. (i) Soil particle size had a significant impact on soil spectral reflectance. The smaller the soil particle size was, the greater the soil spectral reflectance. (ii) The sensitive bands for SOM were mainly concentrated in the visible light region (400-760 nm). First derivative (FD) transformation can effectively improve the characteristic spectral information obtained from SOM. (iii) Among the three models established with the characteristic bands, the estimation ability of the PLSR model was better than that of the PCR and SMLR models. (iv) The FD of the original spectral reflectance of the 0.25 mm particles combined with the PLSR model gave the best estimation of the SOM content. When the soil particle size was less than 0.25 mm, the estimation results of the model were not improved. These results provide a basis for effective estimation of the SOM content and improvement of saline-alkali soil in Kenli County in the Yellow River Delta.
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http://dx.doi.org/10.1016/j.saa.2021.119963DOI Listing
November 2021

Spontaneous Formation of β-sheet Nano-barrels during the Early Aggregation of Alzheimer's Amyloid Beta.

Nano Today 2021 Jun 13;38. Epub 2021 Mar 13.

Department of Physics and Astronomy, Clemson University, Clemson, SC 29634, United States.

Soluble low-molecular-weight oligomers formed during the early aggregation of amyloid peptides have been hypothesized as a major toxic species of amyloidogenesis. Herein, we performed the first synergic , and validations of the structure, dynamics and toxicity of Aβ42 oligomers. Aβ peptides readily assembled into β-rich oligomers comprised of extended β-hairpins and β-strands. Nanosized β-barrels were observed with certainty with simulations, transmission electron microscopy and Fourier transform infrared spectroscopy, corroborated by immunohistochemistry, cell viability, apoptosis, inflammation, autophagy and animal behavior assays. Secondary and tertiary structural proprieties of these oligomers, such as the sequence regions with high β-sheet propensities and inter-residue contact frequency patterns, were similar to the properties known for Aβ fibrils. The unambiguous spontaneous formation of β-barrels in the early aggregation of Aβ42 supports their roles as the common toxic intermediates in Alzheimer's pathobiology and a target for Alzheimer's therapeutics.
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http://dx.doi.org/10.1016/j.nantod.2021.101125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8081394PMC
June 2021

Identification of hepatitis B virus core protein residues critical for capsid assembly, pgRNA encapsidation and resistance to capsid assembly modulators.

Antiviral Res 2021 07 30;191:105080. Epub 2021 Apr 30.

Baruch S. Blumberg Institute, Doylestown, Pennsylvanian, USA. Electronic address:

Assembly of hepatitis B virus (HBV) capsids is driven by the hydrophobic interaction of core protein (Cp) at dimer-dimer interface. Binding of core protein allosteric modulators (CpAMs) to a hydrophobic "HAP" pocket formed between the inter-dimer interface strengths the dimer-dimer interaction and misdirects the assembly of Cp dimers into non-capsid Cp polymers or morphologically normal capsids devoid of viral pregenomic (pg) RNA and DNA polymerase. In this study, we performed a systematic mutagenesis analysis to identify Cp amino acid residues at Cp dimer-dimer interface that are critical for capsid assembly, pgRNA encapsidation and resistance to CpAMs. By analyzing 70 mutant Cp with a single amino acid substitution of 25 amino acid residues around the HAP pocket, our study revealed that residue W102 and Y132 are critical for capsid assembly. However, substitution of many other residues did not significantly alter the amount of capsids, but reduced the amount of encapsidated pgRNA, suggesting their critical roles in pgRNA packaging. Interestingly, several mutant Cp with a single amino acid substitution of residue P25, T33 or I105 supported high levels of DNA replication, but conferred strong resistance to multiple chemotypes of CpAMs. In addition, we also found that WT Cp, but not the assembly incompetent Cp, such as Y132A Cp, interacted with HBV DNA polymerase (Pol). This later finding implies that encapsidation of viral DNA polymerase may depend on the interaction of Pol with a capsid assembly intermediate, but not free Cp dimers. Taking together, our findings reported herein shed new light on the mechanism of HBV nucleocapsid assembly and mode of CpAM action.
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http://dx.doi.org/10.1016/j.antiviral.2021.105080DOI Listing
July 2021

Hepatitis B virus nucleocapsid uncoating: biological consequences and regulation by cellular nucleases.

Emerg Microbes Infect 2021 Dec;10(1):852-864

Department of Experimental Medicine, Baruch S. Blumberg Institute, Doylestown, PA, USA.

Upon infection of hepatocyte, Hepatitis B virus (HBV) genomic DNA in nucleocapsid is transported into the nucleus and converted into a covalently closed circular (ccc) DNA to serve as the template for transcription of viral RNAs. Viral DNA in the cytoplasmic progeny nucleocapsid is another resource to fuel cccDNA amplification. Apparently, nucleocapsid disassembly, or viral genomic DNA uncoating, is an essential step for cccDNA synthesis from both infection and intracellular amplification pathways, and has a potential to activate DNA sensors and induce an innate immune response in infected hepatocytes. However, where and how the nucleocapsid disassembly occurs is not well understood. The work reported herein showed that the enhanced disassembly of progeny mature nucleocapsids in the cytoplasm supported cccDNA intracellular amplification, but failed to activate the cGAS-STING-mediated innate immune response in hepatocytes. Interestingly, while expression of a cytoplasmic exonuclease TREX1 in human hepatoma cells supporting HBV replication significantly reduced the amounts of cccDNA as well as its precursor, deproteinized relaxed circular (rc) DNA, expression of TREX1 in sodium taurocholate cotransporting polypeptide-expressing human hepatoma cells did not inhibit cccDNA synthesis from HBV infection. The results from this cytoplasmic nuclease protection assay imply that the disassembly of progeny mature nucleocapsids and removal of viral DNA polymerase covalently linked to the 5' end of minus strand of rcDNA take place in the cytoplasm. On the contrary, the disassembly of virion-derived nucleocapsids during infection may occur at a different subcellular compartment and possibly distinct mechanisms.
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http://dx.doi.org/10.1080/22221751.2021.1919034DOI Listing
December 2021

Self-Assembled pH-Sensitive Polymeric Nanoparticles for the Inflammation-Targeted Delivery of Cu/Zn-Superoxide Dismutase.

ACS Appl Mater Interfaces 2021 Apr 25;13(15):18152-18164. Epub 2021 Mar 25.

School of Life Sciences, Jilin University, No.2699, Qianjin Street, Changchun, Jilin 130012, China.

The use of superoxide dismutase (SOD) is currently limited by its short half-life, rapid plasma clearance rate, and instability. We synthesized a small library of biofriendly amphiphilic polymers that comprise methoxy poly(ethylene glycol)-poly(cyclohexane-1,4-diyl acetone dimethyleneketal) (mPEG-PCADK) and mPEG-poly((cyclohexane, 1,5-pentanediol)-1,4-diyl acetone dimethylene ketal) (PK3) for the targeted delivery of SOD. The novel polymers could self-assemble into micellar nanoparticles with favorable hydrolysis kinetics, biocompatibility, long circulation time, and inflammation-targeting effects. These materials generated a better pH-response curve and exhibited better hydrolytic kinetic behavior than PCADK and PK3. The polymers showed good biocompatibility with protein drugs and did not induce an acidic microenvironment during degradation in contrast to materials such as PEG--poly(lactic--glycolic acid) (PLGA) and PLGA. The SOD that contained reverse micelles based on mPEG2000-PCADK exhibited good circulation and inflammation-targeting properties. Pharmacodynamic results indicated exceptional antioxidant and anti-inflammatory activities in a rat adjuvant-induced arthritis model and a rat peritonitis model. These results suggest that these copolymers are ideal protein carriers for targeting inflammation treatment.
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http://dx.doi.org/10.1021/acsami.1c03589DOI Listing
April 2021

The membrane axis of Alzheimer's nanomedicine.

Adv Nanobiomed Res 2021 Jan 26;1(1). Epub 2020 Nov 26.

Zhongshan Hospital, Fudan University, 111 Yixueyuan Rd, Xuhui District, Shanghai, 200032, China.

Alzheimer's disease (AD) is a major neurological disorder impairing its carrier's cognitive function, memory and lifespan. While the development of AD nanomedicine is still nascent, the field is evolving into a new scientific frontier driven by the diverse physicochemical properties and theranostic potential of nanomaterials and nanocomposites. Characteristic to the AD pathology is the deposition of amyloid plaques and tangles of amyloid beta (Aβ) and tau, whose aggregation kinetics may be curbed by nanoparticle inhibitors via sequence-specific targeting or nonspecific interactions with the amyloidogenic proteins. As literature implicates cell membrane as a culprit in AD pathogenesis, here we summarize the membrane axis of AD nanomedicine and present a new rationale that the field development may greatly benefit from harnessing our existing knowledge of Aβ-membrane interaction, nanoparticle-membrane interaction and Aβ-nanoparticle interaction.
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http://dx.doi.org/10.1002/anbr.202000040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7971452PMC
January 2021

Repurposing CFDA-approved drug carrimycin as an antiviral agent against human coronaviruses, including the currently pandemic SARS-CoV-2.

Acta Pharm Sin B 2021 Mar 11. Epub 2021 Mar 11.

Institute of Medicinal Biotechnology, Chinese Academy of Medical Science, Beijing 100050, China.

COVID-19 pandemic caused by SARS-CoV-2 infection severely threatens global health and economic development. No effective antiviral drug is currently available to treat COVID-19 and any other human coronavirus infections. We report herein that a CFDA-approved macrolide antibiotic, carrimycin, potently inhibited the cytopathic effects (CPE) and reduced the levels of viral protein and RNA in multiple cell types infected by human coronavirus 229E, OC43, and SARS-CoV-2. Time-of-addition and pseudotype virus infection studies indicated that carrimycin inhibited one or multiple post-entry replication events of human coronavirus infection. In support of this notion, metabolic labelling studies showed that carrimycin significantly inhibited the synthesis of viral RNA. Our studies thus strongly suggest that carrimycin is an antiviral agent against a broad-spectrum of human coronaviruses and its therapeutic efficacy to COVID-19 is currently under clinical investigation.
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http://dx.doi.org/10.1016/j.apsb.2021.02.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946546PMC
March 2021

Hippocampal miRNA-144 Modulates Depressive-Like Behaviors in Rats by Targeting PTP1B.

Neuropsychiatr Dis Treat 2021 10;17:389-399. Epub 2021 Feb 10.

Department of Geriatric Internal Medicine, The Affiliated Hospital of Qingdao University, Qingdao City, Shandong Province, 266000, People's Republic of China.

Background: Depression is the common mental disorder in the world. However, the pathophysiology mechanism underlying depression remains elusive. It has been reported that aberrant expression of miR-144 is closely related to depression. This study was to investigate whether and how miR-144 involves in depressive-like behaviors in a chronic unpredictable mild stress (CUMS) animal model.

Methods: A rat model of CUMS was established, and qRT-PCR was performed to detect the expression of miR-144 in the hippocampus of a depressed rat. The lentiviral vector carried miR-144 (LV-miR-144) was injected into the hippocampus of the CUMS rat to investigate the effects of miR-144 on the behaviors and PTP1B/TrkB/BDNF signal transduction in the hippocampus of the rat. The interaction between miR-144 and PTP1B was investigated by biological analyses and dual-luciferase reporter assay.

Results: The results showed that CUMS rats had typical depressive behaviors, and the expression of miR-144 in the hippocampus of CUMS rats was significantly lower than that of the control group. In addition, PTP1B protein expression was significantly up-regulated, while the expression of pTrkB and BDNF protein was significantly down-regulated in the hippocampus of CUMS rats. Moreover, PTP1B was a direct target of miR-144, and miR-144 could activate the downstream TrkB/BDNF signaling pathway by inhibiting the expression of PTP1B in primary hippocampus neurons.

Conclusion: MiR-144 played an anti-depressive role in hippocampus dysfunction by inhibiting PTP1B and activating the TrkB/BDNF signaling pathway in the hippocampus of CUMS rats.
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http://dx.doi.org/10.2147/NDT.S263079DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7883630PMC
February 2021

New sesquiterpeniod esters form (L.) DC. and their anti-influenza virus activity.

Nat Prod Res 2020 Dec 17:1-10. Epub 2020 Dec 17.

State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou medical university, Guiyang, China.

Phytochemical studies led to the isolation of five new sesquiterpeniod esters, named balsamiferine N-R, along with ten known compounds (6-15) from the leaves of (L.) DC. The skeletons of nine known sesquiterpeniods belong to guaiane and eudesmane. The structures of the new compounds including their absolute configurations were elucidated by comprehensive spectroscopic analysis, and quantum-chemical electronic circular dichroism (ECD) calculation. Compounds and showed significant inhibitory effects on influenza A virus (H3N2) with IC values of 46.23 μg/mL and 38.49 μg/mL, respectively. It was the first report on the anti-influenza A virus constituents from .
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http://dx.doi.org/10.1080/14786419.2020.1861615DOI Listing
December 2020

Scalable Synthesis, In Vitro cccDNA Reduction, and In Vivo Antihepatitis B Virus Activity of a Phosphonomethoxydeoxythreosyl Adenine Prodrug.

J Med Chem 2020 11 16;63(22):13851-13860. Epub 2020 Nov 16.

Medicinal Chemistry, KU Leuven, Rega Institute for Medical Research, Herestraat 49-box 1041, 3000 Leuven, Belgium.

Standard literature procedures for the chemical synthesis of l-threose nucleosides generally employ l-ascorbic acid as starting material. Herein, we have explored two alternative routes that start from either l-arabitol or l-diethyl tartrate, both affording 2--methyl-l-threofuranose as a key building block for nucleobase incorporation. The access to multigram quantities of this glycosyl donor in a reproducible fashion allows for the preparation of 2'-deoxy-α-l-threofuranosyl phosphonate nucleosides on a large scale. This methodology was applied to the gram scale synthesis of an aryloxy amidate prodrug of phosphonomethoxydeoxythreosyl adenine. This prodrug exerted potent activity against an entecavir-resistant hepatitis B virus (HBV) strain, while leading to a significant reduction in the levels of HBV covalently closed circular DNA in a cellular assay. Furthermore, its remarkable anti-HBV efficacy was also confirmed in vivo using a hydrodynamic injection-based HBV mouse model, without relevant toxicity and systemic exposure occurring.
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http://dx.doi.org/10.1021/acs.jmedchem.0c01381DOI Listing
November 2020

Synthetic analogues of memantine as neuroprotective and influenza viral inhibitors: in vitro and physicochemical studies.

Amino Acids 2020 Dec 15;52(11-12):1559-1580. Epub 2020 Nov 15.

Krestov's Institute of Solution Chemistry, Russian Academy of Sciences, 153045, Ivanovo, Russia.

Drug compounds including memantine moieties are an important group of biologically active agents for different pathologies, including the Alzheimer's disease. In the present study, a series of memantine derivatives incorporating amino acid residues have been synthesized and their neuroprotective in vitro evaluation in respect of the Alzheimer's disease, involving the effects on the resistance to Aβ toxicity, excitotoxicity, oxidative stress, hypoxia, and neuroinflammation has been studied. The cytotoxicities of the compounds were detected by CPE assay. TC and IC were determined using Reed and Muench method. Solubility and distribution were measured using a shake-flask method. Permeability of the compounds was studied using Franz diffusion cell and Permeapad™ barrier. These compounds displayed apparent multi-neuroprotective effects against copper-triggered Aβ toxicity, glutamate-induced excitotoxicity, and oxidative and hypoxic injuries. They also showed the ability to inhibit the inflammatory cytokine release from the activated microglia and potential anti-neuroinflammatory effects. Especially, two most promising compounds H-4-F-Phe-memantine and H-Tyr-memantine demonstrated the equivalent functional bioactivities in comparison with the positive control memantine hydrochloride. Higher solubility in muriatic buffer than in phosphate buffer was detected. The distribution coefficients showed the optimal lipophilicity for compounds. The presented results propose new class of memantine derivatives as potential drug compounds. Based on the experimental results, the correlations have been obtained between the biological, physicochemical parameters and structural descriptors. The correlation equations have been proposed to predict the properties of new memantine derivatives knowing only the structural formula.
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http://dx.doi.org/10.1007/s00726-020-02914-4DOI Listing
December 2020

mA Regulates Liver Metabolic Disorders and Hepatogenous Diabetes.

Genomics Proteomics Bioinformatics 2020 08 5;18(4):371-383. Epub 2020 Nov 5.

State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China; Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing 100101, China. Electronic address:

N-methyladenosine (mA) is one of the most abundant modifications on mRNAs and plays important roles in various biological processes. The formation of mA is catalyzed by a methyltransferase complex (MTC) containing a key factor methyltransferase-like 3 (Mettl3). However, the functions of Mettl3 and mA modification in hepatic lipid and glucose metabolism remain unclear. Here, we showed that both Mettl3 expression and mA level increased in the livers of mice with high fat diet (HFD)-induced metabolic disorders. Overexpression of Mettl3 aggravated HFD-induced liver metabolic disorders and insulin resistance. In contrast, hepatocyte-specific knockout of Mettl3 significantly alleviated HFD-induced metabolic disorders by slowing weight gain, reducing lipid accumulation, and improving insulin sensitivity. Mechanistically, Mettl3 depletion-mediated mA loss caused extended RNA half-lives of metabolism-related genes, which consequently protected mice against HFD-induced metabolic syndrome. Our findings reveal a critical role of Mettl3-mediated mA in HFD-induced metabolic disorders and hepatogenous diabetes.
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http://dx.doi.org/10.1016/j.gpb.2020.06.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8242261PMC
August 2020

Implications of the Human Gut-Brain and Gut-Cancer Axes for Future Nanomedicine.

ACS Nano 2020 11 2;14(11):14391-14416. Epub 2020 Nov 2.

CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety and CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology of China, Beijing 100190, China.

Recent clinical and pathological evidence have implicated the gut microbiota as a nexus for modulating the homeostasis of the human body, impacting conditions from cancer and dementia to obesity and social behavior. The connections between microbiota and human diseases offer numerous opportunities in medicine, most of which have limited or no therapeutic solutions available. In light of this paradigm-setting trend in science, this review aims to provide a comprehensive and timely summary of the mechanistic pathways governing the gut microbiota and their implications for nanomedicines targeting cancer and neurodegenerative diseases. Specifically, we discuss in parallel the beneficial and pathogenic relationship of the gut microbiota along the gut-brain and gut-cancer axes, elaborate on the impact of dysbiosis and the gastrointestinal corona on the efficacy of nanomedicines, and highlight a molecular mimicry that manipulates the universal cross-β backbone of bacterial amyloid to accelerate neurological disorders. This review further offers a forward-looking section on the rational design of cancer and dementia nanomedicines exploiting the gut-brain and gut-cancer axes.
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http://dx.doi.org/10.1021/acsnano.0c07258DOI Listing
November 2020

Functional nano-vector boost anti-atherosclerosis efficacy of berberine in mice.

Acta Pharm Sin B 2020 Sep 8;10(9):1769-1783. Epub 2020 Apr 8.

State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Beijing City Key Laboratory of Drug Delivery Technology and Novel Formulations, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.

Atherosclerosis (AS) is the leading cause of heart attacks, stroke, and peripheral vascular disease. Berberine (BBR), a botanical medicine, has diversified anti-atherosclerotic effects but with poor absorption. The aim of this study was to develop an effective BBR-entrapped nano-system for treating AS in high-fat diet (HFD)-fed mice, and also explore the possible underlying mechanisms involved. Three d--tocopherol polyethylene glycol (PEG) succinate (TPGS) analogues with different PEG chain lengths were synthesized to formulate BBR-entrapped micelles. HFD-fed mice were administered with optimized formula (BBR, 100 mg/kg/day) orally for 5 months. The artery plaque onset and related metabolic disorders were evaluated, and the underlying mechanisms were studied. Our data showed that, BTM increased BBR deposition in liver and adipose by 107.6% and 172.3%, respectively. In the mice, BTM ameliorated HFD-induced hyperlipidemia and lipid accumulation in liver and adipose. BTM also suppressed HFD-induced chronic inflammation as evidenced by the reduced liver and adipose levels of interleukin-6 (IL-6), tumor necrosis factor- (TNF-) and interleukin-1IL-1); and decreased plasma level of TNF-, IL-6, IL-1, interferon-IFN-), monocyte chemotactic protein (MCP), and macrophage inflammatory factor (MIP). The mechanism study showed that BTM changed and gene expression, and interrupted a crosstalk process between adipocytes and macrophages. Further investigation proved that BTM decreased endothelial lesion and subsequent macrophage activation, cytokines release, as well as cholesteryl ester gathering in the aortic arch, resulting in ameliorated artery plaque build-up. Our results provide a practical strategy for treating AS using a BBR-entrapped nano-system.
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http://dx.doi.org/10.1016/j.apsb.2020.03.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564017PMC
September 2020

Accelerated Amyloid Beta Pathogenesis by Bacterial Amyloid FapC.

Adv Sci (Weinh) 2020 Sep 16;7(18):2001299. Epub 2020 Jul 16.

ARC Centre of Excellence in Convergent Bio-Nano Science and Technology Monash Institute of Pharmaceutical Sciences Monash University 381 Royal Parade Parkville VIC 3052 Australia.

The gut-brain axis has attracted increasing attention in recent years, fueled by accumulating symptomatic, physiological, and pathological findings. In this study, the aggregation and toxicity of amyloid beta (A), the pathogenic peptide associated with Alzheimer's disease (AD), seeded by FapC amyloid fragments (FapCS) of that colonizes the gut microbiome through infections are examined. FapCS display favorable binding with A and a catalytic capacity in seeding the peptide amyloidosis. Upon seeding, twisted A fibrils assume a much-shortened periodicity approximating that of FapC fibrils, accompanied by a 37% sharp rise in the fibrillar diameter, compared with the control. The robust seeding capacity for A by FapCS and the biofilm fragments derived from entail abnormal behavior pathology and immunohistology, as well as impaired cognitive function of zebrafish. Together, the data offer the first concrete evidence of structural integration and inheritance in peptide cross-seeding, a crucial knowledge gap in understanding the pathological correlations between different amyloid diseases. The catalytic role of infectious bacteria in promoting A amyloidosis may be exploited as a potential therapeutic target, while the altered mesoscopic signatures of A fibrils may serve as a prototype for molecular assembly and a biomarker for screening bacterial infections in AD.
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http://dx.doi.org/10.1002/advs.202001299DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7509637PMC
September 2020

A molecular-logic gate for COX-2 and NAT based on conformational and structural changes: visualizing the progression of liver disease.

Chem Sci 2020 Jun 25;11(24):6209-6216. Epub 2020 May 25.

Henan Key Laboratory of Green Chemical Media and Reactions , Ministry of Education , Henan Key Laboratory of Organic Functional Molecules and Drug Innovation , School of Chemistry and Chemical Engineering , School of Physics , Henan Normal University , Xinxiang 453007 , P. R. China . Email:

Lighting up the relevant lesion boundaries during operations is vital for guiding the effective resection of hepatopathic tissue. We envisioned that molecular-logic gates, which are known for their excellent digital correlation between input and output signals, could be used to facilitate differential visualization of lesion boundaries. Herein, a series of flexible molecules, naphthalene imide-indole derivatives () were prepared and evaluated as molecular-logic gates. The input and output signals of the derivatives were successfully used to highlight different hepatopathic regions in order to facilitate boundary differentiation. The derivatives produce different signals due to collaborative changes in the conformation and structure. The hepatopathy-related enzymes (COX-2 and NAT) were used to induce conformational and structural changes in derivatives. Based on these enzyme induced synergistic effects, can sensitively emit different coloured signals such as green, cyan and blue (output signals) as a function of the different input signals, the different activity of COX-2 and NAT in solution and living cells. Significantly, the derivatives were successfully used to distinguish the boundaries of hepatopathic lesions in tissues after spraying with derivatives (mild cirrhosis, severe cirrhosis, in addition to early and late hepatocellular carcinoma) under a hand held lamp at 365 nm by naked eye.
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http://dx.doi.org/10.1039/d0sc00574fDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480271PMC
June 2020

Transcriptional repression of p21 by EIF1AX promotes the proliferation of breast cancer cells.

Cell Prolif 2020 Oct 14;53(10):e12903. Epub 2020 Sep 14.

State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.

Objective: Dysregulation of the cell cycle is associated with the progression of malignant cancer, but its precise functional contribution is unknown.

Materials And Methods: The expression of EIF1AX in breast cancer tissues was detected by qRT-PCR and immunohistochemistry staining. Colony formation and tumour xenograft assays were used to examine the tumorigenesis-associated function of EIF1AX in vitro and in vivo. RNA-Seq analysis was used to select the downstream target genes of EIF1AX. Flow cytometry, ChIP and luciferase assays were used to investigate the molecular mechanisms by which EIF1AX regulates p21 in breast cancer cells.

Results: EIF1AX promoted breast cancer cell proliferation by promoting the G1/S cell cycle transition. A mechanistic investigation showed that EIF1AX inhibited the expression of p21, which is an essential cell cycle regulator. We identified that the transcriptional regulation of p21 by EIF1AX was p53-independent. Clinically, EIF1AX levels were significantly elevated in breast cancer tissues, and the high level of EIF1AX was associated with lower survival rates in breast cancer patients.

Conclusions: Our results imply that EIF1AX may play a key role in the incidence and promotion of breast cancer and may, thus, serve as a valuable target for breast cancer therapy.
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http://dx.doi.org/10.1111/cpr.12903DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7574879PMC
October 2020

Amyloidosis Inhibition, a New Frontier of the Protein Corona.

Nano Today 2020 Dec 22;35. Epub 2020 Jul 22.

CAS Center for Excellence in Nanoscience and CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology of China, Beijing 100190, China.

The protein corona has served as a central dogma and a nuisance to the applications of nanomedicine and nanobiotechnology for well over a decade. Here we introduce the emerging field of amyloidosis inhibition, which aims to understand and harness the interfacial phenomena associated with a nanoparticle interacting with pathogenic amyloid proteins. Much of this interaction correlates with our understanding of the protein corona, and yet much differs, as elaborated for the first time in this . Specifically, we examine the , and features of the new class of "amyloid protein corona", and discuss how the interactions with nanoparticles may halt the self-assembly of amyloid proteins. As amyloidosis is driven off pathway by the nanoparticles, the oligomeric and protofibrillar populations are suppressed to ameliorate their cytotoxicity. Furthermore, as amyloid proteins spread via the transport of bodily fluids or cross seeding, amyloidosis is inherently associated with dynamic proteins and ligands to evoke the immune system. Accordingly, we ponder the structural and medical implications of the amyloid protein corona in the presence of their stimulated cytokines. Understanding and exploiting the amyloid protein corona may facilitate the development of new theranostics against a range of debilitating amyloid diseases.
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http://dx.doi.org/10.1016/j.nantod.2020.100937DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7388636PMC
December 2020

The application of GPR to the detection of soil wetted bodies formed by drip irrigation.

PLoS One 2020 22;15(7):e0235489. Epub 2020 Jul 22.

College of Resources and Environment, Shandong Agricultural University, Tai'an, China.

The ability to accurately measure the geometric characteristics of soil wetted bodies (SWBs) is very important for conserving water in agriculture. However, measurements of SWBs obtained using conventional methods have a number of defects. Ground penetrating radar (GPR) is a promising technique for detecting buried features. In this paper, we used GPR to nondestructively investigate SWBs formed under drip irrigation. First, numerical simulations were performed to obtain the theoretical radar-gram of SWBs. Then, controlled irrigation experiments were performed to obtain radar scan datasets in a laboratory. The GPR image was interpreted according to the numerical simulation results, and the SWB thickness detection accuracy was estimated. Finally, GPR detection was performed in the field with different irrigation volumes, and the detection effect was assessed. The GPR reflections in the laboratory and field measurements were more complex than in the numerical simulation images, but the location and thickness of SWBs were still clear; the accuracy of the measured thickness was high, and the accuracy decreased with an increase in irrigation volume. The radar image resolution and thickness accuracy measured in the field were slightly less than the values measured in the laboratory. Thus, GPR is able to quickly and accurately characterize SWBs formed by drip irrigation based on the thickness and relative position in the soil. Furthermore, the F-K offset transformation was an effective GPR data processing method for focusing reflections from SWBs to obtain their true position and physical extent.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0235489PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7375588PMC
September 2020

Sulfoxide-Containing Polymer-Coated Nanoparticles Demonstrate Minimal Protein Fouling and Improved Blood Circulation.

Adv Sci (Weinh) 2020 Jul 17;7(13):2000406. Epub 2020 May 17.

ARC Centre of Excellence in Convergent Bio-Nano Science and Technology and Australian Institute for Bioengineering and Nanotechnology The University of Queensland Brisbane QLD 4072 Australia.

Minimizing the interaction of nanomedicines with the mononuclear phagocytic system (MPS) is a critical challenge for their clinical translation. Conjugating polyethylene glycol (PEG) to nanomedicines is regarded as an effective approach to reducing the sequestration of nanomedicines by the MPS. However, recent concerns about the immunogenicity of PEG highlight the demand of alternative low-fouling polymers as innovative coating materials for nanoparticles. Herein, a highly hydrophilic sulfoxide-containing polymer-poly(2-(methylsulfinyl)ethyl acrylate) (PMSEA)-is used for the surface coating of iron oxide nanoparticles (IONPs). It is found that the PMSEA polymer coated IONPs have a more hydrophilic surface than their PEGylated counterparts, and demonstrate remarkably reduced macrophage cellular uptake and much less association with human plasma proteins. In vivo study of biodistribution and pharmacokinetics further reveals a much-extended blood circulation (≈2.5 times longer in terms of elimination half-life ) and reduced accumulation (approximately two times less) in the organs such as the liver and spleen for IONPs coated by PMSEA than those by PEG. It is envisaged that the highly hydrophilic sulfoxide-containing polymers have huge potential to be employed as an advantageous alternative to PEG for the surface functionalization of a variety of nanoparticles for long circulation and improved delivery.
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http://dx.doi.org/10.1002/advs.202000406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7341081PMC
July 2020

Nanomaterial synthesis, an enabler of amyloidosis inhibition against human diseases.

Nanoscale 2020 Jul;12(27):14422-14440

Zhongshan Hospital, Fudan University, 111 Yixueyuan Rd, Xuhui District, Shanghai, China and ARC Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, VIC 3052, Australia.

Amyloid diseases are global epidemics with no cure currently available. In the past decade, the use of engineered nanomaterials as inhibitors or probes against the pathogenic aggregation of amyloid peptides and proteins has emerged as a new frontier in nanomedicine. In this Minireview, we summarize for the first time the pivotal role of chemical synthesis in enabling the development of this multidisciplinary field.
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http://dx.doi.org/10.1039/d0nr04273kDOI Listing
July 2020

2-((4-Arylpiperazin-1-yl)methyl)benzonitrile Derivatives as Orally Available Inhibitors of Hepatitis C Virus with a Novel Mechanism of Action.

J Med Chem 2020 06 20;63(11):5972-5989. Epub 2020 May 20.

CAMS Key Laboratory of Antiviral Drug Research, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.

Although the direct-acting antivirals revolutionized the hepatitis C virus (HCV) infection treatment in the last decade, more efforts are needed to reach the elimination of HCV in the absence of a vaccine. 4-(Piperazin-1-yl)-2-((-tolylamino)methyl)-benzonitrile (1) is a modest HCV inhibitor identified from an in-house screening using a HCV-infected Huh7.5 cell culture. Starting from it, the chemical optimization afforded a new 2-((4-arylpiperazin-1-yl)methyl)benzonitrile scaffold with significantly increased antiviral activity against HCV. A highly effective HCV inhibitor, (, EC = 0.022 μM, SI > 600), was identified by the structure-activity relationship study. The biological study revealed that could block HCV replication by acting on the HCV entry stage. The high sensitivity to clinical resistant HCV mutants and synergistic effect with clinical drugs were observed for this compound. The further pharmaceutical studies demonstrated that is long-lasting, is orally available, and has low toxicity in vivo. These results show as a promising HCV entry inhibitor for single or combinational therapeutic potential.
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http://dx.doi.org/10.1021/acs.jmedchem.0c00232DOI Listing
June 2020
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