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Medicinal chemistry strategies towards the development of non-covalent SARS-CoV-2 Mpro inhibitors

Acta Pharmaceutica Sinica B 2024年第1期14卷 87-109页

作者： Letian Song Shenghua Gao Bing Ye Mianling Yang Yusen Cheng Dongwei Kang fan Yi Jin-Peng Sun Luis Menéndez-Arias Johan Neyts Xinyong Liu Peng Zhan Department of Medicinal Chemistry Key Laboratory of Chemical Biology(Ministry of Education)School of Pharmaceutical SciencesCheeloo College of MedicineShandong UniversityJinan 250012China Shenzhen Research Institute of Shandong University Shenzhen 518057China The Key Laboratory of Infection and Immunity of Shandong Province Department of PharmacologySchool of Basic Medical SciencesShandong UniversityJinan 250012China Key Laboratory Experimental Teratology of the Ministry of Education Department of Biochemistry and Molecular BiologySchool of Basic Medical SciencesCheeloo College of MedicineShandong UniversityJinan 250012China Centro de Biologı´a Molecular“Severo Ochoa”(Consejo Superior de Investigaciones Cientı´ficas&Autonomous University of Madrid) Madrid 28049Spain KU Leuven Department of Microbiology and ImmunologyRega Institute for Medical ResearchLaboratory of Virology and ChemotherapyLeuven 3000Belgium

The main protease(M^(pro))of SARS-CoV-2 is an attractive target in anti-COVID-19 therapy for its high conservation and major role in the virus life *** covalent M^(pro)inhibitor nirmatrelvir(in combination with ritonavir,a pharmacokinetic enhancer)and the non-covalent inhibitor ensitrelvir have shown efficacy in clinical trials and have been approved for therapeutic *** antiviral drugs are needed to fight the pandemic,while non-covalent M^(pro)inhibitors could be promising alternatives due to their high selectivity and favorable *** non-covalent M^(pro)inhibitors with desirable properties have been developed based on available crystal structures of M^(pro).In this article,we describe medicinal chemistry strategies applied for the discovery and optimization of non-covalent M^(pro)inhibitors,followed by a general overview and critical analysis of the available *** viewpoints and insights into current strategies for the development of non-covalent M^(pro)inhibitors are also discussed.

关键词： COVID-19 SARS-CoV-2 Main protease Non-covalent inhibitors Medicinal chemistry strategies

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Short-and long-term effects of an extreme case of autotomy:does“tail”loss and subsequent constipation decrease the locomotor performance of male and female scorpions?

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Integrative Zoology 2022年第5期17卷 672-688页

作者： Solimary GARCÍA-hernÁndez Glauco MACHADO Programa de Pós-graduação em Ecologia Instituto de BiociênciasUniversidade de São PauloSão PauloBrazil LAGE do Departamento de Ecologia Instituto de BiociênciasUniversidade de São PauloSão PauloBrazil

In many taxa,individuals voluntarily detach a body part as a form to increase their chances of escaping *** defense mechanism,known as autotomy,has several consequences,such as changes in locomotor performance that may affectﬁ*** of the genus Ananteris autotomize the“tail”,which in fact corresponds to the last abdominal *** autotomy,individuals lose nearly 25%of their body mass and the last portion of the digestive tract,including the anus,which prevents defecation and leads to constipation,because regeneration does not ***,we experimentally investigated the short-and long-term effects of tail loss on the locomotor performance of Ananteris *** a short-term experiment,the maximum running speed(MRS)of males and females did not change after ***,the relative mass of the lost tail did not affect the change in MRS after *** a long-term experiment,autotomy had a negative effect on the MRS of males,but not of *** over-fed individuals suffered from severe constipation but were not slower than autotomized normally fed *** conclusion,tail loss has no immediate effect on the locomotor performance of *** long-term decrease in the locomotor performance of autotomized males may impair mate ***,because death by constipation takes several months,males have a long time toﬁnd mates and ***,the prolonged period between autotomy and death by constipation is crucial for understanding the evolution of one of the most extreme cases of autotomy in nature.

关键词： ﬁtness costs maximum running speed sex differences tail loss weight loss

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Data-driven drug repositioning using olfactory omics profiles:challenges and perspectives in neurodegeneration

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Neural Regeneration Research 2025年第7期20卷 1997-1998页

作者： Paz Cartas-Cejudo Adriana Cortés Mercedes Lachén-Montes Elena Anaya-Cubero Joaquín fernández-Irigoyen Enrique Santamaría Clinical Neuroproteomics Unit Proteomics PlatformNavarrabiomedHospitalario Universitario de Navarra(HUN)Universidad Pública de Navarra(UPNA)IdiSNANavarra Institute for Health ResearchPamplonaSpain

Data-driven drug repositioning using olfactory omics profiles-challenges and perspectives in neurodegeneration:Neurodegenerative diseases are characterized by progressive degeneration and loss of neuronal function in the central nervous *** diseases are often characterized as proteinopathies,which are disorders primarily driven by the aggregation or misfolding of specific amyloid proteins within cells,leading to their dysfunction and eventual *** the gain-of-function hypothesis related to the aggregation of these proteins,recently,an alternative hypothesis regarding the loss-of-function of the soluble monomeric proteins during the process of aggregation into amyloids is gaining *** last event is called proteinopenia and refers to conditions characterized by a deficiency or decrease in the levels of specific soluble proteins in the body(Ezzat et al.,2023).It has been demonstrated that levels of soluble proteins involved in neurodegenerative diseases are decreased.

关键词： diseases drug amyloid

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Attempts to restore loss of function in damaged ACD cells open the way to non-mutational oncogenesis

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Genes & Diseases 2024年第3期11卷 5-6页

作者： Vladimir f.Niculescu 86420 Diedorf Germany Kirschenweg

This correspondence to Gene&Diseases calls attention to the controversy between proponents of genetic modification in carcinogenesis and supporters of non-mutational *** from molecular cancer research and findings from evolutionary cancer cell biology support the latter claim and provide no rationale for the mutational origin of sporadic *** is more conceivable that the general susceptibility of asymmetric cell division(ACD)phenotypes to oxygen leads to irreparable DNA defects and dysregulated defective symmetric cell division(DscD)phenotypes.

关键词： rational latter finding

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Heat and mass transfer of a circular porous moist object located in a triangular shaped vented cavity

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Journal of Central South University 2024年第6期31卷 1956-1972页

作者： SELIMEfENDIGIL fatih OZCAN COBAN Seda OZTOP Hakan f Department of Mechanical Engineering College of EngineeringKing Faisal UniversityAl Ahsa 31982Saudi Arabia Department of Mechanical Engineering Manisa Celal Bayar UniversityManisa 45140Turkey Department of Mechanical Engineering Technology FacultyFırat UniversityElazığTurkey

Heat and mass transfer of a circular-shaped porous moist object inside a two-dimensional triangle cavity is investigated by using finite element *** porous object is considered to be a moist food sample,located in the middle of the cavity with inlet and outlet ports with different configurations of inlet/outlet *** drying performance is numerically assessed for different values of Reynolds numbers(between 50 and 250),dry air inlet temperature(between 40 and 80℃)and different locations of the *** is observed that changing the port locations has significant impacts on the flow recirculaitons inside the triangular chamber while convective drying performance is highly *** moisture content reduces with longer time and for higher Reynolds number(Re)*** P4 where inlet and outlet ports are in the middle of the walls provides the most effective configuration in terms of convective drying performance while the worst case is seen for P1 case where inlet and outlet are closer to the corners of the *** is a 192% difference between the moisture reduction of these two cases at Re=250,T=80℃ and t=120 min.

关键词： convective drying porous domain cavity flow inlet/exit port finite element method

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A Probabilistic Description of the Impact of Vaccine-Induced Immunity in the Dynamics of COVID-19 Transmission

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Open Journal of Modelling and Simulation 2024年第2期12卷 59-73页

作者： Javier Blecua Juan fernández-Recio José Manuel Gutiérrez Instituto de Ciencias de la Vid y del Vino (ICVV) CSIC-Universidad de La Rioja-Gobierno de La Rioja Logro&#241o Spain Departamento de Matemá ticas y Computaci&#243n Universidad de La Rioja Logro&#241o Spain

The recent outbreak of COVID-19 has caused millions of deaths worldwide and a huge societal and economic impact in virtually all countries. A large variety of mathematical models to describe the dynamics of COVID-19 transmission have been reported. Among them, Bayesian probabilistic models of COVID-19 transmission dynamics have been very efficient in the interpretation of early data from the beginning of the pandemic, helping to estimate the impact of non-pharmacological measures in each country, and forecasting the evolution of the pandemic in different potential scenarios. These models use probability distribution curves to describe key dynamic aspects of the transmission, like the probability for every infected person of infecting other individuals, dying or recovering, with parameters obtained from experimental epidemiological data. However, the impact of vaccine-induced immunity, which has been key for controlling the public health emergency caused by the pandemic, has been more challenging to describe in these models, due to the complexity of experimental data. Here we report different probability distribution curves to model the acquisition and decay of immunity after vaccination. We discuss the mathematical background and how these models can be integrated in existing Bayesian probabilistic models to provide a good estimation of the dynamics of COVID-19 transmission during the entire pandemic period.

关键词： COVID-19 Transmission Dynamics Probabilistic Model Bayesian Analysis Markov Chain Monte Carlo

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The relationship between DNA fragmentation and the intensity of morphologically abnormal human spermatozoa

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Asian pacific Journal of Reproduction 2024年第1期13卷 22-27页

作者： Mercedes González-Martínez Pascual Sánchez-Martín Carmen López-fernández Stephen D.Johnston Jaime Gosálvez Clínica Ginemed Unidad de ReproducciónSevillaSpain Department of Biology Universidad Autónoma de MadridCantoblancoMadridSpain School of Environment The University of QueenslandGattonAustralia School of Veterinary Science The University of QueenslandGattonAustralia

Objective:To determine the relationship between teratozoospermia and sperm DNA fragmentation(SDf)in the human ***:This retrospective study included 100 normozoospermic men as a control cohort(abnormal forms>14%),210 patients with a high level of abnormal forms(≤4%)and 65 patients presenting with a moderate level of abnormal forms(>4%to≤14%)based on the World Health Organization *** morphology was assessed using bright field *** DNA fragmentation was assessed using the sperm chromatin dispersion ***-parametric analyses were conducted to examine the relationship between abnormal sperm morphology and sperm DNA fragmentation;receiver operating characteristic(ROC)analyses were conducted to assess sensitivity and specificity of this ***:A correlation analysis revealed that the higher the proportion of abnormal spermatozoa in the ejaculate,the higher the level of SDf(Spearman's Rho=-0.230;Pficant differences in the proportion of SDf were found when all cohorts were compared(Pficant differences were also retained when the different cohorts were compared *** analysis showed a moderate but significant predictive value for SDf to differentiate patients with different levels of ***:Although analysis of a more continuous range of values for teratozoospermia would help further clarify any causal relationship with SDf,there is clearly a synergistic or coincident affiliation between these variables that needs to be acknowledged by the clinician when interpreting the spermiogram.

关键词： Teratozoospermia Sperm morphology Sperm DNA fragmentation Male factor Human reproduction Human fertility

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Linking IL-10 signaling with lipid metabolic programs in macrophages:dysregulated ceramide homeostasis drives colitis

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Signal Transduction and Targeted Therapy 2024年第7期9卷 2835-2836页

作者： Imke Atreya Markus f.Neurath Department of Medicine 1 University Hospital of ErlangenFriedrich-Alexander University Erlangen-NürnbergErlangenGermany Deutsches Zentrum Immuntherapie(DZI) ErlangenGermany

In a recent study published in Nature,York and coworkers identified the immunometabolic regulation of mono-unsaturated fatty acid(MUfA)pools and the subsequent increase in sphingolipid biosynthesis in TLR2-activated macrophages as an important link between impaired IL-10 signaling and the development of intestinal inflammation.1 Thus,targeted interference with the newly identified IL-10/MUfA/sphingolipid axis appears as a promising strategy to restore immunometabolic homeostasis in the intestine of patients with inflammatory bowel diseases(IBD).

关键词： homeostasis impaired intestine

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All-optical nonlinear chiral ultrafast magnetization dynamics driven by circularly polarized magnetic fields

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High Power Laser Science and Engineering 2023年第6期11卷 154-161页

作者： Luis Sánchez-Tejerina Rodrigo Martín-hernández Rocío Yanes Luis Plaja Luis López-Díaz Carlos hernández-García Grupo de Investigación en Aplicaciones del Láser y fotónica Departamento de Física AplicadaUniversidad de SalamancaSalamancaSpain Present address:Departamento de Electricidad y Electrónica Universidad de ValladolidValladolidSpain Departamento de física Aplicada Universidad de SalamancaSalamancaSpain Unidad de Excelencia en Luz y Materia Estructuradas(LUMES) Universidad de SalamancaSalamancaSpain

Ultrafast laser pulses provide unique tools to manipulate magnetization dynamics at femtosecond timescales,where the interaction of the electric field usually dominates over the magnetic *** proposals using structured laser beams have demonstrated the possibility to produce regions where intense oscillating magnetic fields are isolated from the electric *** these conditions,we show that technologically feasible tesla-scale circularly polarized high-frequency magnetic fields induce purely precessional nonlinear magnetization *** fundamental result not only opens an avenue in the study of laser-induced ultrafast magnetization dynamics,but also sustains technological implications as a route to promote all-optical non-thermal magnetization dynamics both at shorter timescales-towards the subfemtosecond regime-and at THz frequencies.

关键词： chiral behavior nonlinear dynamics ultrafast dynamics

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Endoplasmic reticulum stress,autophagy,neuroinflammation,and sigma 1 receptors as contributors to depression and its treatment

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Neural Regeneration Research 2024年第10期19卷 2202-2211页

作者： Chika fujii Charles f.Zorumski Yukitoshi Izumi Department of Psychiatry Washington University School of MedicineSt.LouisMOUSA Taylor family Institute for Innovative Psychiatric Research Washington University School of MedicineSt.LouisMOUSA

The etiological factors contributing to depression and other neuropsychiatric disorders are largely undefined. Endoplasmic reticulum stress pathways and autophagy are well-defined mechanisms that play critical functions in recognizing and resolving cellular stress and are possible targets for the pathophysiology and treatment of psychiatric and neurologic illnesses. An increasing number of studies indicate the involvement of endoplasmic reticulum stress and autophagy in the control of neuroinflammation, a contributing factor to multiple neuropsychiatric illnesses. Initial inflammatory triggers induce endoplasmic reticulum stress, leading to neuroinflammatory responses. Subsequently, induction of autophagy by neurosteroids and other signaling pathways that converge on autophagy induction are thought to participate in resolving neuroinflammation. The aim of this review is to summarize our current understanding of the molecular mechanisms governing the induction of endoplasmic reticulum stress, autophagy, and neuroinflammation in the central nervous system. Studies focused on innate immune factors, including neurosteroids with anti-inflammatory roles will be reviewed. In the context of depression, animal models that led to our current understanding of molecular mechanisms underlying depression will be highlighted, including the roles of sigma 1 receptors and pharmacological agents that dampen endoplasmic reticulum stress and associated neuroinflammation.

关键词： allopregnanolone fluvoxamine ketamine neurosteroids postpartum depression quercetin

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