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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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Snapshot Survey of the Presence of Perfluoroalkyl Substances in Products, Articles, and the Environment in Ecuador

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Engineering 2024年第6期37卷 49-61页

作者： Heidelore Fiedler luis Vega-Bustillos Jenny arias-Pastrano Lander Vinicio Pérez-Aldás Jose Castro-Díaz MTM Research Centre School of Science and TechnologyÖrebro UniversityÖrebro 70182Sweden Undersecretariat of Environmental Quality Ministry of EnvironmentWater and Ecological Transition of EcuadorQuito 170525Ecuador Department of Environmental Chemistry The Technical University of AmbatoHuachi CampusAmbato 180207Ecuador Alternativavision Ambiental Cia.Ltda. Mexico 03100Mexico

The Stockholm Convention on Persistent Organic Pollutants(POPs)is a legally binding instrument for 186 Parties(status:April 2023).Accordingly,among other responsibilities,countries are obliged to report the production,import,or export of the POPs listed in Annexes A,B,or C;provide information to registers;maintain inventories;and monitor the presence of POPs in the *** the broader context of international chemicals and waste management,producer responsibilities,harmonized reporting,and compliance with national and international regulations,Ecuador has addressed the newly listed group of perfluorinated alkyl substances(PFAS)in its national implementation plan and sent selected products from its national market for PFAS *** products analyzed came from the initially listed fields of specific exemptions and acceptable purposes,including:fire-fighting foams;photographic aids;greasers/degreasers;various kinds of paper/packaging;textiles;and leather,coatings,cleaners,metal plating,and *** results showed that the three PFAS presently listed in the Stockholm Convention could be quantified in only a few samples;additional PFAS,not yet listed in the Convention also had low detection *** the number of samples was limited,the samples covered a large spectrum of sample matrices,making it possible to conclude that—once these products become waste and are regulated under the Basel Convention—they would not constitute a disposal ***,verification of the presence of PFAS in products on the market is expected to pose an analytical challenge for both,developed and developing countries.

关键词： Emerging or newly listed POPs Stockholm Convention Products and articles PFAS analysis Developing countries

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Targeting Metalloenzymes HIV-1 Reverse Transcriptase-associated RNase H and Integrase for Antiviral Therapeutic Intervention

Targeting Metalloenzymes HIV-1 Reverse Transcriptase-associa...

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中国化学会第十届全国无机化学学术会议

作者： Ping Gao Xiqiang Cheng Lin Sun Christophe Pannecouque Erik De Clercq luis menéndez-arias Xinyong Liu Peng Zhan Department of Medicinal Chemistry Key Laboratory of Chemical BiologyMinistry of EducationSchool of Pharmaceutical SciencesShandong University

Metalloenzymes represent a vast and largely untapped space for antiviral drug development. Such proteins contain one or more metal ion cofactors, prevalently located in the active site, which are essential to perform biological functions. Typically, metalloenzyme inhibitors are drug-like small molecules that incorporate a metal binding group to coordinate the active site metal ion. Our drug discovery program focuses on some viral enzymes containing magnesium as a metal cofactor, including HIV reverse transcriptase（RT）-associated ribonuclease H（RNase H） and integrase（IN）. Different strategies have been employed to design effective inhibitors against these proteins（Figure 1）. Recently, 1-hydroxypyrido[2,3-d]pyrimidin-2（1 H）-ones（as exemplified by IIA-2） were identified as novel selective HIV IN inhibitors obtained via privileged substructure-based compound libraries, with anti-HIV EC50 values ranging from 0.92 to 26.85μM in MT-4 cells. 5-Hydroxypyrido[2,3-b]pyrazin-6（5 H）-one derivatives（as exemplified by 7 a） were identified as novel dual inhibitors of HIV-1 RNase H and IN. We also found that 3-hydroxyquinazoline-2,4（1 H,3 H）-dione and galloyl derivatives（as exemplified by II-4 and II-25） were effective inhibitors of HIV-1 RNase H at sub to low micromolar concentrations. Molecular modeling studies of galloyl predict key interactions with RT residues His539 and Arg557, while providing helpful insight for further optimization（Figure 1）. We envisioned that examining the bioinorganic chemistry of these metal active sites and better understanding of the coordination chemistry in these metalloenzymes may lead to improved inhibitors.

关键词： Metalloenzymes Antiviral Drug design HIV Ribonuclease H Integrase

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Emerging drug design strategies in anti-influenza drug discovery

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Acta Pharmaceutica Sinica B 2023年第12期13卷 4715-4732页

作者： Chuanfeng Liu Lide Hu Guanyu Dong Ying Zhang Edeildo Ferreira da Silva-Jinior Xinyong Liu luis menendez-arias Peng Zhan Department of Medicinal Chemistry Key Laboratory of Chemical Biology(Ministry of Education)School of Pharmaceutical SciencesShandong UniversityJinan 250012China Laboratory of Medicinal Chemistry Institute of Pharmaceutical SciencesFederal University of AlagoasMaceio 57072-970AlagoasBrazil Centro de Biologia Molecular“Severo Ochoa”(Consejo Superior de Investigaciones Cientificas&Universidad Autonoma de Madrid) Madrid 28049Spain

Influenza is an acute respiratory infection caused by influenza viruses(IFV),According to the World Health Organization(WHO),seasonal IFV epidemics result in approximately 3-5 million cases of severe illness,leading to about half a million deaths worldwide,along with severe economic losses and social ***,frequent mutations in IFV lead to a certain lag in vaccine development as well as resistance to existing antiviral ***,it is of great importance to develop anti-IFV drugs with high efficiency against wild-type and resistant strains,needed in the fight against current and future outbreaks caused by different IFV *** this review,we summarize general strategies used for the discovery and development of antiviral agents targeting multiple IFV strains(including those resistant to available drugs).Structure-based drug design,mechanism-based drug design,multivalent interaction-based drug design and drug repurposing are amongst the most relevant strategies that provide a framework for the development of antiviral drugs targeting IFV.

关键词： Influenza virus Drug design strategies Anti-drugresistance High efficiency Broad spectrum

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Song divergence indicates an unclear relationship between the Neotropical and Nearctic Horned Larks

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Avian Research 2021年第2期12卷 161-172页

作者： Jimmy Alexander Vargas-Puentes luis Alejandro arias-Sosa Carolina Ramos-Montaño Grupo Ecología de Organismos(GEO-UPTC) Escuela de Ciencias BiológicasUniversidad Pedagógica Y Tecnológica de ColombiaTunjaColombia

Background:Some studies have indicated that the Horned Larks(Eremophila alpestris)should be considered as a species *** it split into four species or clades and seven subclades based on genetic,morphological,and biogeographic ***,other aspects like song divergence have not been studied and several subspe-cies have not been evaluated,leading to important information gaps in this group of *** this work,we aimed to assess the differences in song traits and playback response between the Nearctic subclade and the Neotropical or Colombian subspecies ***:We compared six song traits between these groups and performed field playback experiments,to test the response of the Neotropical larks to both *** tested the difference in the variables for separate as well as by principal component analysis(PCA).Results:We found significant differences(p<0.05)in the individual song traits and the PCA analysis between the two ***,the PCA analysis showed a clearer divergence of the Neotropical songs in comparison to the Nearctic songs of different locations within North ***,the playback analysis showed a significantly lower response of *** to the songs of the Nearctic ***:Besides this song divergence,there are important ecological and biogeographic differences between the Neotropical and Nearctic Horned Larks,that indicate an unclear relationship between these two ***,further morphological and genetic studies are required to clarify the taxonomy of the Neotropical Horned Lark and define if they share the same evolutionary history as the other subspecies of the Nearctic subclade.

关键词： Birdsong Eremophila alpestris peregrina Song features Speciation Reproductive barrier

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The flowerpiercers interactions with a community of high Andean plants

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Avian Research 2021年第2期12卷 181-194页

作者： Jairo Andrés Cuta-Pineda luis Alejandro arias-Sosa Roxibell C.Pelayo Research Group“Grupo Ecología de Organismos(GEO-UPTC)” TunjaColom-bia Maestría en Ciencia Biológicas Universidad Pedagógica y Tecnológica de ColombiaTunjaColombia Instituto de Ciencias Ambientales y Ecológicas(ICAE) Universidad de Los AndesMéridaVenezuela

Background:Flowerpiercers(Diglossa)are traditionally considered as“parasites”of the pollination processes,as they can access the nectar without entering in contact with the reproductive structures of the ***,the effect of flowerpiercers seems to vary according to their behavior and the flower’s ***,in this work,we aimed to explore the floral characteristics that may determine the susceptibility to robbing and pollen transport by ***,we identified the potential types of interactions and studied interaction network ***:We collected the information of 16 ornithophilic plants regarding their floral traits and robbing ***,we captured 4 species of flowerpiercers and evaluated pollen transport(frequency and loads).We tested the correlation between floral traits,robbing frequency,and pollen ***,we used these variables in a cluster and principal component analyses to identify the potential types of ***,we analyzed and com-pared the structure of the plants-flowerpiercers interaction ***:Nectar production significantly influenced both nectar robbing and pollen *** the corolla length was only correlated to the robbing ***,we found that particular flowerpiercers species trans-ported higher loads of some plant pollen,which can be related to the differences in behavior and morphometric *** proposed the classification of five different types of plant-flowerpiercer interactions,that showed differ-ent potential mutualist or antagonist relations based on the affectation of nectar robbing and the service of pollen *** interaction networks consisted of 49 links,with 2.4 links per species,and presented indicators of a medium to high resilience,stability,and resistance(nestedness,connectance,and robustness).Also,the network presented medium to low specialization and substantial niche ***:The ecological role of

关键词： Diglossa Flower traits Nectar robbing Nectivorous birds Pollen transport Pollination

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Convex Variational Formulation with Smooth Coupling for Multicomponent Signal Decomposition and Recovery

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高等学校计算数学学报：英文版 2009年第4期2卷 485-508页

作者： luis M.Briceo-arias Patrick L.Combettes UPMC Universite Paris 06 Laboratoire Jacques-Louis Lions-UMR 7598 and Equipe Combinatoire et Optimisation-UMR 7090 UPMC Universite Paris 06 Laboratoire Jacques-Louis Lions-UMR 7598

A convex variational formulation is proposed to solve multicomponent signal processing problems in Hilbert *** cost function consists of a separable term, in which each component is modeled through its own potential,and of a coupling term, in which constraints on linear transformations of the components are penalized with smooth *** algorithm with guaranteed weak convergence to a solution to the problem is *** multicomponent signal decomposition and recovery applications are discussed.

关键词：信号分解变分形式耦合光滑多组分多分量信号空间处理希尔伯特

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A half century (1961-2011) of applying microsurgery to experimental liver research

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World Journal of Hepatology 2012年第7期4卷 199-208页

作者： Maria-Angeles Aller Natalia arias Isabel Prieto Salvador Agudo Carlos Gilsanz Laureano Lorente Jorge-luis arias Jaime arias Surgery I Department School of Medicine Complutense University of Madrid 28040 Madrid Spain Neurosciences Lab Psychobiology Department School of Psychology University of Oviedo 33003 Oviedo Spain Surgery Department La Paz Hospital School of Medicine Autonomous University of Madrid 28049 Madrid Spain General Surgery Unit Sudeste Hospital Arganda del Rey 28500 Madrid Spain

The development of microsurgery has been dependent on experimental animals. Microsurgery could be a very valuable technique to improve experimental models of liver diseases. Microdissection and microsutures are the two main microsurgical techniques that can be considered for classifying the experimental models developed for liver research in the rat. Partial portal vein ligation, extrahepatic cholestasis and hepatectomies are all models based on microdissection. On the other hand, in portacaval shunts, orthotopic liver transplantation and partial heterotopic liver transplantation, the microsuture techniques stand out. By reducing surgical complications, these microsurgical techniques allow for improving the resulting experimental models. If good experimental models for liver research are successfully developed, the results obtained from their study might be particularly useful in patients with liver disease. Therefore experimental liver microsurgery could be an invaluable way to translate laboratory data on liver research into new clinical diagnostic and therapeutic strategies.

关键词： Microsurgery Portacaval shunts Cholestasis Hepatectomies Liver transplantation Portal hypertension

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Effects of medium-and long-distance running on cardiac damage markers in amateur runners:a systematic review,meta-analysis,and metaregression

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Journal of Sport and Health Science 2021年第2期10卷 192-200页

作者： Jacobo A.Rubio-arias luis Andreu luis Manuel Martinez-Aranda Alejandro Martinez-Rodriguez Pedro Manonelles Domingo J.Ramos-Campo Faculty of Sport Catholic University of San Antonio(UCAM)Murcia 30107Spain LFE Research Group Department of Health and Human PerformanceFaculty of Physical Activity and Sport Science-INEFUniversidad Politecnica de MadridMadrid 28040Spain International Chair of Sports Medicine Catholic University of San Antonio(UCAM)Murcia 30107Spain Neuroscience of Human Movement Research Group(Neuromove) Catholic University of San Antonio(UCAM)Murcia 30107Spain Faculty of Sciences University of AlicanteAlicante 03690Spain

Background:To finish an endurance race,athletes perform a vigorous effort that induces the release of cardiac damage *** are several factors that can affect the total number of these markers,so the aim of this review was to analyze the effect of endurance running races on cardiac damage markers and to identify the factors that modify the levels of segregation of these cardiac damage ***:A systematic search of PubMed,Web of Science,and the Cochrane Library databases was *** analysis included studies where the acute effects of running races on cardiac damage markers(troponin I and troponin T)were analyzed,assessing the levels of these markers before and after the ***:The effects of running races on troponin I(mean difference=0.0381 ng/mL)and troponin T(mean difference=0.0256 ng/mL)levels were *** ages(R^(2)=14.4%,p=0.033)and body mass indexes(R^(2)=14.5%,p=0.045)of the athletes had a significant interaction with troponin *** addition,gender,mean speed,time to finish the race,and type of race can affect the level of cardiac damage ***:Endurance running races induce the release of cardiac-damage markers that remain elevated for at least 24 h after the *** addition,young male athletes with high body mass indexes who perform races combining long duration and moderate intensity(i.e.,marathons)release the highest levels of cardiac damage *** should take into consideration these results in the diagnosis and treatment of patients admitted to the hospital days after finishing endurance running races.

关键词： Endurance races Troponin I Troponin T Ultra-endurance

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Preparation and Characterization of Flexible, Transparent and Thermally Stable Aromatic Co-polyamides

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Chinese Journal of Polymer Science 2019年第2期37卷 136-141页

作者： José Antonio Tec-Sánchez Andrés Iván Oliva arias Manuel Aguilar-Vega Juan Valerio Cauich-Rodríguez José luis Santiago-García Unidad de Materiales Centro de Investigación Científica de Yucatán A. C. Centro de Investigación y de Estudios Avanzados del IPN Unidad Mérida Departamento de Física Aplicada

Two aromatic co-polyamides were synthesized combining two diacid monomers containing bulky pendant groups, 5-(9,10-dihydro-9,10-ethanoanthracene-11,12-dicarboximido)isophthalic acid(DEAIA) and 5-tert-butylisophthalic acid(TERT), with 4,4′-(hexafluoroisopropylidene)dianiline(HFA) or 2,3,5,6-tetramethyl-1,4-phenylenediamine(Durene) by direct polycondensation. The structures of the obtained aromatic co-polyamides were confirmed by FTIR, Raman and 1 H-NMR. The co-copolyamide films, DHTH and DDTD, exhibited rms-roughness values between 0.94 and 1.60 nm, respectively. Moreover, they presented good thermal stability up to300 °C. Young's moduli of the co-polyamide films were between 4.1 and 4.3 GPa. X-ray diffraction results showed that the co-polyamide films were amorphous due to the incorporation of both bulky pendant groups, tert-butyl and dibenzobarrelene. The combination of bulky pendant groups provided intrinsically transparent co-polyamide films with a transmittance higher than 88% in the range of 400-780 *** to these outstanding film and optical properties, they are suggested to be flexible substrates in applications for solar cell and other portable electronic devices.

关键词： Co-polyamides Flexible films Transmittance Thermal stability Polycondensation

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