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Discovery of N-benzyl hydroxypyridone carboxamides as a novel and potent antiviral chemotype against human cytomegalovirus (HCMV)

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Acta Pharmaceutica Sinica B 2022年第4期12卷 1671-1684页

作者： Sameera Senaweera Tiffany C.Edwards jayakanth Kankanala Yan Wang Rajkumar Lalji Sahani jiashu Xie robert J.Geraghty Zhengqiang Wang Center for Drug Design College of PharmacyUniversity of MinnesotaMinneapolisMN 55455USA Translational Medicine R&D Center Shenzhen Institutes of Advanced TechnologyChinese Academy of SciencesShenzhen 518055China

Current drugs for treating human cytomegalovirus(HCMV)infections are limited by resistance and treatment-associated toxicities.In developing mechanistically novel HCMV antivirals,we discovered an N-benzyl hydroxypyridone carboxamide antiviral hit(8a)inhibiting HCMV in submicromolar range.We describe herein the structure–activity relationship(SAR)for 8a,and the characterization of potent analogs for cytotoxicity/cytostatic property,the preliminary mechanism of action,and the absorption,distribution,metabolism and excretion(ADME)properties.The SAR revealed a few pharmacophore features conferring optimal antiviral profile,including the 5-OH,the N-1 benzyl,at least one–CH_(2)−in the linker,and a di-halogen substituted phenyl ring in the amide moiety.In the end,we identified numerous analogs with sub-micromolar antiviral potency and good selectivity index.The preliminary mechanism of action characterization used a pUL89-C biochemical endonuclease assay,a virus entry assay,a time-of-addition assay,and a compound withdrawal assay.ADME profiling measuring aqueous solubility,plasma and liver microsomal stability,and parallel artificial membrane permeability assay(PAMPA)permeability demonstrated largely favorable drug-like properties.Together,these studies validate the N-benzyl hydroxypyridone carboxamide as a viable chemotype for potent and mechanistically distinct antivirals against HCMV.

关键词： Human cytomegalovirus N-Benzyl hydroxypyridone carboxamides Structureeactivity relationship Mechanism of action

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The Orosirian(1800–2050 Ma)plate tectonic episode:Key for reconstructing the Proterozoic tectonic record

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Geoscience Frontiers 2023年第3期14卷 1-9页

作者： robert j.Stern Geosciences Dept. U Texas at DallasRichardsonTX 75083-0688United States

Eight lines of evidence indicate that the Orosirian Period in mid-Paleoproterozoic time was characterized by plate tectonics:ophiolites,low T/P metamorphism including eclogites,passive margin formation,tall mountains,paleomagnetic constraints,ore deposits,abundant S-type granites,and seismic images of paleo-subduction zones.This plate tectonic episode occurred about 1 billion years earlier than the present plate tectonic episode began in Neoproterozoic time.The two plate tectonic episodes bracket the‘Boring Billion’,which may have been a protracted single lid tectonic episode that began when the supercontinent Nuna or Columbia formed.Recognition of multiple lines of evidence for Orosirian plate tectonics demonstrates that Earth’s tectonic style can be reconstructed with some confidence back to at least Early Paleoproterozoic time,and thus the absence of compelling evidence for Mesoproterozoic plate tectonics is not obvious due to poor preservation.A tectono-magmatic lull2.3 Ga suggests an earlier episode of single lid tectonics.Evidence for two episodes of plate tectonics and two episodes of single lid tectonics indicates that Earth switched between single lid and plate tectonics multiple times during the last 2.4 Ga.

关键词： Plate tectonics Single lid tectonics Urey ratio Paleoproterozoic

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Wild rice research: Advancing plant science and food security

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Molecular Plant 2022年第4期15卷 563-565页

作者： robert j.Henry Queensland Alliance for Agriculture and Food Innovation University of QueenslandBrisbaneQLD 4072Australia ARC Centre of Excellence for Plant Success in Nature and Agriculture University of QueenslandBrisbaneQLD 4072Australia

Rice was domesticated in Asia(Oryza sativa)and Africa(Oryza glaberrima)from Oryza rufipogon and Oryza bathii,respectively.The Oryza genus has a pantropical distribution.The genetic diversity in Oryza provides an extensive gene pool to adapt rice to climate change and address future food security.The primary gene pool of domesticated rice includes species that are readily accessible for rice breeding due to ease of crossing,while more distant species are also sources of useful genes that can be recovered with greater difficulty(Figure 1).Advances in genomics and gene editing provide a path for use of this wider diversity.Studies of Oryza species also offer potential insights into rice biology that may be critical for ongoing rice food security.

关键词： sativa Oryza breeding

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高度难熔源区在俯冲起始形成伊豆-小笠原-马里亚纳岛弧中的意义

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Science Bulletin 2022年第2期67卷 119-121,M0003页

作者： Scott A.Whattam robert j.Stern Department of Geosciences King Fahd University of Petroleum and MineralsDhahran 31261Saudi Arabia Department of Geosciences University of Texas at DallasRichardsonTX 75083-0688USA

The ascendent theory that unifies the Earth Sciences is Plate Tectonics, a regime which is unique to Earth. Other convectively active, solid silicate bodies of our Solar System (Venus, Mars, and Io) are encased in a single deforming "lid";on these, multiple plates and hence plate motions do not exist [1]. As Earth’s tectonic plates are driven by the sinking of old and cold oceanic lithosphere at subduction zones, understanding how new subduction zones originate is vital for a complete plate tectonic theory. Proposed mechanisms of subduction initiation (SI) are controversial but can be either spontaneous, i.e., caused by forces originating at the SI site, or induced by ongoing plate motions [2].

关键词： Earth tectonic Solar

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Diagnosis and treatment of heart failure with preserved left ventricular ejection fraction

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World journal of Cardiology 2020年第1期12卷 7-25页

作者： robert j Henning College of Public Health University of South Florida

Nearly six million people in United States have heart failure.Fifty percent of these people have normal left ventricular(LV)systolic heart function but abnormal diastolic function due to increased LV myocardial stiffness.Most commonly,these patients are elderly women with hypertension,ischemic heart disease,atrial fibrillation,obesity,diabetes mellitus,renal disease,or obstructive lung disease.The annual mortality rate of these patients is 8%-12%per year.The diagnosis is based on the history,physical examination,laboratory data,echocardiography,and,when necessary,by cardiac catheterization.Patients with obesity,hypertension,atrial fibrillation,and volume overload require weight reduction,an exercise program,aggressive control of blood pressure and heart rate,and diuretics.Miniature devices inserted into patients for pulmonary artery pressure monitoring provide early warning of increased pulmonary pressure and congestion.If significant coronary heart disease is present,coronary revascularization should be considered.

关键词： Diastolic heart failure Myocardial stiffness Incomplete left ventricular relaxation Echocardiographic heart failure criteria Pulmonary artery pressure monitoring Drug treatment

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P2X7 receptor in skin biology and diseases

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World journal of Dermatology 2016年第2期5卷 72-83页

作者： Nicholas j.geraghty Debbie Watson Sam R Adhikary Ronald Sluyter School of Biological Sciences University of Wollongong Illawarra Health and Medical Research Institute

The P2X7 receptor is a trimeric ligand-gated cation channel present on immune and other cells. Activation of this receptor by its natural ligand extracellular adenosine triphosphate results in a variety of downstream responses, including the release of pro-inflammatory mediators and cell death. In normal skin, P2X7 is present on keratinocytes, Langerhans cells and fibroblasts, while the presence of this receptor on other cutaneous cells is mainly inferred from studies of equivalent cell types present in other tissues. Mast cells in normal skin however express negligible amounts of P2X7, which can be upregulated in cutaneous disease. This review discusses the potential significance of P2X7 in skin biology, and the role of this receptor in inflammatory skin disorders such as irritant and chronic dermatitis, psoriasis, graft-versus-host disease, as well is in wound healing, transplantation and skin cancer.

关键词： P2X7 receptor Purinergic receptor Extracellular adenosine triphosphate CD39 Skin biology Skin immune system

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Access to biodiversity for food production:Reconciling open access digital sequence information with access and benefit sharing

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Molecular Plant 2021年第5期14卷 701-704页

作者： Brad Sherman robert j.Henry ARC Centre of Excellence for Plant Success in Nature and Agriculture BrisbaneQLD 4072Australia ARC Centre of Excellence for Synthetic Biology University of QueenslandBrisbaneQLD 4072Australia

CHALLENGES TO EXiSTING LEGAL SCHEMES Over the last 40 years or so,a complex web of international legal agreements was developed that regulate the access,transfer,and use of plant genetic resources.These include the Convention on Biological Diversity(CBD),the Nagoya Protocol,and the International Treaty on Plant Genetic Resources(Figure 1).

关键词： Access Figure legal

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Ophiolites:Identification and tectonic significance in space and time

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Geoscience Frontiers 2023年第6期14卷 380-385页

作者： Kent C.Condie robert j.Stern Department of Earth&Environmental Science New Mexico Institute of Mining and TechnologySocorroNM 87801USA Geosciences Department University of Texas at DallasRichardsonTX 75080USA

Ophiolites are fragments of oceanic lithosphere that are produced at spreading centers at ocean ridges,back arc basins,or forearcs during subduction initiation,and are key indicators of plate tectonics.Although it is widely agreed that ophiolites are remnants of oceanic crust and associated depleted mantle preserved in orogens,the recognition of ophiolites and their tectonic significance is still a topic of discussion and disagreement.We propose that ophiolites can be recognized in the geologic record by some combination of genetically related pillow basalt,layered gabbro,sheeted dykes,podiform chromite,harzburgite or/and dunite.Mafic igneous rocks have either ocean-ridge basalt or immature oceanic arc basalt chemical compositions.Using a scoring system of 1–11 for ophiolite confidence level,scores of8 are considered confident,6–8 probable,andjormua and Purtuniq ophiolites at 2000–1950 Ma.Ophiolites do not become geographically widespread until after 900 Ma,and most ophiolites of all ages formed in a forearc(subduction initiation)tectonic setting.If ophiolite production requires plate tectonics,subduction must have begun at least locally by 2700 Ma but did not become widespread until after 2000 Ma.The abundance of ophiolites after 900 Ma may reflect better preservation of subduction-related ophiolites,or to an increasing global network of interconnected plates.Ophiolite frequency peaks in the geologic record partially reflect geographic regions where ophiolites have been extensively studied rather than monitoring the production rate of ophiolites,but the scarcity of>900 Ma ophiolites is probably real.

关键词： Ophiolite Plate tectonics Subduction initiation Forearc Ocean ridge Tectonic setting Supercontinent

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Extracellular vesicles and angiotensin-converting enzyme 2 in COVID-19 disease

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BIOCELL 2024年第1期48卷 1-8页

作者： YU LIU robert j.KASPER NATALIE j.S.CHOI Department of Family and Community Medicine Northwestern University Feinberg School of MedicineChicagoIllinois

Extracellular vesicles(EVs)are membranous vesicular structures released from almost all eukaryotic cell types under different physiological or pathological conditions.Growing evidence demonstrates that EVs can serve as mediators of intercellular communication between donor and recipient cells or microorganism-infected and noninfected cells.Coronavirus disease 2019(COVID-19)disease is caused by infection of the severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)of host cells in the respiratory system and various extra-pulmonary tissue/organs,resulting in complications of multiple organ systems.As the cell surface receptor,angiotensin-converting enzyme 2(ACE2)mediates cellular entry of SARS-CoV-2 into the host cells in patients with COVID-19.Recent studies have found that ACE2 can be released with EVs,which have been shown to interfere with the entry of the virus into host cells and thus may be involved in COVID-19 pathophysiology.In addition,ACE2,neprilysin(NEP),and thimet oligopeptidase(TOP)are the key enzymes that regulate angiotensin metabolism by converting angiotensin II or angiotensin I to angiotensin 1-7,the latter of which has protective effects in counterbalancing the harmful effects of angiotensin II in COVID-19 disease.This review summarizes the recent research progress regarding EV-associated ACE2,NEP,and TOP and the perspectives of their potential involvement in the pathophysiology of COVID-19 disease.

关键词： Extracellular vesicles COVID-19 Angiotensin converting enzyme 2 Thimet oligopeptidase

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Early Cretaceous subduction initiation beneath southern Tibet caused the northward flight of India

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Geoscience Frontiers 2020年第4期11卷 1123-1131页

作者： Haoyu Hu robert j.Stern Geosciences Department University of Texas at DallasRichardsonTX75083-0688USA

Collision between the Indian and Eurasian plates formed the ~2500 km long Yarlung Zangbo Suture Zone and produced the Himalaya mountains and Tibetan plateau.Here we offer a new explanation for tectonic events leading to this collision:that the northward flight of India was caused by an Early Cretaceous episode of subduction initiation on the southern margin of Tibet.Compiled data for ophiolites along the Yarlung Zangbo Suture Zone show restricted ages between 120 Ma and 130 Ma,and their supra-subduction zone affinities are best explained by seafloor spreading in what became the forearc of a north-dipping subduction zone on the southern margin of Tibet.The subsequent evolution of this new subduction zone is revealed by integrating data for arcrelated igneous rocks of the Lhasa terrane and Xigaze forearc basin deposits.Strong slab pull from this new subduction zone triggered the rifting of India from East Gondwana in Early Cretaceous time and pulled it northward to collide with Tibet in Early Paleogene time.

关键词： Cretaceous northward subduction

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