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      Dissecting lipid metabolism alterations in SARS-CoV-2

      review-article
      a , 1 , b , c , 1 , d , e , f , a , *
      Progress in Lipid Research
      Elsevier Ltd.
      Lipid Metabolism, coronavirus, SARS-CoV-2, COVID-19, dyslipidaemia, AA, arachidonic acid, ACE2, angiotensin-converting enzyme 2, AUC, area under curve, COVID-19, coronavirus disease 19, cPLA2 α, cytosolic phospholipase A2α, CTD, C-terminal domain, DAGs, diacylglycerols, DHA, C22:6 docosahexaenoic acid, DIC, disseminated intravascular coagulation, DMV, double-membrane vesicles, DPA, C22: 5 docosapentaenoic acid, DVT, deep vein thrombosis, EBOV, Ebola virus, EPA, C20:5 eicosapentaenoic acid, ER, endoplasmic reticulum, ERGIC, ER-Golgi intermediate compartment, GM3, monosialodihexosyl ganglioside, HDL, high density lipoproteins, IDL, intermediate density lipoproteins, IFNα, interferon α, ISTH, International Society on Thrombosis and Haemostasis, LC-MS, liquid chromatography, LDs, lipid droplets, LMs, lipid mediators, LPA, lysophosphatidic acid, LPCs, glycerophosphocholines, LPLs, Lysophospholipids, LysoPC, lysophosphatidylcholine, MAE, microwave-assisted extraction, MALDI, matrix-assisted laser desorption/ionization, MCS, membrane contact site, MERS-CoV, Middle East respiratory syndrome coronavirus, MVB, multivesicular body, NEFA, non-esterified fatty acid, NET, neutrophil extracellular trap, NHC, National Health Commission, NPC1, receptor Niemann-Pick C1, NTD, N-terminal domain, ORF, open-reading frame, PAs, phosphatidic acids, PAF, platelet-activating factor, PCs, phosphatidylcholines, Pes, glycerophosphoethanolamines, PI3K, phosphoinositide 3-kinase, PLA2, phospholipase A2, plasmenyl-PC, plasmenyl phosphatidylcholine, PSTPIPP2, proline-serine-threonine phosphatase-interacting protein 2, PtdIns, Phosphoinositides, PtdIns3P, monophosphate phosphatidylinositol 3-phosphate, PtdIns(3,5)P2, bisphosphate phosphatidylinositol 3,5-bisphosphate, PUFAs, poly-unsaturated fatty acids, QqQ, triple quadrupoles, RBD, receptor-binding domain, RO, replication organelles, RvE3, resolvin E3, SARS-CoV, Severe Acute Respiratory Syndrome, SARS-CoV-2, Severe acute respiratory syndrome coronavirus 2, S protein, spike protein, S1P, sphingosine 1-phosphates, SMs, sphingomyelins, SPE, solid-phase extraction, SPME, solid-phase microextraction, SREBPs, sterol regulatory element-binding proteins, TAGs, triacylglycerols, TC, total cholesterol, TMPRSS2, type II transmembrane serine host cell protease, UAE, ultrasonic-assisted extraction, VLDL, very low-density lipoproteins, VTE, venous thromboembolism.

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          Abstract

          Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the COVID-19 pandemic that has infected over sixteen million people globally. There have been more than two million deaths recorded worldwide, with no end in sight until a vaccine is developed. Current research has centred on different aspects of the virus interaction with cell surface receptors, but more needs to be done to further understand its mechanism of action in order to develop a targeted therapy and a method to control the spread of the virus. Lipids play a crucial role throughout the viral life cycle, and viruses are known to exploit lipid signalling and synthesis to affect host cell lipidome. Emerging studies using untargeted metabolomic and lipidomic approaches are providing new insight into the host response to COVID-19 infection. Indeed, metabolomic and lipidomic approaches have identified numerous circulating lipids that directly correlate to the severity of the disease, making lipid metabolism a potential therapeutic target. Circulating lipids play a key function in the pathogenesis of the virus and exert an inflammatory response. A better knowledge of lipid metabolism in the host-pathogen interaction will provide valuable insights into viral pathogenesis and to develop novel therapeutic targets.

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          Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China

          Summary Background A recent cluster of pneumonia cases in Wuhan, China, was caused by a novel betacoronavirus, the 2019 novel coronavirus (2019-nCoV). We report the epidemiological, clinical, laboratory, and radiological characteristics and treatment and clinical outcomes of these patients. Methods All patients with suspected 2019-nCoV were admitted to a designated hospital in Wuhan. We prospectively collected and analysed data on patients with laboratory-confirmed 2019-nCoV infection by real-time RT-PCR and next-generation sequencing. Data were obtained with standardised data collection forms shared by WHO and the International Severe Acute Respiratory and Emerging Infection Consortium from electronic medical records. Researchers also directly communicated with patients or their families to ascertain epidemiological and symptom data. Outcomes were also compared between patients who had been admitted to the intensive care unit (ICU) and those who had not. Findings By Jan 2, 2020, 41 admitted hospital patients had been identified as having laboratory-confirmed 2019-nCoV infection. Most of the infected patients were men (30 [73%] of 41); less than half had underlying diseases (13 [32%]), including diabetes (eight [20%]), hypertension (six [15%]), and cardiovascular disease (six [15%]). Median age was 49·0 years (IQR 41·0–58·0). 27 (66%) of 41 patients had been exposed to Huanan seafood market. One family cluster was found. Common symptoms at onset of illness were fever (40 [98%] of 41 patients), cough (31 [76%]), and myalgia or fatigue (18 [44%]); less common symptoms were sputum production (11 [28%] of 39), headache (three [8%] of 38), haemoptysis (two [5%] of 39), and diarrhoea (one [3%] of 38). Dyspnoea developed in 22 (55%) of 40 patients (median time from illness onset to dyspnoea 8·0 days [IQR 5·0–13·0]). 26 (63%) of 41 patients had lymphopenia. All 41 patients had pneumonia with abnormal findings on chest CT. Complications included acute respiratory distress syndrome (12 [29%]), RNAaemia (six [15%]), acute cardiac injury (five [12%]) and secondary infection (four [10%]). 13 (32%) patients were admitted to an ICU and six (15%) died. Compared with non-ICU patients, ICU patients had higher plasma levels of IL2, IL7, IL10, GSCF, IP10, MCP1, MIP1A, and TNFα. Interpretation The 2019-nCoV infection caused clusters of severe respiratory illness similar to severe acute respiratory syndrome coronavirus and was associated with ICU admission and high mortality. Major gaps in our knowledge of the origin, epidemiology, duration of human transmission, and clinical spectrum of disease need fulfilment by future studies. Funding Ministry of Science and Technology, Chinese Academy of Medical Sciences, National Natural Science Foundation of China, and Beijing Municipal Science and Technology Commission.
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            A SARS-CoV-2 Protein Interaction Map Reveals Targets for Drug-Repurposing

            SUMMARY The novel coronavirus SARS-CoV-2, the causative agent of COVID-19 respiratory disease, has infected over 2.3 million people, killed over 160,000, and caused worldwide social and economic disruption 1,2 . There are currently no antiviral drugs with proven clinical efficacy, nor are there vaccines for its prevention, and these efforts are hampered by limited knowledge of the molecular details of SARS-CoV-2 infection. To address this, we cloned, tagged and expressed 26 of the 29 SARS-CoV-2 proteins in human cells and identified the human proteins physically associated with each using affinity-purification mass spectrometry (AP-MS), identifying 332 high-confidence SARS-CoV-2-human protein-protein interactions (PPIs). Among these, we identify 66 druggable human proteins or host factors targeted by 69 compounds (29 FDA-approved drugs, 12 drugs in clinical trials, and 28 preclinical compounds). Screening a subset of these in multiple viral assays identified two sets of pharmacological agents that displayed antiviral activity: inhibitors of mRNA translation and predicted regulators of the Sigma1 and Sigma2 receptors. Further studies of these host factor targeting agents, including their combination with drugs that directly target viral enzymes, could lead to a therapeutic regimen to treat COVID-19.
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              Structural basis of receptor recognition by SARS-CoV-2

              Summary A novel SARS-like coronavirus (SARS-CoV-2) recently emerged and is rapidly spreading in humans 1,2 . A key to tackling this epidemic is to understand the virus’s receptor recognition mechanism, which regulates its infectivity, pathogenesis and host range. SARS-CoV-2 and SARS-CoV recognize the same receptor - human ACE2 (hACE2) 3,4 . Here we determined the crystal structure of SARS-CoV-2 receptor-binding domain (RBD) (engineered to facilitate crystallization) in complex of hACE2. Compared with SARS-CoV RBD, a hACE2-binding ridge in SARS-CoV-2 RBD takes a more compact conformation; moreover, several residue changes in SARS-CoV-2 RBD stabilize two virus-binding hotspots at the RBD/hACE2 interface. These structural features of SARS-CoV-2 RBD enhance its hACE2-binding affinity. Additionally, we showed that RaTG13, a bat coronavirus closely related to SARS-CoV-2, also uses hACE2 as its receptor. The differences among SARS-CoV-2, SARS-CoV and RaTG13 in hACE2 recognition shed light on potential animal-to-human transmission of SARS-CoV-2. This study provides guidance for intervention strategies targeting receptor recognition by SARS-CoV-2.
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                Author and article information

                Journal
                Prog Lipid Res
                Prog Lipid Res
                Progress in Lipid Research
                Elsevier Ltd.
                0163-7827
                1873-2194
                8 February 2021
                8 February 2021
                : 101092
                Affiliations
                [a ]Metabolic Signalling Group, Curtin Medical School, Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia 6102, Australia
                [b ]Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
                [c ]Center for Translational Research on Autoimmune and Allergic Diseases, University of Piemonte Orientale, Novara, Italy
                [d ]Platelet Research Group, Perth Blood Institute, West Perth, WA 6005, Australia
                [e ]Western Australian Centre for Thrombosis and Haemostasis, Health Futures Institute, Murdoch University, Perth, WA 6150, Australia
                [f ]Curtin Medical School, Curtin Health and Innovation Research Institute, Faculty of Health Sciences, Curtin University, Perth, WA 6102, Australia
                Author notes
                [* ]Corresponding author at: Metabolic Signalling Group, Curtin Medical School, Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia 6102, Australia.
                [1]

                These authors contributed equally to this work.

                Article
                S0163-7827(21)00008-4 101092
                10.1016/j.plipres.2021.101092
                7869689
                33571544
                3d0b521b-47f2-4b29-97ca-daa3367c878e
                © 2021 Elsevier Ltd. All rights reserved.

                Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

                History
                : 30 October 2020
                : 23 January 2021
                : 26 January 2021
                Categories
                Review

                Biochemistry
                lipid metabolism,coronavirus,sars-cov-2,covid-19,dyslipidaemia,aa, arachidonic acid,ace2, angiotensin-converting enzyme 2,auc, area under curve,covid-19, coronavirus disease 19,cpla2 α, cytosolic phospholipase a2α,ctd, c-terminal domain,dags, diacylglycerols,dha, c22:6 docosahexaenoic acid,dic, disseminated intravascular coagulation,dmv, double-membrane vesicles,dpa, c22: 5 docosapentaenoic acid,dvt, deep vein thrombosis,ebov, ebola virus,epa, c20:5 eicosapentaenoic acid,er, endoplasmic reticulum,ergic, er-golgi intermediate compartment,gm3, monosialodihexosyl ganglioside,hdl, high density lipoproteins,idl, intermediate density lipoproteins,ifnα, interferon α,isth, international society on thrombosis and haemostasis,lc-ms, liquid chromatography,lds, lipid droplets,lms, lipid mediators,lpa, lysophosphatidic acid,lpcs, glycerophosphocholines,lpls, lysophospholipids,lysopc, lysophosphatidylcholine,mae, microwave-assisted extraction,maldi, matrix-assisted laser desorption/ionization,mcs, membrane contact site,mers-cov, middle east respiratory syndrome coronavirus,mvb, multivesicular body,nefa, non-esterified fatty acid,net, neutrophil extracellular trap,nhc, national health commission,npc1, receptor niemann-pick c1,ntd, n-terminal domain,orf, open-reading frame,pas, phosphatidic acids,paf, platelet-activating factor,pcs, phosphatidylcholines,pes, glycerophosphoethanolamines,pi3k, phosphoinositide 3-kinase,pla2, phospholipase a2,plasmenyl-pc, plasmenyl phosphatidylcholine,pstpipp2, proline-serine-threonine phosphatase-interacting protein 2,ptdins, phosphoinositides,ptdins3p, monophosphate phosphatidylinositol 3-phosphate,ptdins(3,5)p2, bisphosphate phosphatidylinositol 3,5-bisphosphate,pufas, poly-unsaturated fatty acids,qqq, triple quadrupoles,rbd, receptor-binding domain,ro, replication organelles,rve3, resolvin e3,sars-cov, severe acute respiratory syndrome,sars-cov-2, severe acute respiratory syndrome coronavirus 2,s protein, spike protein,s1p, sphingosine 1-phosphates,sms, sphingomyelins,spe, solid-phase extraction,spme, solid-phase microextraction,srebps, sterol regulatory element-binding proteins,tags, triacylglycerols,tc, total cholesterol,tmprss2, type ii transmembrane serine host cell protease,uae, ultrasonic-assisted extraction,vldl, very low-density lipoproteins,vte, venous thromboembolism.
                Biochemistry
                lipid metabolism, coronavirus, sars-cov-2, covid-19, dyslipidaemia, aa, arachidonic acid, ace2, angiotensin-converting enzyme 2, auc, area under curve, covid-19, coronavirus disease 19, cpla2 α, cytosolic phospholipase a2α, ctd, c-terminal domain, dags, diacylglycerols, dha, c22:6 docosahexaenoic acid, dic, disseminated intravascular coagulation, dmv, double-membrane vesicles, dpa, c22: 5 docosapentaenoic acid, dvt, deep vein thrombosis, ebov, ebola virus, epa, c20:5 eicosapentaenoic acid, er, endoplasmic reticulum, ergic, er-golgi intermediate compartment, gm3, monosialodihexosyl ganglioside, hdl, high density lipoproteins, idl, intermediate density lipoproteins, ifnα, interferon α, isth, international society on thrombosis and haemostasis, lc-ms, liquid chromatography, lds, lipid droplets, lms, lipid mediators, lpa, lysophosphatidic acid, lpcs, glycerophosphocholines, lpls, lysophospholipids, lysopc, lysophosphatidylcholine, mae, microwave-assisted extraction, maldi, matrix-assisted laser desorption/ionization, mcs, membrane contact site, mers-cov, middle east respiratory syndrome coronavirus, mvb, multivesicular body, nefa, non-esterified fatty acid, net, neutrophil extracellular trap, nhc, national health commission, npc1, receptor niemann-pick c1, ntd, n-terminal domain, orf, open-reading frame, pas, phosphatidic acids, paf, platelet-activating factor, pcs, phosphatidylcholines, pes, glycerophosphoethanolamines, pi3k, phosphoinositide 3-kinase, pla2, phospholipase a2, plasmenyl-pc, plasmenyl phosphatidylcholine, pstpipp2, proline-serine-threonine phosphatase-interacting protein 2, ptdins, phosphoinositides, ptdins3p, monophosphate phosphatidylinositol 3-phosphate, ptdins(3,5)p2, bisphosphate phosphatidylinositol 3,5-bisphosphate, pufas, poly-unsaturated fatty acids, qqq, triple quadrupoles, rbd, receptor-binding domain, ro, replication organelles, rve3, resolvin e3, sars-cov, severe acute respiratory syndrome, sars-cov-2, severe acute respiratory syndrome coronavirus 2, s protein, spike protein, s1p, sphingosine 1-phosphates, sms, sphingomyelins, spe, solid-phase extraction, spme, solid-phase microextraction, srebps, sterol regulatory element-binding proteins, tags, triacylglycerols, tc, total cholesterol, tmprss2, type ii transmembrane serine host cell protease, uae, ultrasonic-assisted extraction, vldl, very low-density lipoproteins, vte, venous thromboembolism.

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