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• A SARS-CoV-2 protein interaction map reveals targets for drug repurposing.Nature. 2020.
• COVID-19 and the cardiovascular system: implications for risk assessment, diagnosis, and treatment options.Cardiovasc Res. 2020.
• COVID-19: Immunology and treatment options.Clin Immunol. 2020.
• Histopathology and genetic susceptibility in COVID-19 pneumonia.Eur J Clin Invest. 2020.
• A Rapid Systematic Review of Clinical Trials Utilizing Chloroquine and Hydroxychloroquine as a Treatment for COVID-19.Acad Emerg Med. 2020.

• Format: Abstract

Nature. 2020 Apr 30. doi: 10.1038/s41586-020-2286-9. [Epub ahead of print]

A SARS-CoV-2 protein interaction map reveals targets for drug repurposing.

Gordon DE^1,2,3,4, Jang GM^1,2,3,4, Bouhaddou M^1,2,3,4, Xu J^1,2,3,4, Obernier K^1,2,3,4, White KM^5,6, O'Meara MJ⁷, Rezelj VV⁸, Guo JZ^1,2,3,4, Swaney DL^1,2,3,4, Tummino TA^1,2,9, Huettenhain R^1,2,3,4, Kaake RM^1,2,3,4, Richards AL^1,2,3,4, Tutuncuoglu B^1,2,3,4, Foussard H^1,2,3,4, Batra J^1,2,3,4, Haas K^1,2,3,4, Modak M^1,2,3,4, Kim M^1,2,3,4, Haas P^1,2,3,4, Polacco BJ^1,2,3,4, Braberg H^1,2,3,4, Fabius JM^1,2,3,4, Eckhardt M^1,2,3,4, Soucheray M^1,2,3,4, Bennett MJ^1,2,3,4, Cakir M^1,2,3,4, McGregor MJ^1,2,3,4, Li Q^1,2,3,4, Meyer B⁸, Roesch F⁸, Vallet T⁸, Mac Kain A⁸, Miorin L^5,6, Moreno E^5,6, Naing ZZC^1,2,3,4, Zhou Y^1,2,3,4, Peng S^1,2,9, Shi Y^1,2,4,10, Zhang Z^1,2,4,10, Shen W^1,2,4,10, Kirby IT^1,2,4,10, Melnyk JE^1,2,4,10, Chorba JS^1,2,4,10, Lou K^1,2,4,10, Dai SA^1,2,4,10, Barrio-Hernandez I¹¹, Memon D¹¹, Hernandez-Armenta C¹¹, Lyu J^1,2,9, Mathy CJP^1,2,12,13, Perica T^1,2,12, Pilla KB^1,2,12, Ganesan SJ^1,2,12, Saltzberg DJ^1,2,12, Rakesh R^1,2,12, Liu X^1,2,9, Rosenthal SB¹⁴, Calviello L^1,15, Venkataramanan S^1,15, Liboy-Lugo J^1,15, Lin Y^1,15, Huang XP¹⁶, Liu Y¹⁶, Wankowicz SA^1,2,10,17, Bohn M^1,2,9, Safari M^1,2,18, Ugur FS^1,2,4,9, Koh C⁸, Savar NS⁸, Tran QD⁸, Shengjuler D⁸, Fletcher SJ⁸, O'Neal MC¹⁹, Cai Y¹⁹, Chang JCJ¹⁹, Broadhurst DJ¹⁹, Klippsten S¹⁹, Sharp PP⁴, Wenzell NA^1,2,4, Kuzuoglu D^1,2,4,20,21, Wang HY^1,2,4, Trenker R^1,2,22, Young JM²³, Cavero DA^3,24, Hiatt J^3,25,24, Roth TL^3,25,24, Rathore U^3,24, Subramanian A^1,2,24, Noack J^1,2,24, Hubert M²⁶, Stroud RM^1,2,18, Frankel AD^1,2,18, Rosenberg OS^1,2,18,27, Verba KA^1,2,9, Agard DA^1,2,18, Ott M^1,2,3,27, Emerman M²⁸, Jura N^1,2,4,22, von Zastrow M^1,2,4,29, Verdin E^1,27,30, Ashworth A^1,2,20, Schwartz O²⁶, d'Enfert C³¹, Mukherjee S^1,2,24, Jacobson M^1,2,9, Malik HS²³, Fujimori DG^1,2,4,9, Ideker T^1,32, Craik CS^1,2,9,20, Floor SN^1,15,20, Fraser JS^1,2,12, Gross JD^1,2,9, Sali A^1,2,9,12, Roth BL¹⁶, Ruggero D^1,2,4,20,21, Taunton J^1,2,4, Kortemme T^1,2,12,13, Beltrao P^1,11, Vignuzzi M³³, García-Sastre A^34,35,36,37, Shokat KM^38,39,40,41, Shoichet BK^42,43,44, Krogan NJ^{45,46,47,48,49}.

Abstract

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.

PMID:

32353859

DOI:

10.1038/s41586-020-2286-9

• Cardiovasc Res. 2020 Apr 30. pii: cvaa106. doi: 10.1093/cvr/cvaa106. [Epub ahead of print]
  COVID-19 and the cardiovascular system: implications for risk assessment, diagnosis, and treatment options.
  
  Guzik TJ^1,2, Mohiddin SA^3,4, Dimarco A³, Patel V³, Savvatis K³, Marelli-Berg FM⁴, Madhur MS⁵, Tomaszewski M⁶, Maffia P^7,8, D'Acquisto F⁹, Nicklin SA¹, Marian AJ¹⁰, Nosalski R^1,2, Murray EC¹, Guzik B¹¹, Berry C¹, Touyz RM¹, Kreutz R¹², Wang DW¹³, Bhella D¹⁴, Sagliocco O¹⁵, Crea F¹⁶, Thomson EC^7,14,17, McInnes IB⁷.
  Author information
  Abstract
  

  The novel coronavirus disease (COVID-19) outbreak, caused by SARS-CoV-2, represents the greatest medical challenge in decades. We provide a comprehensive review of the clinical course of COVID-19, its comorbidities, and mechanistic considerations for future therapies. While COVID-19 primarily affects the lungs, causing interstitial pneumonitis and severe acute respiratory distress syndrome (ARDS), it also affects multiple organs, particularly the cardiovascular system. Risk of severe infection and mortality increase with advancing age and male sex. Mortality is increased by comorbidities: cardiovascular disease, hypertension, diabetes, chronic pulmonary disease, and cancer. The most common complications include arrhythmia (atrial fibrillation, ventricular tachyarrhythmia, and ventricular fibrillation), cardiac injury [elevated highly sensitive troponin I (hs-cTnI) and creatine kinase (CK) levels], fulminant myocarditis, heart failure, pulmonary embolism, and disseminated intravascular coagulation (DIC).
  
   Mechanistically, SARS-CoV-2, following proteolytic cleavage of its S protein by a serine protease, binds to the transmembrane angiotensin-converting enzyme 2 (ACE2) -a homologue of ACE-to enter type 2 pneumocytes, macrophages, perivascular pericytes, and cardiomyocytes. This may lead to myocardial dysfunction and damage, endothelial dysfunction, microvascular dysfunction, plaque instability, and myocardial infarction (MI). While ACE2 is essential for viral invasion, there is no evidence that ACE inhibitors or angiotensin receptor blockers (ARBs) worsen prognosis. Hence, patients should not discontinue their use. Moreover, renin-angiotensin-aldosterone system (RAAS) inhibitors might be beneficial in COVID-19.
   Initial immune and inflammatory responses induce a severe cytokine storm [interleukin (IL)-6, IL-7, IL-22, IL-17, etc.] during the rapid progression phase of COVID-19. Early evaluation and continued monitoring of cardiac damage (cTnI and NT-proBNP) and coagulation (D-dimer) after hospitalization may identify patients with cardiac injury and predict COVID-19 complications. Preventive measures (social distancing and social isolation) also increase cardiovascular risk. Cardiovascular considerations of therapies currently used, including remdesivir, chloroquine, hydroxychloroquine, tocilizumab, ribavirin, interferons, and lopinavir/ritonavir, as well as experimental therapies, such as human recombinant ACE2 (rhACE2), are discussed.
  

  Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.

  KEYWORDS:

  ACE2; Acute coronary syndrome; COVID-19; Cardiac; Endothelium; Microvascular; Myocardial infarction; Myocarditis; Vascular; Virus

  PMID:

  32352535

  DOI:

  10.1093/cvr/cvaa106

•