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Rev. Hosp. Ital. B. Aires (2004) ; 40(2): 63-75, jun. 2020. graf, ilus, tab
Article in Spanish | LILACS (Americas) | ID: covidwho-679089


El objetivo de este artículo es proporcionar una guía que sirva para la interpretación y seguimiento de los esfuerzos que se están desarrollando en todo el mundo con el objetivo de obtener una vacuna que pueda generar inmunidad contra el nuevo coronavirus SARS-CoV-2 de 2019, el agente causante de la enfermedad por coronavirus denominada COVID-19. Cinco meses después de haber sido detectada la enfermedad, ya hay 102 vacunas en distintos estadios de desarrollo, registradas por la Organización Mundial de la Salud (OMS), correspondientes a 8 plataformas vacunales con diferentes estrategias, y todos los días aparecen nuevas. Esto representará un enorme desafío de organismos internacionales, para la evaluación, comparación y selección de aquellas que cumplan con los criterios regulatorios indispensables de seguridad y eficacia y que, por otro lado, puedan ser producidas en cantidades suficientes para abastecer la demanda mundial. (AU)

The objective of this article is to provide a guide to help the interpretation and monitoring the efforts that are being carried out worldwide to obtain a vaccine that will be able to generate immunity against the new 2019 SARS-CoV-2 coronavirus, the viral agent causes the disease named COVID-19. Five months after the disease was detected, there are already 102 vaccines at different stages of development, registered by World Health Organization (WHO), corresponding to 8 vaccination platforms base on different strategies, and every day new ones appear. This will represent a huge challenge for international organizations, to evaluate, compare and selects those that will meet the essential regulatory criteria of safety and efficacy and that, would be able to be produced in enough quantities to supply the worldwide demand. Key words: SARS-Cov-2 vaccine, vaccine platform, COVID-19 strategy, attenuated virus, viral vector, viral proteins, viral DNA, viral RNA, nucleic acids, viral like particles, WHO. (AU)

Humans , Male , Female , Coronavirus Infections/therapy , SARS Virus/immunology , Pneumonia, Viral/therapy , DNA/therapeutic use , RNA/therapeutic use , Vaccines/therapeutic use , Nucleic Acids/therapeutic use , Protein S/immunology , Coronavirus Infections/virology , SARS Virus/physiology , SARS Virus/genetics , Disease Vectors
Theranostics ; 10(16): 7150-7162, 2020.
Article in English | MEDLINE | ID: covidwho-639991


In December 2019, a new coronavirus disease (COVID-19) outbreak occurred in Wuhan, China. Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), which is the seventh coronavirus known to infect humans, is highly contagious and has rapidly expanded worldwide since its discovery. Quantitative nucleic acid testing has become the gold standard for diagnosis and guiding clinical decisions regarding the use of antiviral therapy. However, the RT-qPCR assays targeting SARS-CoV-2 have a number of challenges, especially in terms of primer design. Primers are the pivotal components of a RT-qPCR assay. Once virus mutation and recombination occur, it is difficult to effectively diagnose viral infection by existing RT-qPCR primers. Some primers and probes have also been made available on the WHO website for reference. However, no previous review has systematically compared the previously reported primers and probes and described how to design new primers in the event of a new coronavirus infection. This review focuses on how primers and probes can be designed methodically and rationally, and how the sensitivity and specificity of the detection process can be improved. This brief review will be useful for the accurate diagnosis and timely treatment of the new coronavirus pneumonia.

Betacoronavirus/genetics , Coronavirus Infections/diagnosis , Pneumonia, Viral/diagnosis , RNA, Viral/genetics , RNA/genetics , Real-Time Polymerase Chain Reaction/methods , Base Sequence , Coronavirus Infections/epidemiology , Coronavirus Infections/virology , Drug Design , Genes, Viral , Humans , Nucleic Acid Conformation , Pandemics , Pneumonia, Viral/epidemiology , Pneumonia, Viral/virology , RNA/chemistry , RNA Probes/genetics , RNA, Viral/chemistry , Real-Time Polymerase Chain Reaction/statistics & numerical data , Sensitivity and Specificity , Theranostic Nanomedicine
J Struct Biol ; 211(2): 107548, 2020 08 01.
Article in English | MEDLINE | ID: covidwho-593332


We report the crystal structure of the SARS-CoV-2 putative primase composed of the nsp7 and nsp8 proteins. We observed a dimer of dimers (2:2 nsp7-nsp8) in the crystallographic asymmetric unit. The structure revealed a fold with a helical core of the heterotetramer formed by both nsp7 and nsp8 that is flanked with two symmetry-related nsp8 ß-sheet subdomains. It was also revealed that two hydrophobic interfaces one of approx. 1340 Å2 connects the nsp7 to nsp8 and a second one of approx. 950 Å2 connects the dimers and form the observed heterotetramer. Interestingly, analysis of the surface electrostatic potential revealed a putative RNA binding site that is formed only within the heterotetramer.

Betacoronavirus/chemistry , DNA Primase/chemistry , Viral Nonstructural Proteins/chemistry , Binding Sites , Crystallography, X-Ray , DNA Primase/metabolism , Models, Molecular , Multiprotein Complexes , Protein Conformation , Protein Multimerization , RNA/metabolism , Viral Nonstructural Proteins/metabolism
J Hematol Oncol ; 13(1): 43, 2020 05 04.
Article in English | MEDLINE | ID: covidwho-165275


The novel coronavirus (2019-nCoV) is an emerging causative agent that was first described in late December 2019 and causes a severe respiratory infection in humans. Notably, many of affected patients of COVID-19 were people with malignancies. Moreover, cancer has been identified as an individual risk factor for COVID-19. In addition, the expression of angiotensin converting enzyme 2 (ACE2), the receptor of COVID-19, were aberrantly expressed in many tumors. However, a systematic analysis of ACE2 aberration remained to be elucidated in human cancers. Here, we analyzed genetic alteration, RNA expression, and DNA methylation of ACE2 across over 30 tumors. Notably, overexpression of ACE2 have been observed in including colon adenocarcinoma (COAD), kidney renal papillary cell carcinoma (KIRP), pancreatic adenocarcinoma (PAAD), rectum adenocarcinoma (READ), stomach adenocarcinoma (STAD), and lung adenocarcinoma (LUAD). In addition, hypo DNA methylation of ACE2 has also been identified in most of these ACE2 highly expressed tumors. Conclusively, our study for the first time curated both genetic and epigenetic variations of ACE2 in human malignancies. Notably, because our study is a bioinformatics assay, further functional and clinical validation is warranted.

Betacoronavirus , Coronavirus Infections , Neoplasms/enzymology , Pandemics , Peptidyl-Dipeptidase A , Pneumonia, Viral , Receptors, Virus , Coronavirus Infections/enzymology , Coronavirus Infections/etiology , Coronavirus Infections/virology , DNA Methylation , DNA, Neoplasm/metabolism , Humans , Neoplasms/complications , Peptidyl-Dipeptidase A/biosynthesis , Peptidyl-Dipeptidase A/genetics , Pneumonia, Viral/enzymology , Pneumonia, Viral/etiology , Pneumonia, Viral/virology , RNA/biosynthesis , Receptors, Virus/biosynthesis , Receptors, Virus/genetics
J Biol Chem ; 295(15): 4773-4779, 2020 04 10.
Article in English | MEDLINE | ID: covidwho-1988


Antiviral drugs for managing infections with human coronaviruses are not yet approved, posing a serious challenge to current global efforts aimed at containing the outbreak of severe acute respiratory syndrome-coronavirus 2 (CoV-2). Remdesivir (RDV) is an investigational compound with a broad spectrum of antiviral activities against RNA viruses, including severe acute respiratory syndrome-CoV and Middle East respiratory syndrome (MERS-CoV). RDV is a nucleotide analog inhibitor of RNA-dependent RNA polymerases (RdRps). Here, we co-expressed the MERS-CoV nonstructural proteins nsp5, nsp7, nsp8, and nsp12 (RdRp) in insect cells as a part a polyprotein to study the mechanism of inhibition of MERS-CoV RdRp by RDV. We initially demonstrated that nsp8 and nsp12 form an active complex. The triphosphate form of the inhibitor (RDV-TP) competes with its natural counterpart ATP. Of note, the selectivity value for RDV-TP obtained here with a steady-state approach suggests that it is more efficiently incorporated than ATP and two other nucleotide analogs. Once incorporated at position i, the inhibitor caused RNA synthesis arrest at position i + 3. Hence, the likely mechanism of action is delayed RNA chain termination. The additional three nucleotides may protect the inhibitor from excision by the viral 3'-5' exonuclease activity. Together, these results help to explain the high potency of RDV against RNA viruses in cell-based assays.

Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Antiviral Agents/pharmacology , Middle East Respiratory Syndrome Coronavirus/enzymology , Nucleic Acid Synthesis Inhibitors/pharmacology , RNA Replicase/antagonists & inhibitors , Virus Replication/drug effects , Adenosine Monophosphate/chemistry , Adenosine Monophosphate/pharmacology , Alanine/chemistry , Alanine/pharmacology , Animals , Antiviral Agents/chemistry , Coronavirus/enzymology , Ebolavirus/enzymology , Gene Expression , Nucleic Acid Synthesis Inhibitors/chemistry , RNA , RNA Replicase/genetics , Sf9 Cells , Viral Nonstructural Proteins/genetics