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2.
J Exp Med ; 218(12)2021 12 06.
Artículo en Inglés | MEDLINE | ID: mdl-34623376

RESUMEN

Broadly protective vaccines against SARS-related coronaviruses that may cause future outbreaks are urgently needed. The SARS-CoV-2 spike receptor-binding domain (RBD) comprises two regions, the core-RBD and the receptor-binding motif (RBM); the former is structurally conserved between SARS-CoV-2 and SARS-CoV. Here, in order to elicit humoral responses to the more conserved core-RBD, we introduced N-linked glycans onto RBM surfaces of the SARS-CoV-2 RBD and used them as immunogens in a mouse model. We found that glycan addition elicited higher proportions of the core-RBD-specific germinal center (GC) B cells and antibody responses, thereby manifesting significant neutralizing activity for SARS-CoV, SARS-CoV-2, and the bat WIV1-CoV. These results have implications for the design of SARS-like virus vaccines.


Asunto(s)
Anticuerpos Antivirales/inmunología , Anticuerpos ampliamente neutralizantes/inmunología , COVID-19/inmunología , Polisacáridos/inmunología , Virus del SRAS/inmunología , SARS-CoV-2/inmunología , Glicoproteína de la Espiga del Coronavirus/inmunología , Secuencias de Aminoácidos , Animales , COVID-19/genética , COVID-19/prevención & control , Vacunas contra la COVID-19/genética , Vacunas contra la COVID-19/inmunología , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Polisacáridos/genética , Dominios Proteicos , Virus del SRAS/genética , SARS-CoV-2/genética , Glicoproteína de la Espiga del Coronavirus/genética
3.
J Med Case Rep ; 15(1): 505, 2021 Oct 08.
Artículo en Inglés | MEDLINE | ID: mdl-34625101

RESUMEN

BACKGROUND: The clinical presentation of severe acute respiratory syndrome coronavirus-2 infection is highly variable from asymptomatic infection to fulminant disease. The reasons for the variation are only starting to unravel, with risk factors including age and certain comorbidities as well as genetic defects causing immunological perturbations in the interferon pathways. CASE PRESENTATION: We report the case of an otherwise healthy Caucasian man, who at ages 60 and 64 years suffered from severe H1N1 influenza virus infection and severe acute respiratory syndrome coronavirus-2 infections, respectively. In both cases, there were acute kidney impairment and the need for intensive care unit admission as well as mechanical ventilation. Fortunately, after both infections there was full clinical recovery. The severity of the infections indicates an underlying impairment in the ability to control these kinds of infections. Challenge of patient peripheral blood mononuclear cells showed impaired type I and III antiviral interferon responses and reduced interferon-stimulated gene expression. However, despite investigation of patient samples by whole exome sequencing and enzyme-linked immunosorbent assay, no known disease-causing genetic variants related to interferon pathways were found, nor were interferon autoantibodies demonstrated. Thus, any underlying immunological cause of this unusual susceptibility to severe viral infections remains unresolved. CONCLUSION: The patient experienced very similar severe clinical pictures triggered by H1N1 and severe acute respiratory syndrome coronavirus-2 infections, indicating an underlying inability to contain these infections. We were unable to show that the patient had any of the currently known types of immune incompetence but identified genetic changes possibly contributing to the severe course of both infections. Further analyses to delineate contribution factors are needed.


Asunto(s)
COVID-19 , Subtipo H1N1 del Virus de la Influenza A , Virus del SRAS , Humanos , Leucocitos Mononucleares , Masculino , Persona de Mediana Edad , SARS-CoV-2
4.
Autoimmun Rev ; 20(11): 102941, 2021 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-34508917

RESUMEN

Although vaccination represents the most promising way to stop or contain the coronavirus disease 2019 (COVID-19) pandemic and safety and effectiveness of available vaccines were proven, a small number of individuals who received anti-SARS-CoV-2 vaccines developed a prothrombotic syndrome. Vaccine-induced immune thrombotic thrombocytopenia (VITT) can be triggered by the adenoviral vector-based vaccine, whereas lipid nanoparticle-mRNA-based vaccines can induce rare cases of deep vein thrombosis (DVT). Although the main pathogenic mechanisms behind this rare phenomenon have not yet been identified, both host and vaccine factors might be involved, with pathology at least in part being related to the vaccine-triggered autoimmune reaction. In this review, we are considering some aspects related to pathogenesis, major risk factors, as well as peculiarities of diagnosis and treatment of this rare condition.


Asunto(s)
COVID-19 , Virus del SRAS , Vacunas Virales , Autoinmunidad , Vacunas contra la COVID-19 , Humanos , SARS-CoV-2 , Vacunación/efectos adversos
5.
PLoS One ; 16(9): e0257965, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34587192

RESUMEN

Many important questions remain regarding severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the viral pathogen responsible for COVID-19. These questions include the mechanisms explaining the high percentage of asymptomatic but highly infectious individuals, the wide variability in disease susceptibility, and the mechanisms of long-lasting debilitating effects. Bioinformatic analysis of four coronavirus datasets representing previous outbreaks (SARS-CoV-1 and MERS-CoV), as well as SARS-CoV-2, revealed evidence of diverse host factors that appear to be coopted to facilitate virus-induced suppression of interferon-induced innate immunity, promotion of viral replication and subversion and/or evasion of antiviral immune surveillance. These host factors merit further study given their postulated roles in COVID-19-induced loss of smell and brain, heart, vascular, lung, liver, and gut dysfunction.


Asunto(s)
COVID-19/tratamiento farmacológico , COVID-19/epidemiología , SARS-CoV-2/efectos de los fármacos , Antivirales/uso terapéutico , COVID-19/metabolismo , Infecciones por Coronavirus/epidemiología , Bases de Datos Factuales , Interacciones Huésped-Patógeno , Humanos , Evasión Inmune/inmunología , Inmunidad Innata/inmunología , Coronavirus del Síndrome Respiratorio de Oriente Medio/efectos de los fármacos , Coronavirus del Síndrome Respiratorio de Oriente Medio/patogenicidad , Virus del SRAS/efectos de los fármacos , Virus del SRAS/patogenicidad , SARS-CoV-2/patogenicidad , Síndrome Respiratorio Agudo Grave/epidemiología , Replicación Viral/efectos de los fármacos
6.
Biosci Rep ; 41(9)2021 09 30.
Artículo en Inglés | MEDLINE | ID: mdl-34519332

RESUMEN

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused the global pandemic of the Coronavirus disease in late 2019 (COVID-19). Vaccine development efforts have predominantly been aimed at 'Extra-viral' Spike (S) protein as vaccine vehicles, but there are concerns regarding 'viral immune escape' since multiple mutations may enable the mutated virus strains to escape from immunity against S protein. The 'Intra-viral' Nucleocapsid (N-protein) is relatively conserved among mutant strains of coronaviruses during spread and evolution. Herein, we demonstrate novel vaccine candidates against SARS-CoV-2 by using the whole conserved N-protein or its fragment/peptides. Using ELISA assay, we showed that high titers of specific anti-N antibodies (IgG, IgG1, IgG2a, IgM) were maintained for a reasonably long duration (> 5 months), suggesting that N-protein is an excellent immunogen to stimulate host immune system and robust B-cell activation. We synthesized three peptides located at the conserved regions of N-protein among CoVs. One peptide showed as a good immunogen for vaccination as well. Cytokine arrays on post-vaccination mouse sera showed progressive up-regulation of various cytokines such as IFN-γ and CCL5, suggesting that TH1 associated responses are also stimulated. Furthermore, vaccinated mice exhibited an elevated memory T cells population. Here, we propose an unconventional vaccine strategy targeting the conserved N-protein as an alternative vaccine target for coronaviruses. Moreover, we generated a mouse monoclonal antibody specifically against an epitope shared between SARS-CoV and SARS-CoV-2, and we are currently developing the First-in-Class humanized anti-N-protein antibody to potentially treat patients infected by various CoVs in the future.


Asunto(s)
Anticuerpos Antivirales/sangre , Vacunas contra la COVID-19/inmunología , COVID-19/prevención & control , Proteínas de la Nucleocápside de Coronavirus/inmunología , Animales , Anticuerpos Monoclonales de Origen Murino , Anticuerpos Antivirales/inmunología , COVID-19/inmunología , COVID-19/virología , Vacunas contra la COVID-19/administración & dosificación , Vacunas contra la COVID-19/genética , Proteínas de la Nucleocápside de Coronavirus/genética , Epítopos/inmunología , Humanos , Evasión Inmune , Inmunogenicidad Vacunal , Ratones , Modelos Animales , Pandemias/prevención & control , Virus del SRAS/genética , Virus del SRAS/inmunología , SARS-CoV-2/genética , SARS-CoV-2/inmunología , Homología de Secuencia de Aminoácido , Glicoproteína de la Espiga del Coronavirus/inmunología , Células TH1/inmunología , Vacunas de Subunidad/administración & dosificación , Vacunas de Subunidad/genética , Vacunas de Subunidad/inmunología
7.
Biosensors (Basel) ; 11(9)2021 Aug 28.
Artículo en Inglés | MEDLINE | ID: mdl-34562891

RESUMEN

The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease-19 (COVID-19), has severely influenced public health and economics. For the detection of SARS-CoV-2, clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR associated protein (Cas)-based assays have been emerged because of their simplicity, sensitivity, specificity, and wide applicability. Herein, we have developed a CRISPR-Cas12-based assay for the detection of SARS-CoV-2. In the assay, the target amplicons are produced by isothermal reverse transcription recombinase polymerase amplification (RT-RPA) and recognized by a CRISPR-Cas12a/guide RNA (gRNA) complex that is coupled with the collateral cleavage activity of fluorophore-tagged probes, allowing either a fluorescent measurement or naked-eye detection on a lateral flow paper strip. This assay enables the sensitive detection of SARS-CoV-2 at a low concentration of 10 copies per sample. Moreover, the reliability of the method is verified by using nasal swabs and sputum of COVID-19 patients. We also proved that the current assay can be applied to other viruses, such as Middle East respiratory syndrome coronavirus (MERS-CoV) and severe acute respiratory syndrome coronavirus (SARS-CoV), with no major changes to the basic scheme of testing. It is anticipated that the CRISPR-Cas12-based assay has the potential to serve as a point-of-care testing (POCT) tool for a wide range of infectious viruses.


Asunto(s)
Proteínas Bacterianas/metabolismo , Proteínas Asociadas a CRISPR/metabolismo , Endodesoxirribonucleasas/metabolismo , Coronavirus del Síndrome Respiratorio de Oriente Medio/aislamiento & purificación , Virus del SRAS/aislamiento & purificación , SARS-CoV-2/aislamiento & purificación , Virosis/diagnóstico , Sistemas CRISPR-Cas , Colorantes Fluorescentes/química , Humanos , Coronavirus del Síndrome Respiratorio de Oriente Medio/genética , Nariz/virología , Pruebas en el Punto de Atención , ARN Guia/química , ARN Guia/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Virus del SRAS/genética , SARS-CoV-2/genética , Sensibilidad y Especificidad , Esputo/virología
8.
Cladistics ; 37(5): 461-488, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-34570933

RESUMEN

The severe acute respiratory syndrome coronavirus (SARS-CoV) emerged in humans in 2002. Despite reports showing Chiroptera as the original animal reservoir of SARS-CoV, many argue that Carnivora-hosted viruses are the most likely origin. The emergence of the Middle East respiratory syndrome coronavirus (MERS-CoV) in 2012 also involves Chiroptera-hosted lineages. However, factors such as the lack of comprehensive phylogenies hamper our understanding of host shifts once MERS-CoV emerged in humans and Artiodactyla. Since 2019, the origin of SARS-CoV-2, causative agent of coronavirus disease 2019 (COVID-19), added to this episodic history of zoonotic transmission events. Here we introduce a phylogenetic analysis of 2006 unique and complete genomes of different lineages of Orthocoronavirinae. We used gene annotations to align orthologous sequences for total evidence analysis under the parsimony optimality criterion. Deltacoronavirus and Gammacoronavirus were set as outgroups to understand spillovers of Alphacoronavirus and Betacoronavirus among ten orders of animals. We corroborated that Chiroptera-hosted viruses are the sister group of SARS-CoV, SARS-CoV-2 and MERS-related viruses. Other zoonotic events were qualified and quantified to provide a comprehensive picture of the risk of coronavirus emergence among humans. Finally, we used a 250 SARS-CoV-2 genomes dataset to elucidate the phylogenetic relationship between SARS-CoV-2 and Chiroptera-hosted coronaviruses.


Asunto(s)
Quirópteros/virología , Interacciones Huésped-Patógeno/fisiología , Coronavirus del Síndrome Respiratorio de Oriente Medio/fisiología , Filogenia , Virus del SRAS/fisiología , SARS-CoV-2/fisiología , Animales , Genoma Viral , Humanos , Funciones de Verosimilitud , Pangolines/virología , Recombinación Genética/genética , Glicoproteína de la Espiga del Coronavirus/metabolismo
10.
N Engl J Med ; 385(15): 1401-1406, 2021 10 07.
Artículo en Inglés | MEDLINE | ID: mdl-34407341

RESUMEN

Emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern pose a challenge to the effectiveness of current vaccines. A vaccine that could prevent infection caused by known and future variants of concern as well as infection with pre-emergent sarbecoviruses (i.e., those with potential to cause disease in humans in the future) would be ideal. Here we provide data showing that potent cross-clade pan-sarbecovirus neutralizing antibodies are induced in survivors of severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1) infection who have been immunized with the BNT162b2 messenger RNA (mRNA) vaccine. The antibodies are high-level and broad-spectrum, capable of neutralizing not only known variants of concern but also sarbecoviruses that have been identified in bats and pangolins and that have the potential to cause human infection. These findings show the feasibility of a pan-sarbecovirus vaccine strategy. (Funded by the Singapore National Research Foundation and National Medical Research Council.).


Asunto(s)
Anticuerpos Antivirales/sangre , Anticuerpos ampliamente neutralizantes/sangre , Vacunas contra la COVID-19/inmunología , COVID-19/inmunología , Virus del SRAS/inmunología , SARS-CoV-2/inmunología , Síndrome Respiratorio Agudo Grave/inmunología , Linfocitos B , Humanos , Inmunogenicidad Vacunal , Filogenia , Virus del SRAS/genética , SARS-CoV-2/genética , Sobrevivientes
12.
Mar Drugs ; 19(8)2021 Jul 26.
Artículo en Inglés | MEDLINE | ID: mdl-34436255

RESUMEN

Over 182 million confirmed cases of COVID-19 and more than 4 million deaths have been reported to date around the world. It is essential to identify broad-spectrum antiviral agents that may prevent or treat infections by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) but also by other coronaviruses that may jump the species barrier in the future. We evaluated the antiviral selectivity of griffithsin and sulfated and non-sulfated polysaccharides against SARS-CoV-1 and SARS-CoV-2 using a cytotoxicity assay and a cell-based pseudoviral model. The half-maximal cytotoxic concentration (CC50) and half-maximal effective concentration (EC50) were determined for each compound, using a dose-response-inhibition analysis on GraphPad Prism v9.0.2 software (San Diego, CA, USA). The therapeutic index (TI = CC50/EC50) was calculated for each compound. The potential synergistic, additive, or antagonistic effect of different compound combinations was determined by CalcuSyn v1 software (Biosoft, Cambridge, UK), which estimated the combination index (CI) values. Iota and lambda carrageenan showed the most potent antiviral activity (EC50 between 3.2 and 7.5 µg/mL). Carrageenan and griffithsin combinations exhibited synergistic activity (EC50 between 0.2 and 3.8 µg/mL; combination index <1), including against recent SARS-CoV-2 mutations. The griffithsin and carrageenan combination is a promising candidate to prevent or treat infections by SARS-CoV-1 and SARS-CoV-2.


Asunto(s)
Antivirales/farmacología , Carragenina/farmacología , Lectinas de Plantas/farmacología , Virus del SRAS/efectos de los fármacos , SARS-CoV-2/efectos de los fármacos , COVID-19/tratamiento farmacológico , COVID-19/virología , Sinergismo Farmacológico , Células HeLa , Humanos , Modelos Biológicos , Polisacáridos/farmacología
13.
Bioorg Med Chem ; 46: 116301, 2021 09 15.
Artículo en Inglés | MEDLINE | ID: mdl-34332853

RESUMEN

Severe Acute Respiratory Syndrome (SARS) is a severe febrile respiratory disease caused by the beta genus of human coronavirus, known as SARS-CoV. Last year, 2019-n-CoV (COVID-19) was a global threat for everyone caused by the outbreak of SARS-CoV-2. 3CLpro, chymotrypsin-like protease, is a major cysteine protease that substantially contributes throughout the viral life cycle of SARS-CoV and SARS-CoV-2. It is a prospective target for the development of SARS-CoV inhibitors by applying a repurposing strategy. This review focuses on a detailed overview of the chemical synthesis and computational chemistry perspectives of peptidomimetic inhibitors (PIs) and small-molecule inhibitors (SMIs) targeting viral proteinase discovered from 2004 to 2020. The PIs and SMIs are one of the primary therapeutic inventions for SARS-CoV. The journey of different analogues towards the evolution of SARS-CoV 3CLpro inhibitors and complete synthetic preparation of nineteen derivatives of PIs and ten derivatives of SMIs and their computational chemistry perspectives were reviewed. From each class of derivatives, we have identified and highlighted the most compelling PIs and SMIs for SARS-CoV 3CLpro. The protein-ligand interaction of 29 inhibitors were also studied that involved with the 3CLpro inhibition, and the frequent amino acid residues of the protease were also analyzed that are responsible for the interactions with the inhibitors. This work will provide an initiative to encourage further research for the development of effective and drug-like 3CLpro inhibitors against coronaviruses in the near future.


Asunto(s)
Antivirales/farmacología , Proteasas 3C de Coronavirus/antagonistas & inhibidores , Inhibidores de Cisteína Proteinasa/farmacología , Peptidomiméticos/farmacología , Virus del SRAS/efectos de los fármacos , Animales , Antivirales/síntesis química , Línea Celular Tumoral , Inhibidores de Cisteína Proteinasa/síntesis química , Humanos , Peptidomiméticos/síntesis química , Virus del SRAS/enzimología , SARS-CoV-2/enzimología
14.
Viruses ; 13(8)2021 08 15.
Artículo en Inglés | MEDLINE | ID: mdl-34452480

RESUMEN

We compared the electrostatic properties of the spike proteins (S-proteins) of three coronaviruses, SARS-CoV, MERS-CoV, and SARS-CoV-2, and their interactions with photosensitizers (PSs), octacationic octakis(cholinyl)zinc phthalocyanine (Zn-PcChol8+) and monocationic methylene blue (MB). We found a major common PS binding site at the connection of the S-protein stalk and head. The molecules of Zn-PcChol8+ and MB also form electrostatic encounter complexes with large area of negative electrostatic potential at the head of the S-protein of SARS-CoV-2, between fusion protein and heptad repeat 1 domain. The top of the SARS-CoV spike head demonstrates a notable area of electrostatic contacts with Zn-PcChol8+ and MB that corresponds to the N-terminal domain. The S-protein protomers of SARS-CoV-2 in "open" and "closed" conformations demonstrate different ability to attract PS molecules. In contrast with Zn-PcChol8+, MB possesses the ability to penetrate inside the pocket formed as a result of SARS-CoV-2 receptor binding domain transition into the "open" state. The existence of binding site for cationic PSs common to the S-proteins of SARS-CoV, SARS-CoV-2, and MERS-CoV creates prospects for the wide use of this type of PSs to combat the spread of coronaviruses.


Asunto(s)
Indoles/metabolismo , Coronavirus del Síndrome Respiratorio de Oriente Medio/química , Compuestos Organometálicos/metabolismo , Fármacos Fotosensibilizantes/metabolismo , Glicoproteína de la Espiga del Coronavirus/metabolismo , Sitios de Unión , Indoles/química , Azul de Metileno/metabolismo , Modelos Moleculares , Simulación de Dinámica Molecular , Compuestos Organometálicos/química , Conformación Proteica , Dominios Proteicos , Subunidades de Proteína/química , Virus del SRAS/química , SARS-CoV-2/química , Glicoproteína de la Espiga del Coronavirus/química , Electricidad Estática
15.
Viruses ; 13(8)2021 08 18.
Artículo en Inglés | MEDLINE | ID: mdl-34452503

RESUMEN

Recent outbreaks of zoonotic coronaviruses, such as Middle East respiratory syndrome coronavirus (MERS-CoV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), have caused tremendous casualties and great economic shock. Although some repurposed drugs have shown potential therapeutic efficacy in clinical trials, specific therapeutic agents targeting coronaviruses have not yet been developed. During coronavirus replication, a replicase gene cluster, including RNA-dependent RNA polymerase (RdRp), is alternatively translated via a process called -1 programmed ribosomal frameshift (-1 PRF) by an RNA pseudoknot structure encoded in viral RNAs. The coronavirus frameshifting has been identified previously as a target for antiviral therapy. In this study, the frameshifting efficiencies of MERS-CoV, SARS-CoV and SARS-CoV-2 were determined using an in vitro -1 PRF assay system. Our group has searched approximately 9689 small molecules to identify potential -1 PRF inhibitors. Herein, we found that a novel compound, 2-(5-acetylthiophen-2yl)furo[2,3-b]quinoline (KCB261770), inhibits the frameshifting of MERS-CoV and effectively suppresses viral propagation in MERS-CoV-infected cells. The inhibitory effects of 87 derivatives of furo[2,3-b]quinolines were also examined showing less prominent inhibitory effect when compared to compound KCB261770. We demonstrated that KCB261770 inhibits the frameshifting without suppressing cap-dependent translation. Furthermore, this compound was able to inhibit the frameshifting, to some extent, of SARS-CoV and SARS-CoV-2. Therefore, the novel compound 2-(5-acetylthiophen-2yl)furo[2,3-b]quinoline may serve as a promising drug candidate to interfere with pan-coronavirus frameshifting.


Asunto(s)
Antivirales/farmacología , Sistema de Lectura Ribosómico/efectos de los fármacos , Coronavirus del Síndrome Respiratorio de Oriente Medio/efectos de los fármacos , Quinolinas/farmacología , Virus del SRAS/efectos de los fármacos , SARS-CoV-2/efectos de los fármacos , Células A549 , Animales , Línea Celular , Sistema de Lectura Ribosómico/fisiología , Humanos , Coronavirus del Síndrome Respiratorio de Oriente Medio/genética , Coronavirus del Síndrome Respiratorio de Oriente Medio/fisiología , Virus del SRAS/genética , Virus del SRAS/fisiología , SARS-CoV-2/genética , SARS-CoV-2/fisiología , Bibliotecas de Moléculas Pequeñas , Zoonosis Virales/virología , Replicación Viral/efectos de los fármacos
16.
Viruses ; 13(8)2021 08 23.
Artículo en Inglés | MEDLINE | ID: mdl-34452529

RESUMEN

An escalating pandemic of the novel SARS-CoV-2 virus is impacting global health, and effective antivirals are needed. Umifenovir (Arbidol) is an indole-derivative molecule, licensed in Russia and China for prophylaxis and treatment of influenza and other respiratory viral infections. It has been shown that umifenovir has broad spectrum activity against different viruses. We evaluated the sensitivity of different coronaviruses, including the novel SARS-CoV-2 virus, to umifenovir using in vitro assays. Using a plaque assay, we revealed an antiviral effect of umifenovir against seasonal HCoV-229E and HCoV-OC43 coronaviruses in Vero E6 cells, with estimated 50% effective concentrations (EC50) of 10.0 ± 0.5 µM and 9.0 ± 0.4 µM, respectively. Umifenovir at 90 µM significantly suppressed plaque formation in CMK-AH-1 cells infected with SARS-CoV. Umifenovir also inhibited the replication of SARS-CoV-2 virus, with EC50 values ranging from 15.37 ± 3.6 to 28.0 ± 1.0 µM. In addition, 21-36 µM of umifenovir significantly suppressed SARS-CoV-2 virus titers (≥2 log TCID50/mL) in the first 24 h after infection. Repurposing of antiviral drugs is very helpful in fighting COVID-19. A safe, pan-antiviral drug such as umifenovir could be extremely beneficial in combating the early stages of a viral pandemic.


Asunto(s)
Antivirales/farmacología , Coronavirus Humano 229E/efectos de los fármacos , Coronavirus Humano OC43/efectos de los fármacos , Indoles/farmacología , Virus del SRAS/efectos de los fármacos , SARS-CoV-2/efectos de los fármacos , Animales , Antivirales/administración & dosificación , Supervivencia Celular/efectos de los fármacos , Chlorocebus aethiops , Coronavirus Humano 229E/fisiología , Coronavirus Humano OC43/fisiología , Efecto Citopatogénico Viral/efectos de los fármacos , Humanos , Indoles/administración & dosificación , Pruebas de Sensibilidad Microbiana , Virus del SRAS/fisiología , SARS-CoV-2/fisiología , Células Vero , Carga Viral/efectos de los fármacos , Ensayo de Placa Viral , Replicación Viral/efectos de los fármacos
17.
Sci Rep ; 11(1): 17365, 2021 08 30.
Artículo en Inglés | MEDLINE | ID: mdl-34462471

RESUMEN

The SARS-CoV-2 pandemic prompts evaluation of recombination in human coronavirus (hCoV) evolution. We undertook recombination analyses of 158,118 public seasonal hCoV, SARS-CoV-1, SARS-CoV-2 and MERS-CoV genome sequences using the RDP4 software. We found moderate evidence for 8 SARS-CoV-2 recombination events, two of which involved the spike gene, and low evidence for one SARS-CoV-1 recombination event. Within MERS-CoV, 229E, OC43, NL63 and HKU1 datasets, we noted 7, 1, 9, 14, and 1 high-confidence recombination events, respectively. There was propensity for recombination breakpoints in the non-ORF1 region of the genome containing structural genes, and recombination severely skewed the temporal structure of these data, especially for NL63 and OC43. Bayesian time-scaled analyses on recombinant-free data indicated the sampled diversity of seasonal CoVs emerged in the last 70 years, with 229E displaying continuous lineage replacements. These findings emphasize the importance of genomic based surveillance to detect recombination in SARS-CoV-2, particularly if recombination may lead to immune evasion.


Asunto(s)
Coronavirus del Síndrome Respiratorio de Oriente Medio/genética , Recombinación Genética , Virus del SRAS/genética , SARS-CoV-2/genética , Teorema de Bayes , Bases de Datos Genéticas , Genoma Viral , Humanos , Evasión Inmune , Coronavirus del Síndrome Respiratorio de Oriente Medio/clasificación , Virus del SRAS/clasificación , SARS-CoV-2/clasificación , Glicoproteína de la Espiga del Coronavirus/genética , Proteínas no Estructurales Virales/genética
20.
Int J Mol Sci ; 22(15)2021 Jul 21.
Artículo en Inglés | MEDLINE | ID: mdl-34360529

RESUMEN

Nowadays, type II diabetes mellitus, more specifically ensuing diabetic nephropathy, and severe COVID-19 disease are known to be closely associated. The exact mechanisms behind this association are less known. An implication for the angiotensin-converting enzyme 2 remains controversial. Some researchers have started looking into other potential actors, such as neuropilin-1, mitochondrial glutathione, vitamin D, and DPP4. In particular, neuropilin-1 seems to play an important role in the underlying mechanism linking COVID-19 and diabetic nephropathy. We suggest, based on the findings in this review, that its up-regulation in the diabetic kidney facilitates viral entry in this tissue, and that the engagement of both processes leads to a depletion of neuropilin-1, which was demonstrated to be strongly associated with the pathogenesis of DN. More studies are needed to confirm this hypothesis, and research should be directed towards elucidating the potential roles of all these suggested actors and eventually discovering new therapeutic strategies that could reduce the burden of COVID-19 in patients with diabetic nephropathy.


Asunto(s)
COVID-19/complicaciones , COVID-19/inmunología , Nefropatías Diabéticas/complicaciones , Nefropatías Diabéticas/inmunología , Enzima Convertidora de Angiotensina 2/metabolismo , Dipeptidil Peptidasa 4/metabolismo , Glutatión/metabolismo , Humanos , Neuropilina-1/metabolismo , Virus del SRAS/inmunología , Vitamina D/metabolismo
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