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1.
Cancers (Basel) ; 13(20)2021 Oct 13.
Article in English | MEDLINE | ID: covidwho-1480594

ABSTRACT

The ribosomal protein S6 kinase beta 2 (S6K2) is thought to play an important role in malignant cell proliferation, but is understudied compared to its closely related homolog S6 kinase beta 1 (S6K1). To better understand the biological function of S6K2, chemical probes are needed, but the high similarity between S6K2 and S6K1 makes it challenging to selectively address S6K2 with small molecules. We were able to design the first potent and highly isoform-specific S6K2 inhibitor from a known S6K1-selective inhibitor, which was merged with a covalent inhibitor engaging a cysteine located in the hinge region in the fibroblast growth factor receptor kinase (FGFR) 4 via a nucleophilic aromatic substitution (SNAr) reaction. The title compound shows a high selectivity over kinases with an equivalently positioned cysteine, as well as in a larger kinase panel. A good stability towards glutathione and Nα-acetyl lysine indicates a non-promiscuous reactivity pattern. Thus, the title compound represents an important step towards a high-quality chemical probe to study S6K2-specific signaling.

2.
Pharmaceuticals (Basel) ; 14(9)2021 Sep 17.
Article in English | MEDLINE | ID: covidwho-1430938

ABSTRACT

SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus-2) affects the central nervous system (CNS), which is shown in a significant number of patients with neurological events. In this study, an updated literature review was carried out regarding neurological disorders in COVID-19. Neurological symptoms are more common in patients with severe infection according to their respiratory status and divided into three categories: (1) CNS manifestations; (2) cranial and peripheral nervous system manifestations; and (3) skeletal muscle injury manifestations. Patients with pre-existing cerebrovascular disease are at a higher risk of admission to the intensive care unit (ICU) and mortality. The neurological manifestations associated with COVID-19 are of great importance, but when life-threatening abnormal vital signs occur in severely ill COVID-19 patients, neurological problems are usually not considered. It is crucial to search for new treatments for brain damage, as well as for alternative therapies that recover the damaged brain and reduce the inflammatory response and its consequences for other organs. In addition, there is a need to diagnose these manifestations as early as possible to limit long-term consequences. Therefore, much research is needed to explain the involvement of SARS-CoV-2 causing these neurological symptoms because scientists know zero about it.

3.
Pharmacol Res ; 157: 104859, 2020 07.
Article in English | MEDLINE | ID: covidwho-1318929

ABSTRACT

Outbreak and pandemic of coronavirus SARS-CoV-2 in 2019/2020 will challenge global health for the future. Because a vaccine against the virus will not be available in the near future, we herein try to offer a pharmacological strategy to combat the virus. There exists a number of candidate drugs that may inhibit infection with and replication of SARS-CoV-2. Such drugs comprise inhibitors of TMPRSS2 serine protease and inhibitors of angiotensin-converting enzyme 2 (ACE2). Blockade of ACE2, the host cell receptor for the S protein of SARS-CoV-2 and inhibition of TMPRSS2, which is required for S protein priming may prevent cell entry of SARS-CoV-2. Further, chloroquine and hydroxychloroquine, and off-label antiviral drugs, such as the nucleotide analogue remdesivir, HIV protease inhibitors lopinavir and ritonavir, broad-spectrum antiviral drugs arbidol and favipiravir as well as antiviral phytochemicals available to date may limit spread of SARS-CoV-2 and morbidity and mortality of COVID-19 pandemic.


Subject(s)
Betacoronavirus/drug effects , Coronavirus Infections/drug therapy , Peptidyl-Dipeptidase A/drug effects , Pneumonia, Viral/drug therapy , Serine Endopeptidases/drug effects , Angiotensin-Converting Enzyme 2 , Angiotensin-Converting Enzyme Inhibitors/pharmacology , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , COVID-19 , Coronavirus Infections/epidemiology , Coronavirus Infections/mortality , Humans , Pandemics , Pneumonia, Viral/epidemiology , Pneumonia, Viral/mortality , SARS-CoV-2 , Serine Proteinase Inhibitors/pharmacology
4.
Sci Rep ; 11(1): 11998, 2021 06 07.
Article in English | MEDLINE | ID: covidwho-1260954

ABSTRACT

Due to the high rate of transmissibility, Brazil became the new COVID-19 outbreak epicenter and, since then, is being monitored to understand how SARS-CoV-2 mutates and spreads. We combined genomic and structural analysis to evaluate genomes isolated from different regions of Brazil and show that the most prevalent mutations were located in the S, N, ORF3a and ORF6 genes, which are involved in different stages of viral life cycle and its interaction with the host cells. Structural analysis brought to light the positions of these mutations on protein structures, contributing towards studies of selective structure-based drug discovery and vaccine development.


Subject(s)
COVID-19/genetics , Mutation/genetics , SARS-CoV-2/genetics , Viral Proteins/genetics , Brazil , Genome, Viral , Genomics , Humans , SARS-CoV-2/pathogenicity , Severity of Illness Index
5.
J Med Chem ; 65(2): 955-982, 2022 01 27.
Article in English | MEDLINE | ID: covidwho-1253871

ABSTRACT

The global coronavirus disease-19 (COVID-19) has affected more than 140 million and killed more than 3 million people worldwide as of April 20, 2021. The novel human severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has been identified as an etiological agent for COVID-19. Several kinases have been proposed as possible mediators of multiple viral infections, including life-threatening coronaviruses like SARS-CoV-1, Middle East syndrome coronavirus (MERS-CoV), and SARS-CoV-2. Viral infections hijack abundant cell signaling pathways, resulting in drastic phosphorylation rewiring in the host and viral proteins. Some kinases play a significant role throughout the viral infection cycle (entry, replication, assembly, and egress), and several of them are involved in the virus-induced hyperinflammatory response that leads to cytokine storm, acute respiratory distress syndrome (ARDS), organ injury, and death. Here, we highlight kinases that are associated with coronavirus infections and their inhibitors with antiviral and potentially anti-inflammatory, cytokine-suppressive, or antifibrotic activity.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/drug therapy , Protein Kinase Inhibitors/therapeutic use , Antiviral Agents/pharmacology , COVID-19/virology , Humans , Protein Kinase Inhibitors/pharmacology , SARS-CoV-2/drug effects , SARS-CoV-2/isolation & purification , Signal Transduction/drug effects , Virus Replication/drug effects
6.
J Nanobiotechnology ; 18(1): 130, 2020 Sep 10.
Article in English | MEDLINE | ID: covidwho-755216

ABSTRACT

Fast point-of-care (POC) diagnostics represent an unmet medical need and include applications such as lateral flow assays (LFAs) for the diagnosis of sepsis and consequences of cytokine storms and for the treatment of COVID-19 and other systemic, inflammatory events not caused by infection. Because of the complex pathophysiology of sepsis, multiple biomarkers must be analyzed to compensate for the low sensitivity and specificity of single biomarker targets. Conventional LFAs, such as gold nanoparticle dyed assays, are limited to approximately five targets-the maximum number of test lines on an assay. To increase the information obtainable from each test line, we combined green and red emitting quantum dots (QDs) as labels for C-reactive protein (CRP) and interleukin-6 (IL-6) antibodies in an optical duplex immunoassay. CdSe-QDs with sharp and tunable emission bands were used to simultaneously quantify CRP and IL-6 in a single test line, by using a single UV-light source and two suitable emission filters for readout through a widely available BioImager device. For image and data processing, a customized software tool, the MultiFlow-Shiny app was used to accelerate and simplify the readout process. The app software provides advanced tools for image processing, including assisted extraction of line intensities, advanced background correction and an easy workflow for creation and handling of experimental data in quantitative LFAs. The results generated with our MultiFlow-Shiny app were superior to those generated with the popular software ImageJ and resulted in lower detection limits. Our assay is applicable for detecting clinically relevant ranges of both target proteins and therefore may serve as a powerful tool for POC diagnosis of inflammation and infectious events.


Subject(s)
Biomarkers/analysis , C-Reactive Protein/analysis , Immunoassay/methods , Interleukin-6/analysis , Quantum Dots/chemistry , Sepsis/diagnosis , Antibodies/immunology , Betacoronavirus/isolation & purification , C-Reactive Protein/immunology , COVID-19 , Coronavirus Infections/diagnosis , Coronavirus Infections/virology , Humans , Interleukin-6/immunology , Limit of Detection , Pandemics , Pneumonia, Viral/diagnosis , Pneumonia, Viral/virology , Point-of-Care Systems , SARS-CoV-2 , Sepsis/metabolism , Software , Ultraviolet Rays
7.
Sensors and Actuators B: Chemical ; : 129246, 2020.
Article in English | ScienceDirect | ID: covidwho-949699

ABSTRACT

Modern strategies in precision medicine require diagnostic tools for fast assessment of biomarkers. A popular and well established assay format for the rapid detection of disease markers directly at the point of care are lateral flow assays, which enable medical staff to directly use body fluids like blood or urine for diagnosis, without the need of a professional laboratory environment. Interleukin-6 and thrombin are both clinically relevant biomarkers associated with infectious diseases, inflammation, and blood coagulation thus providing also valuable information on status and treatment-response of COVID-19 patients. This work presents a novel method for the quantification of these biomarkers based on fluorescent green and red quantum dots as labels for interleukin-6 antibodies and thrombin binding aptamers, respectively. For readout, a 3D printed smartphone imager with a built in UV-LED light source was used. Through separation of RGB-channels the acquired images can be processed to compose a fully functional duplex lateral flow assay for simultaneous quantification of interleukin-6 and thrombin on the same test line (optical multiplexing). Furthermore, the assay performs well in complex samples (10% serum samples). In conclusion, this novel combination of antibody and aptamer-based detection in a single lateral flow assay reduces turnaround time while the use of our easy to compose smartphone imager ensures availability especially for low resource settings.

8.
Stem Cell Rev Rep ; 17(1): 44-55, 2021 02.
Article in English | MEDLINE | ID: covidwho-725012

ABSTRACT

Therapeutic clinical and preclinical studies using cultured cells are on the rise, especially now that the World Health Organization (WHO) declared coronavirus disease 2019 (COVID-19) a "public health emergency of international concern", in January, 2020. Thus, this study aims to review the outcomes of ongoing clinical studies on stem cells in Severe Acute Respiratory Syndrome (SARS), Acute Respiratory Distress Syndrome (ARDS), and Middle East Respiratory Syndrome (MERS). The results will be associated with possible applications to COVID-19. Only three clinical trials related to stem cells are considered complete, whereby two are in Phase 1 and one is in Phase 2. Basically, the ongoing studies on coronavirus are using mesenchymal stem cells (MSCs) derived from bone marrow or the umbilical cord to demonstrate their feasibility, safety, and tolerability. The studies not related to coronavirus are all in ARDS conditions; four of them are in Phase 1 and three in Phase 2. With the COVID-19 boom, many clinical trials are being carried out using different sources with an emphasis on MSC-based therapy used to inhibit inflammation. One of the biggest challenges in the current treatment of COVID-19 is the cytokine storm, however MSCs can prevent or mitigate this cytokine storm through their immunomodulatory capacity. We look forward to the results of the ongoing clinical trials to find a treatment for the disease. Researchers around the world are joining forces to help fight COVID-19. Stem cells used in the current clinical studies are a new therapeutic promise for COVID-19 where pharmacological treatments seem insufficient.Graphical Abstract.


Subject(s)
COVID-19/therapy , Coronavirus Infections/therapy , Respiratory Distress Syndrome/therapy , SARS-CoV-2/pathogenicity , COVID-19/drug therapy , COVID-19/epidemiology , COVID-19/virology , Clinical Trials as Topic , Coronavirus Infections/epidemiology , Coronavirus Infections/virology , Humans , Inflammation/pathology , Inflammation/therapy , Inflammation/virology , Mesenchymal Stem Cell Transplantation , Mesenchymal Stem Cells/chemistry , Respiratory Distress Syndrome/epidemiology , Respiratory Distress Syndrome/virology
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