Viral genomic, metagenomic and human transcriptomic characterization and prediction of the clinical forms of COVID-19

COVID-19 is characterized by respiratory symptoms of various severities, ranging from mild upper respiratory signs to acute respiratory failure/acute respiratory distress syndrome associated with a high mortality rate. However, the pathophysiology of the disease is largely unknown. Shotgun metagenomics from nasopharyngeal swabs were used to characterize the genomic, metagenomic and transcriptomic features of patients from the first pandemic wave with various forms of COVID-19, including outpatients, patients hospitalized not requiring intensive care, and patients in the intensive care unit, to identify viral and/or host factors associated with the most severe forms of the disease. Neither the genetic characteristics of SARS-CoV-2, nor the detection of bacteria, viruses, fungi or parasites were associated with the severity of pulmonary disease. Severe pneumonia was associated with overexpression of cytokine transcripts activating the CXCR2 pathway, whereas patients with benign disease presented with a T helper “Th1-Th17” profile. The latter profile was associated with female gender and a lower mortality rate. Our findings indicate that the most severe cases of COVID-19 are characterized by the presence of overactive immune cells resulting in neutrophil pulmonary infiltration which, in turn, could enhance the inflammatory response and prolong tissue damage. These findings make CXCR2 antagonists, in particular IL-8 antagonists, promising candidates for the treatment of patients with severe COVID-19.

Blocking inflammation on the way: Rationale for CXCR2 antagonists for the treatment of COVID-19

An exacerbated and unbalanced immune response may account for the severity of COVID-19, the disease caused by the novel severe acute respiratory syndrome (SARS) coronavirus 2, SARS-CoV-2. In this Viewpoint, we summarize recent evidence for the role of neutrophils in the pathogenesis of COVID-19 and propose CXCR2 inhibition as a promising treatment option to block neutrophil recruitment and activation.

Pendekatan Terapi Asthma-COPD Overlap (ACO)

Asthma and COPD are the most common chronic airways disease and have different clinical manifestations and treatments. Asthma is an airway inflammatory disease mediated by Th2 cytokines, CD4 + lymphocytes and eosinophils, whereas inflammation of COPD is affected by Th1 cytokines, CD8 + lymphocytes and neutrophils. Asthma-COPD overlap (ACO) is the presence of persistent airflow limitations with some symptoms resembling asthma and some other symptoms similar to COPD. Current treatment of ACO is to target the dominant inflammatory phenotype of eosinophils and neutrophils. Treatments given to patients with dominant eosinophil phenotype are inhaled and anti-IgE corticosteroids, and the drugs under reasearch are anti-IL-5, anti-IL-13, GATA3 inhibitors, anti-IL-33, anti-IL-25 and anti-thymic stromal lymphopoietin (anti-TSLP). Treatment given to patients with dominant neutrophil phenotype was macrolide, and treatment under reasearch was anti-IL-1, anti-IL-17A, anti-IL-23, CXCR2 antagonists, p38 MAPK inhibitor / JAK inhibitors and PDE4 inhibitors. Paucygranulocyte patient were given LAMA, LAMA + LABA therapy and bronchial thermoplasty. The therapy currently under study for this group is triple inhalation.

Ligand-based pharmacophore model for the discovery of novel CXCR2 antagonists as anti-cancer metastatic agents

Metastatic cancer is considered a fatal progression of cancer worldwide. It has been shown that a key player in this scenario is the CXC chemokine receptor 2 (CXCR2). To identify novel CXCR2 antagonists, a pharmacophore model was built with the H ip H op program by screening a database containing compounds which were designed based on the known structure–activity relationship (SAR) of the diarylurea series CXCR2 antagonists. Compound 1a bearing the novel skeleton was selected from database screening and subjected to the in vitro biological test which showed a moderate CXCR2 antagonist potential. With further modification and exploration of SAR, compound 1e demonstrated improved CXCR2 antagonist activity with an IC 50 value of 14.8 µM. Furthermore, wound healing assay using the NCI-H1299 cell line indicated that 1e showed an excellent anti-cancer metastatic effect (72% inhibition in cell migration at 50 µg ml −1 ).