Are Hsp90 Inhibitors Good Candidates Against Covid-19?

Ramos, Carlos H.I.; Ayinde, Kehinde Sulaimon

doi:10.2174/1389203721666201111160925

Cited by 7 publications

(7 citation statements)

References 106 publications

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“…In human cell lines infected with SARS-CoV and SARS-CoV-2, HSP90 inhibition resulted in reduction of viral replication, which suggests its involvement in infection []. Taking into account recent studies pointing out HSP90 as a potential target in COVID-19 treatment [ 72 , 73 , 74 , 75 ], this finding especially supports the value of presented here results.…”

Section: Discussionsupporting

confidence: 92%

Thrombosis-related circulating miR-16-5p is associated with disease severity in patients hospitalised for COVID-19

et al. 2022

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SARS-CoV-2 tropism for the ACE2 receptor, along with the multifaceted inflammatory reaction, is likely to drive the generalized hypercoagulable and thrombotic state seen in patients with COVID-19. Using the original bioinformatic workflow and network medicine approaches we reanalysed four coronavirus-related expression datasets and performed co-expression analysis focused on thrombosis and ACE2 related genes. We identified microRNAs (miRNAs) which play role in ACE2-related thrombosis in coronavirus infection and further, we validated the expressions of precisely selected miRNAs-related to thrombosis (miR-16-5p, miR-27a-3p, let-7b-5p and miR-155-5p) in 79 hospitalized COVID-19 patients and 32 healthy volunteers by qRT-PCR. Consequently, we aimed to unravel whether bioinformatic prioritization could guide selection of miRNAs with a potential of diagnostic and prognostic biomarkers associated with disease severity in patients hospitalized for COVID-19. In bioinformatic analysis, we identified EGFR, HSP90AA1, APP, TP53, PTEN, UBC, FN1, ELAVL1 and CALM1 as regulatory genes which could play a pivotal role in COVID-19 related thrombosis. We also found miR-16-5p, miR-27a-3p, let-7b-5p and miR-155-5p as regulators in the coagulation and thrombosis process. In silico predictions were further confirmed in patients hospitalized for COVID-19. The expression levels of miR-16-5p and let-7b in COVID-19 patients were lower at baseline, 7-days and 21-day after admission compared to the healthy controls (p < 0.0001 for all time points for both miRNAs). The expression levels of miR-27a-3p and miR-155-5p in COVID-19 patients were higher at day 21 compared to the healthy controls (p = 0.007 and p < 0.001, respectively). A low baseline miR-16-5p expression presents predictive utility in assessment of the hospital length of stay or death in follow-up as a composite endpoint (AUC:0.810, 95% CI, 0.71–0.91, p < 0.0001) and low baseline expression of miR-16-5p and diabetes mellitus are independent predictors of increased length of stay or death according to a multivariate analysis (OR: 9.417; 95% CI, 2.647–33.506; p = 0.0005 and OR: 6.257; 95% CI, 1.049–37.316; p = 0.044, respectively). This study enabled us to better characterize changes in gene expression and signalling pathways related to hypercoagulable and thrombotic conditions in COVID-19. In this study we identified and validated miRNAs which could serve as novel, thrombosis-related predictive biomarkers of the COVID-19 complications, and can be used for early stratification of patients and prediction of severity of infection development in an individual. Abbreviations: ACE2, angiotensin-converting enzyme 2AF, atrial fibrillationAPP, Amyloid Beta Precursor ProteinaPTT, activated partial thromboplastin timeAUC, Area under the curveAβ, amyloid betaBMI, body mass indexCAD, coronary artery diseaseCALM1, Calmodulin 1 geneCaM, calmodulinCCND1, Cyclin D1CI, confidence intervalCOPD, chronic obstructive pulmonary diseaseC...

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Section: Discussionsupporting

confidence: 92%

Thrombosis-related circulating miR-16-5p is associated with disease severity in patients hospitalised for COVID-19

et al. 2022

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“…The likely target of imatinib in asthma is c-KIT, but it should be noted that imatinib also inhibits tyrosine kinase receptors including the plateletderived growth factor receptor. 99 The half-life of imatinib is approximately 18 hours following oral administration in healthy volunteers, which makes it appropriate for once-daily dosing. 59 The increase in mean imatinib plasma concentration with increasing dosing is linear and dose proportional in the 25-to 1000-mg dosing range.…”

Section: Precise Study Overview To Identify Points Of Interest Accept...mentioning

confidence: 99%

The Precision Interventions for Severe and/or Exacerbation-Prone (PrecISE) Asthma Network: An overview of Network organization, procedures, and interventions

Georas¹,

Wright²,

Ivanova³

et al. 2022

Journal of Allergy and Clinical Immunology

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Asthma is a heterogeneous disease, with multiple underlying inflammatory pathways and structural airway abnormalities that impact disease persistence and severity. Recent progress has been made in developing targeted asthma therapeutics, especially for subjects with eosinophilic asthma. However, there is an unmet need for new approaches to treat patients with severe and exacerbation-prone asthma, who contribute disproportionately to disease burden. Extensive deep phenotyping has revealed the heterogeneous nature of severe asthma and identified distinct disease subtypes. A current challenge in the field is to translate new and emerging knowledge about different pathobiologic mechanisms in asthma into patient-specific therapies, with the ultimate goal of modifying the natural history of disease. Here, we describe the Precision Interventions for Severe and/or Exacerbation-Prone Asthma (PrecISE) Network, a groundbreaking collaborative effort of asthma researchers and biostatisticians from around the United States. The PrecISE Network was designed to conduct phase II/proof-of-concept clinical trials of precision interventions in the population with severe asthma, and is supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health. Using an innovative adaptive platform trial design, the PrecISE Network will evaluate up to 6 interventions simultaneously in biomarker-defined subgroups of subjects. We review the development and organizational structure of the PrecISE Network, and choice of interventions being studied. We hope that the PrecISE Network will enhance our understanding of asthma subtypes and accelerate the development of therapeutics for severe asthma.

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“…This pathway includes heat shock proteins (HSP) (Table 1) that have been described as "facilitators" of infections by several viruses, including coronaviruses and Zika 31 32 . Some, such as HSP90, have been proposed as targets of therapeutic strategies against viral replication 33,34 . The "antigen processing and presentation" pathway also included human leukocyte antigen (HLA) class I molecules and β2-microglobulin (β2-m), which is essential for the conformation of the major histocompatibility complex (MHC) class I protein complex (Table 1).…”

Section: Plasma Cytokine and Proteome Self-organize Temporally And Id...mentioning

confidence: 99%

Biologic correlates of beneficial convalescent plasma therapy in a COVID-19 patient reveal disease resolution mechanisms

Bruiners

Guerrini

Ukey

et al. 2022

Preprint

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BackgroundWhile the biomarkers of COVID-19 severity have been thoroughly investigated, the key biological dynamics associated with COVID-19 resolution are still insufficiently understood.Main bodyWe report a case of full resolution of severe COVID-19 due to convalescent plasma transfusion in a patient with underlying multiple autoimmune syndrome. Following transfusion, the patient showed fever remission, improved respiratory status, and rapidly decreased viral burden in respiratory fluids and SARS-CoV-2 RNAemia. Longitudinal unbiased proteomic analysis of plasma and single-cell transcriptomics of peripheral blood cells conducted prior to and at multiple times after convalescent plasma transfusion identified the key biological processes associated with the transition from severe disease to disease-free state. These included (i) temporally ordered upward and downward changes in plasma proteins reestablishing homeostasis and (ii) post-transfusion disappearance of a particular subset of dysfunctional monocytes characterized by hyperactivated Interferon responses and decreased TNF-α signaling.ConclusionsMonitoring specific subsets of innate immune cells in peripheral blood may provide prognostic keys in severe COVID-19. Moreover, understanding disease resolution at the molecular and cellular level should contribute to identify targets of therapeutic interventions against severe COVID-19.

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Are Hsp90 Inhibitors Good Candidates Against Covid-19?

Cited by 7 publications

References 106 publications

Thrombosis-related circulating miR-16-5p is associated with disease severity in patients hospitalised for COVID-19

Thrombosis-related circulating miR-16-5p is associated with disease severity in patients hospitalised for COVID-19

The Precision Interventions for Severe and/or Exacerbation-Prone (PrecISE) Asthma Network: An overview of Network organization, procedures, and interventions

Biologic correlates of beneficial convalescent plasma therapy in a COVID-19 patient reveal disease resolution mechanisms

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