A Novel Glucocorticoid and Androgen Receptor Modulator Reduces Viral Entry and Innate Immune Inflammatory Responses in the Syrian Hamster Model of SARS-CoV-2 Infection

Rocha, Savannah M.; Fagre, Anna C.; Latham, Amanda S.; Cummings, Jason E.; Aboellail, Tawfik; Reigan, Philip; Aldaz, Devin A.; McDermott, Casey P.; Popichak, Katriana A.; Kading, Rebekah C.; Schountz, Tony; Theise, Neil D.; Slayden, Richard A.; Tjalkens, Ronald B.

doi:10.3389/fimmu.2022.811430

Cited by 13 publications

(12 citation statements)

References 83 publications

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“…Additionally, several computational studies have been performed to prove its potential use for treating COVID-19 by interacting with Mpro as well as other key proteins of SARS-CoV-2. , Dutasteride is a 5-α reductase inhibitor and is also a commonly used antiandrogen. Androgen and androgen receptor (AR) modulator are responsible for transcriptionally regulating the cell surface proteins required for viral entry, so blocking the activity of androgen and AR can decrease COVID-19 severity. , A recent clinical trial has indicated that the use of dutasteride can effectively improve clinical symptoms and prevent inflammatory response in COVID-19 patients . In addition, dutasteride has been identified as a promising inhibitor of SARS-CoV-2 Mpro and RNA-dependent RNA polymerase in molecular dynamics simulations performed by Gul et al…”

Section: Resultsmentioning

confidence: 99%

“…Androgen and androgen receptor (AR) modulator are responsible for transcriptionally regulating the cell surface proteins required for viral entry, so blocking the activity of androgen and AR can decrease COVID-19 severity. 80,81 A recent clinical trial has indicated that the use of dutasteride can effectively improve clinical symptoms and prevent inflammatory response in COVID-19 patients. 82 In addition, dutasteride has been identified as a promising inhibitor of SARS-CoV-2 Mpro and RNA-dependent RNA polymerase in molecular dynamics simulations performed by Gul et al 83 Apart from the above three drugs, GTP-14564, CHIR-124, AT7867, MK-0773, benperidol, telcagepant, rimegepant, and etrasimod are also probable potential candidates for the treatment against COVID-19.…”

Section: Model Interpretation Based On Attention Mechanismmentioning

confidence: 99%

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Attention Mechanism-Based Graph Neural Network Model for Effective Activity Prediction of SARS-CoV-2 Main Protease Inhibitors: Application to Drug Repurposing as Potential COVID-19 Therapy

Wu,

Li,

et al. 2023

J. Chem. Inf. Model.

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Compared to de novo drug discovery, drug repurposing provides a time-efficient way to treat coronavirus disease 19 (COVID-19) that is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 main protease (Mpro) has been proved to be an attractive drug target due to its pivotal involvement in viral replication and transcription. Here, we present a graph neural network-based deep-learning (DL) strategy to prioritize the existing drugs for their potential therapeutic effects against SARS-CoV-2 Mpro. Mpro inhibitors were represented as molecular graphs ready for graph attention network (GAT) and graph isomorphism network (GIN) modeling for predicting the inhibitory activities. The result shows that the GAT model outperforms the GIN and other competitive models and yields satisfactory predictions for unseen Mpro inhibitors, confirming its robustness and generalization. The attention mechanism of GAT enables to capture the dominant substructures and thus to realize the interpretability of the model. Finally, we applied the optimal GAT model in conjunction with molecular docking simulations to screen the Drug Repurposing Hub (DRH) database. As a result, 18 drug hits with best consensus prediction scores and binding affinity values were identified as the potential therapeutics against COVID-19. Both the extensive literature searching and evaluations on adsorption, distribution, metabolism, excretion, and toxicity (ADMET) illustrate the premium drug-likeness and pharmacokinetic properties of the drug candidates. Overall, our work not only provides an effective GAT-based DL prediction tool for inhibitory activity of SARS-CoV-2 Mpro inhibitors but also provides theoretical guidelines for drug discovery in the COVID-19 treatment.

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Section: Resultsmentioning

confidence: 99%

Section: Model Interpretation Based On Attention Mechanismmentioning

confidence: 99%

Attention Mechanism-Based Graph Neural Network Model for Effective Activity Prediction of SARS-CoV-2 Main Protease Inhibitors: Application to Drug Repurposing as Potential COVID-19 Therapy

Wu,

Li,

et al. 2023

J. Chem. Inf. Model.

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“…Total cellular quantification conducted in the bronchial epithelium and parenchyma revealed significant decreases in the amount of total cellular populations at 4 DPI and 10 DPI that recovered to baseline at 21 DPI in animals that were transfected with hACE2 adenovirus and subsequently challenged with SARS-CoV-2 (Figure 5). Notably, SARS-CoV-2 infection in other animal models and reports of clinical cases showed compelling histopathological evidence that SARS-CoV-2 infection leads to immune cell infiltration of the lung parenchyma and collapse of bronchial airways, evident through loss of bronchial epithelium (52)(53)(54)(55). The recruitment of immune cells to the lung in SARS-CoV-2 infection can occur as early as 2 DPI and is often progressive and results in permeant lung damage, severe disease, fibrosis, and/or death (54).…”

Section: Discussionmentioning

confidence: 99%

Regulatory T Cell-like Response to SARS-CoV-2 in Jamaican Fruit Bats (Artibeus jamaicensis) Transduced with Human ACE2

Burke

Rocha

Zhan

et al. 2023

Preprint

Self Cite

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Insectivorous Old World horseshoe bats (Rhinolophus spp.) are the likely source of the ancestral SARS-CoV-2 prior to its spillover into humans and causing the COVID-19 pandemic. Natural coronavirus infections of bats appear to be principally confined to the intestines, suggesting fecal-oral transmission; however, little is known about the biology of SARS-related coronaviruses in bats. Previous experimental challenges of Egyptian fruit bats (Rousettus aegyptiacus) resulted in limited infection restricted to the respiratory tract, whereas insectivorous North American big brown bats (Eptesicus fuscus) showed no evidence of infection. In the present study, we challenged Jamaican fruit bats (Artibeus jamaicensis) with SARS-CoV-2 to determine their susceptibility. Infection was confined to the intestine for only a few days with prominent viral nucleocapsid antigen in epithelial cells, and mononuclear cells of the lamina propria and Peyers patches, but with no evidence of infection of other tissues; none of the bats showed visible signs of disease or seroconverted. Expression levels of ACE2 were low in the lungs, which may account for the lack of pulmonary infection. Bats were then intranasally inoculated with a replication-defective adenovirus encoding human ACE2 and 5 days later challenged with SARS-CoV-2. Viral antigen was prominent in lungs for up to 14 days, with loss of pulmonary cellularity during this time; however, the bats did not exhibit weight loss or visible signs of disease. From day 7, bats had low to moderate IgG antibody titers to spike protein by ELISA, and one bat on day 10 had low-titer neutralizing antibodies by a VSV pseudotyped virus assay. CD4+ helper T cells became activated upon ex vivo recall stimulation with SARS-CoV-2 nucleocapsid peptides and exhibited elevated mRNA expression of the regulatory T cell cytokines interleukin-10 and transforming growth factor beta, which may have limited inflammatory pathology. Collectively, these data show that Jamaican fruit bats are of low susceptibility to SARS-CoV-2 but that expression of human ACE2 in their lungs leads to robust infection and an adaptive immune response with low-titer antibodies and a regulatory T cell-like response that may explain the lack of prominent inflammation in the lungs. This model will allow for insights of how SARS-CoV-2 infects bats and how bat innate and adaptive immune responses engage the virus without overt clinical disease.

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“…Several identified processes offer druggable options for therapeutic treatment. Androgen receptor signaling and its genetic variability have been already linked to COVID-19 severity 11 , 33 and its inhibition proposed as a therapeutic strategy (e.g 34 .). We found several GPCR signaling instances significantly enriched in our network, in particular those related to G i and G q signaling, which mediate vascular inflammation.…”

Section: Discussionmentioning

confidence: 99%

An explainable model of host genetic interactions linked to COVID-19 severity

Onoja

Picchiotti²,

Fallerini³

et al. 2022

Commun Biol

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We employed a multifaceted computational strategy to identify the genetic factors contributing to increased risk of severe COVID-19 infection from a Whole Exome Sequencing (WES) dataset of a cohort of 2000 Italian patients. We coupled a stratified k-fold screening, to rank variants more associated with severity, with the training of multiple supervised classifiers, to predict severity based on screened features. Feature importance analysis from tree-based models allowed us to identify 16 variants with the highest support which, together with age and gender covariates, were found to be most predictive of COVID-19 severity. When tested on a follow-up cohort, our ensemble of models predicted severity with high accuracy (ACC = 81.88%; AUCROC = 96%; MCC = 61.55%). Our model recapitulated a vast literature of emerging molecular mechanisms and genetic factors linked to COVID-19 response and extends previous landmark Genome-Wide Association Studies (GWAS). It revealed a network of interplaying genetic signatures converging on established immune system and inflammatory processes linked to viral infection response. It also identified additional processes cross-talking with immune pathways, such as GPCR signaling, which might offer additional opportunities for therapeutic intervention and patient stratification. Publicly available PheWAS datasets revealed that several variants were significantly associated with phenotypic traits such as “Respiratory or thoracic disease”, supporting their link with COVID-19 severity outcome.

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A Novel Glucocorticoid and Androgen Receptor Modulator Reduces Viral Entry and Innate Immune Inflammatory Responses in the Syrian Hamster Model of SARS-CoV-2 Infection

Cited by 13 publications

References 83 publications

Attention Mechanism-Based Graph Neural Network Model for Effective Activity Prediction of SARS-CoV-2 Main Protease Inhibitors: Application to Drug Repurposing as Potential COVID-19 Therapy

Attention Mechanism-Based Graph Neural Network Model for Effective Activity Prediction of SARS-CoV-2 Main Protease Inhibitors: Application to Drug Repurposing as Potential COVID-19 Therapy

Regulatory T Cell-like Response to SARS-CoV-2 in Jamaican Fruit Bats (Artibeus jamaicensis) Transduced with Human ACE2

An explainable model of host genetic interactions linked to COVID-19 severity

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