Analgesics Induce Alterations in the Expression of SARS-CoV-2 Entry and Arachidonic-Acid-Metabolizing Genes in the Mouse Lungs

Khirfan, Fatima; Jarrar, Yazun; Al-Qirim, Tariq; Goh, Khang Wen; Jarrar, Qais; Ardianto, Chrismawan; Awad, Mohammad; Al‐Ameer, Hamzeh J.; Al-Awaida, Wajdy; Moshawih, Said; Ming, Long Chiau

doi:10.3390/ph15060696

Cited by 6 publications

(8 citation statements)

References 39 publications

(42 reference statements)

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“…A virion is the infectious form of the virus that is released from host cells after viral replication [ 11 ]. It protects the virus genome and facilitates its entry into specific host cells, which have the required receptors or proteins that facilitate its entry [ 11 , 12 ]. The virion contains the genome, and it is surrounded by a capsid, which is made up of proteins, to protect the genome [ 13 ].…”

Section: Disease-causing Virusesmentioning

confidence: 99%

Targeting Human Proteins for Antiviral Drug Discovery and Repurposing Efforts: A Focus on Protein Kinases

Hajjo

Sabbah

Abusara

et al. 2023

Viruses

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Despite the great technological and medical advances in fighting viral diseases, new therapies for most of them are still lacking, and existing antivirals suffer from major limitations regarding drug resistance and a limited spectrum of activity. In fact, most approved antivirals are directly acting antiviral (DAA) drugs, which interfere with viral proteins and confer great selectivity towards their viral targets but suffer from resistance and limited spectrum. Nowadays, host-targeted antivirals (HTAs) are on the rise, in the drug discovery and development pipelines, in academia and in the pharmaceutical industry. These drugs target host proteins involved in the virus life cycle and are considered promising alternatives to DAAs due to their broader spectrum and lower potential for resistance. Herein, we discuss an important class of HTAs that modulate signal transduction pathways by targeting host kinases. Kinases are considered key enzymes that control virus-host interactions. We also provide a synopsis of the antiviral drug discovery and development pipeline detailing antiviral kinase targets, drug types, therapeutic classes for repurposed drugs, and top developing organizations. Furthermore, we detail the drug design and repurposing considerations, as well as the limitations and challenges, for kinase-targeted antivirals, including the choice of the binding sites, physicochemical properties, and drug combinations.

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Section: Disease-causing Virusesmentioning

confidence: 99%

Targeting Human Proteins for Antiviral Drug Discovery and Repurposing Efforts: A Focus on Protein Kinases

Hajjo

Sabbah

Abusara

et al. 2023

Viruses

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“…We did a pilot experiment to choose the appropriate housekeeping gene. We selected beta-actin and gapdh genes according to our previous studies [21,24]. We found that the results of gapdh were more consistent than the results of the beta-actin gene.…”

Section: Gene Expression Analysismentioning

confidence: 99%

“…Briefly, 10 ng of the synthesized cDNA was added to a reaction mixture containing Luna ® Universal Master Mix (catalog number: M3003S) and 10 pmoles of forward and reverse primers. The PCR conditions used were as follows: denaturation at 95 C for 3 min followed by 40 cycles of denaturation at 95 C for 10 s and annealing at 53-58 C for 30 s [24,25]. We did a pilot experiment to choose the appropriate housekeeping gene.…”

Section: Gene Expression Analysismentioning

confidence: 99%

Alterations in the gene expression of SARS‐COV‐2 entry receptors and enzymes in lungs and hearts of controlled and uncontrolled diabetic mice

Alkhawaldeh,

Jarrar,

Gharaibeh

et al. 2023

Fundamemntal Clinical Pharma

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BackgroundThe entry of the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) into the host cell is carried out by specific receptors and enzymes, including human angiotensin‐converting enzyme 2 receptor (ACE2), transmembrane serine protease 2 (TMPRSS2), and cathepsin‐L (CTSL). COVID‐19 patients with comorbidities, such as diabetes mellitus (DM), are more prone to severe symptoms and have a higher risk of mortality.AimsThe present study aimed to investigate the impact of controlled and uncontrolled type 1 DM (T1DM) on the gene expression of mouse Ace2, Tmprss2, and Ctsl and correlate it with the pathological alterations in the lungs and the heart of DM mice.MethodsBalb/c mice were administered a single dose of 240 mg/kg streptozocin to induce T1DM. The blood glucose level was measured to confirm the induction of DM. Normalization of blood glucose levels in T1DM mice was achieved using 0.1 mL/kg Mixtard® insulin therapy. The mice's lungs and hearts were harvested, and the mRNA was extracted and converted to cDNA. The gene expression of Ace2, Tmprss2, Ctsl, Cyp4a11, and Adrb1 genes, which play a role in the homeostasis of lungs and hearts, were measured using quantitative real‐time polymerase chain reaction (RT‐PCR). The pathological alterations in the hearts and lungs induced by T1DM were evaluated using the relative heart and lung weights, in addition to the pathohistological examination.ResultsAfter inducing T1DM for 14 days, we observed a significant reduction in the total weight of uncontrolled DM (UDM) mice (P < 0.05). Pathohistological examination of UDM lung tissues revealed thickening of the alveolar walls with narrowing of the surface of the alveolar sacs. Additionally, we found that UDM mice exhibited downregulation of Ace2 gene expression (P < 0.05) in their lungs, while both UDM and control DM (CDM) mice showed upregulation of Ctsl gene expression in their hearts (P < 0.05). Notably, Cyp4a12 gene expression was significantly downregulated (P < 0.05) in UDM mice but returned to normal levels in CDM mice.ConclusionsWe conclude from this study that T1DM downregulates Ace2 receptor and Cyp4a12 gene expression, which is correlated with the thickening of alveolar walls and narrowing of the surface of alveolar sacs in the lungs. Insulin administration for controlling T1DM ameliorated these pathological alterations. These results can help increase our understanding of the impact of controlled and uncontrolled T1DM on the lungs and may explain, at least in part, why DM patients with COVID‐19 experience exacerbation of symptoms.

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“…After successfully attaching the virus to the ACE2 receptor, an enzyme called protease from the host cell cleaves and activates spike glycoprotein (S) attached to the ACE2. When the attachment and activation of the spike glycoprotein (S) are completed, the virus crosses the cell wall and enters the host cell through direct fusion or endocytosis [25,26] .…”

Section: Viral Entrymentioning

confidence: 99%

Anti-SARS-CoV-2 Biotherapeutics and Chemotherapeutics: An Insight into Product Specifications and Marketing Dynamics

Kotra¹,

Mallem²,

Kanuri³

et al. 2022

Prog Micobes Mol Biol

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Chemotherapeutics and biotherapeutics agents have been explored as a potential treatment for COVID-19. This study was aimed to elucidate latest update related to biotherapeutics and chemotherapeutics against COVID-19 and its variants as well as the product specifications and marketing dynamics of its pharmacotherapies. There are several chemotherapeutics that have been studied for the treatment of COVID-19, including Paxlovid (Nirmatrelvir & Ritonavir) fixed dose combination, nirmatrelvir and ritonavir fixed dose combination, Remdesivir (Vekulary/Covifor) fixed dose combination, chloroquine and hydroxychloroquine, molnupiravir, favipiravir, Infliximab (Remsima®) fixed dose combination tocilizumab (Actimera), casirivimab+imdevimab (Ronapreve) fixed dose combination, ivermectin, methylprednisole. These drugs have been repurposed for use in COVID-19 due to their antiviral properties and ability to reduce inflammation. The COVID-19 death cases have significantly reduced because of tested efficacy of advanced biotherapeutics and chemotherapeutics. As for marketing dynamics, the demand for chemotherapeutics for the treatment of COVID-19 has increased significantly since the outbreak of the pandemic. Hence, the prices of anti-viral and monoclonal antibodies in top COVID-19 affected countries is also presented here. Considering the molecular interactions, therapeutic activity, efficacy, and adverse effects, the USFDA and the WHO recommended the aforementioned drugs. The chances of approval seems favouring biotherapeutics as these have the best characteristics among the chemotherapeutics. Overall, this review contributes to the scientific understanding of the COVID-19. This can help to inform future research and development efforts and contribute to the overall advancement of knowledge in the field of medicine.

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Analgesics Induce Alterations in the Expression of SARS-CoV-2 Entry and Arachidonic-Acid-Metabolizing Genes in the Mouse Lungs

Cited by 6 publications

References 39 publications

Targeting Human Proteins for Antiviral Drug Discovery and Repurposing Efforts: A Focus on Protein Kinases

Targeting Human Proteins for Antiviral Drug Discovery and Repurposing Efforts: A Focus on Protein Kinases

Alterations in the gene expression of SARS‐COV‐2 entry receptors and enzymes in lungs and hearts of controlled and uncontrolled diabetic mice

Anti-SARS-CoV-2 Biotherapeutics and Chemotherapeutics: An Insight into Product Specifications and Marketing Dynamics

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