Molecular effects and retinopathy induced by hydroxychloroquine during SARS-CoV-2 therapy: Role of CYP450 isoforms and epigenetic modulations.

Antimalaria drugs such as chloroquine (CQ) and hydroxychloroquine (HCQ) have been administered to several inflammatory diseases including rheumatoid arthritis and systemic lupus erythematosus, and infectious diseases such as acquired immune deficiency syndrome and influenza. Recently, several patients infected with novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) were given HCQ, and showed a discrepant response. HCQ inhibits SARS-CoV-2 cell entry, and inflammatory cascade by interfering with lysosomal and endosomal activities, and autophagy, impeding virus-membrane fusion, and inhibiting cytokine production resulted from inflammatory pathways activation. Despite ongoing administration of HCQ in a wide spectrum of disorders, there are some reports about several side effects, especially retinopathy in some patients treated with HCQ. Cytochrome P450 (CYP450) and its isoforms are the main metabolizers of HCQ and CQ. Pharmacokinetic properties of CYP enzymes are influenced by CYP polymorphism, non-coding RNAs, and epigenetic mechanisms such as DNA methylation, and histone acetylation. Accumulating evidence about side effects of HCQ in some patients raise the possibility that different response of patients to HCQ might be due to difference in their genome. Therefore, CYP450 genotyping especially for CYP2D6 might be helpful to refine HCQ dosage. Also, regular control of retina should be considered for patients under HCQ treatment. The major focus of the present review is to discuss about the pharmacokinetic and pharmacodynamic properties of CQ and HCQ that may be influenced by epigenetic mechanisms, and consequently cause several side effects especially retinopathy during SARS-CoV-2 therapy.

Comprehensive in silico identification of impacts of ACE2 SNPs on COVID-19 susceptibility in different populations.

The COVID-19 pandemic emerges a reminder that wide spectrum discrepancy in response to SARS-CoV-2 infection and antiviral drugs among different populations might be due to their different ACE2 SNPs and/or miRNAs profile. ACE2 is the major component for SARS-CoV-2s' cell entry, and disruption of its 3D structure could influence virus-ACE2 interaction. In this study we aimed to investigate the consequence of 16,860 SNPs within ACE2 on its expression as well as protein folding, function, and stability by using several beneficial bioinformatics tools. Only 64 SNPs including 60 intronic, and 4 missense showed different frequencies among different populations. Two missense SNPs including rs149039346 and rs147311723 have been predicted to strongly influence the function and stability of ACE2. rs1514283 creates new acceptor splice site. Also, rs4646175 creates new donor and acceptor splice site. PolymiRTS, and miRSNPs have predicted that rs3746444, rs113808830, and rs3751304 showed a MAF > 0.001, and disrupted mRNA target sites or mRNA function. Finally, rs3746444 hsa-miR-499a-3p, rs113808830 hsa-miR-4532, rs3751304 hsa-miR-6763-3p and hsa-miR-26b-5p were strongly hybridized with ACE2 and might influence its function. Collectively, this study shed some light on fundamental roles of ACE2 SNPs for its interaction with COVID-19, and consequently susceptibility to virus. Therefore, different responses of patients with COVID-19 to ACE2 blocker drugs might be due to their unique ACE2 SNPs. We further discussed the impact of SNPs on miRNAs profile as a factor that may modulate drug response or susceptibility to COVID-19.

Emerging role of IL-6 and NLRP3 inflammasome as potential therapeutic targets to combat COVID-19: Role of lncRNAs in cytokine storm modulation.

The world has witnessed a high morbidity and mortality caused by SARS-CoV-2, and global death toll is still rising. Exaggerated inflammatory responses are thought to be more responsible for infiltrated immune cells accumulation, organ damage especially lung, dyspnea, and respiratory failure rather than direct effect of viral replication. IL-6 and NLRP3 inflammasome are the major immune components in immune responses stimulation upon pathogen infection. It's noteworthy that the function and expression of these components are remarkably influenced by non-coding RNAs including long non-coding RNAs. Given the potential role of these components in organ damage and pathological manifestations of patients infected with COVID-19, their blockage might be a hopeful and promising treatment strategy. Notably, more study on long non-coding RNAs involved in inflammatory responses could elevate the efficacy of anti-inflammatory therapy. In this review we discuss the potential impact of IL-6 and NLRP3 inflammasome blocker drugs on inflammatory responses, viral clearance, and pathological and clinical manifestations. Collectively, anti-inflammatory strategy might pave the way to diminish clinical and pathological manifestations and thereby discharging patients infected with COVID-19 from hospital.

First comprehensive computational analysis of functional consequences of TMPRSS2 SNPs in susceptibility to SARS-CoV-2 among different populations

Background & Objective: Current SARS-CoV-2 pandemy mortality created the hypothesis that some populations may be more susceptible to SARS-CoV-2. TMPRSS2 encodes a transmembrane serine protease which plays a crucial role in SARS-CoV-2 cell entry. Single nucleotide polymorphisms (SNPs) in TMPRSS2 might influence SARS-CoV2 entry into the cell. This study aimed to investigate the impact of SNPs on TMPRSS2 function and structure.Methods: In silico tools such as Ensembl, Gtex, ExPASY 2, GEPIA, CCLE, KEGG, and GO were engaged to characterize TMPRSS2 and it's expression profile. The functional effects of SNPs were analyzed by PolyPhen-2, PROVEN, SNAP2, SIFT, and HSF. Also, Phyre2, GOR IV, and PSIPRED were used to predict the secondary structure of TMPRSS2. Moreover, post translational modification (PTM) and secretory properties were analyzed through Modpredand Phobius, respectively. Finally, miRNA profiles were investigated by PolymiRTS and miRSNPs.Results: Out of 11184 retrieved SNPs from dbSNP, 92 showed a different frequency between Asians and other populations. Only 21 SNPs affected the function and structure of TMPRSS2 by influencing the protein folding, PTM, splicing, and miRNA function. Particularly, rs12329760 may create a de novo pocket protein. rs875393 can create a donor site, silencer and broken enhancer motifs. rs12627374 affects a wide spectrum of miRNAs profile.Conclusion: This study highlighted the role of TMPRSS2 SNPs and epigenetic mechanisms especially non-coding RNAs in appearance of different susceptibility to SARS-CoV-2 among different populations. Also, this study could pave the way to potential therapeutic implication of TMPRSS2 in designing antiviral drugs.