Identification of Novel SARS-CoV-2 Drug Targets by Host MicroRNAs and Transcription Factors Co-regulatory Interaction Network Analysis

Abstract

Understanding the host regulatory mechanisms opposing virus infection and virulence can provide actionable insights to identify novel therapeutics against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We have used a network biology approach to elucidate the crucial factors involved in host responses involving host–microRNA (miRNA) interactions with host and virus genes using recently published experimentally verified protein–protein interaction data. We were able to identify 311 host genes to be potentially targetable by 2,197 human miRNAs. These miRNAs are known to be involved in various biological processes, such as T-cell differentiation and activation, virus replication, and immune system. Among these, the anti-viral activity of 38 miRNAs to target 148 host genes is experimentally validated. Six anti-viral miRNAs, namely, hsa-miR-1-3p, hsa-miR-17-5p, hsa-miR-199a-3p, hsa-miR-429, hsa-miR-15a-5p, and hsa-miR-20a-5p, are previously reported to be anti-viral in respiratory diseases and were found to be downregulated. The interaction network of the 2,197 human miRNAs and interacting transcription factors (TFs) enabled the identification of 51 miRNAs to interact with 77 TFs inducing activation or repression and affecting gene expression of linked genes. Further, from the gene regulatory network analysis, the top five hub genes HMOX1 , DNMT1 , PLAT , GDF1 , and ITGB1 are found to be involved in interferon (IFN)-α2b induction, epigenetic modification, and modulation of anti-viral activity. The comparative miRNAs target identification analysis in other respiratory viruses revealed the presence of 98 unique host miRNAs targeting SARS-CoV-2 genome. Our findings identify prioritized key regulatory interactions that include miRNAs and TFs that provide opportunities for the identification of novel drug targets and development of anti-viral drugs.

Anti-SARS-CoV-2 Strategies and the Potential Role of miRNA in the Assessment of COVID-19 Morbidity, Recurrence, and Therapy

“…Sardar et al [180] applied a network biology approach to elucidate key factors involved in miRNA interactions with the host and viral genes. Based on the analysis of the gene regulatory network, it was found that the five major genes, HMOX1, DNMT1, PLAT, GDF1, and ITGB1, are involved in the induction of interferon IFN-α2b, epigenetic modification, and modulation of antiviral activity, making it possible to identify new targets for potential candidates for antiviral drugs.…”

“…Further analysis of miRNA expression selected 49 miRNAs expressed in the lung tissues. They have also identified 38 miRNAs targeting 143 host genes, whose expression is responsible for antiviral activity [180]. Interestingly, six antiviral miRNAs, miR-1-3p, miR-17-5p, miR-199a-3p, miR-429, miR-15a-5p, and miR-20a-5p, have been reported to play a role in respiratory diseases influenza A and respiratory syncytial virus.…”

“…For example, miR-138-5p, miR-622, miR-761, and miR-A3r each have four targets, and miR-15b-5p, miR-18a-5p, miR-A2r, and miR-B1r each have three targets on the SARS-CoV-2 virus. Interestingly, six of these eight miRNAs were found to target the S protein, while seven had two or more targets in the ORF1ab [180,182]. of host's miRNAs with antiviral activity, their targets, and virus baits.…”

“…Interestingly, it was revealed that several miRNA clusters were associated with increased mortality rates of individual SARS-CoV-2 genomes. In addition, [180] of host's miRNAs with antiviral activity, their targets, and virus baits. Among others presented, five major genes (HMOX1, DNMT1, PLAT, GDF1, and ITGB1) directly targeting the SARS-CoV-2 ORF3a and ORF8 proteins were already described to play a role in modulating antiviral immunity and epigenetics [182][183][184].…”

High rate of mutational events in SARS-CoV-2 genomes across Brazilian geographical regions, February 2020 to June 2021

“…Never before has a viral genome been sequenced so globally in such a short time. Even so, numerous reports revealed potential adaptations at the nucleotide (nt), amino acid (aa) and structural heterogeneity of viral proteins, particularly in the S protein (Sardar et al, 2020). At the moment, the world’s concern is focused in about four functionally well-defined variants, B.1.1.7 (Alpha), B.1.351 (Beta), P.1 (Gamma) and B.1.617.2 (Delta) associated with viral fitness changes (Faria et al, 2021; Hodcroft, 2021; McCallum et al, 2021; Tang et al, 2021; Tegally et al, 2021).…”