SARS-CoV-2 variants: A double-edged sword?

Jogalekar, Manasi P.; Veerabathini, Anurag; Gangadaran, Prakash

doi:10.1177/15353702211014146

Cited by 20 publications

(18 citation statements)

References 32 publications

(72 reference statements)

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“…To fight the spreading of highly infective new variants ( Boehm et al, 2021 ; Jogalekar et al, 2021 ; Luo et al, 2021 ) originating from the selection pressure caused by the S-protein based vaccinations, a suitable siRNA therapy must address a region of the viral genome that is well preserved and displays little selection pressure. The target sequences of siV1, as well as of siV6 and siV7, are highly conserved in SARS-CoV-2 variants.…”

Section: Discussionmentioning

confidence: 99%

“…However, we are still far from a global herd immunity threshold. The high infectivity, the global spread and the selection pressure by the S-protein based vaccinations lead to the emergence of escape variants of concern (SARS-CoV-2 alpha to mu; December 2021; Tracking SARS-CoV-2 variants (who.int )) ( Jogalekar et al, 2021 ). Although current vaccines provide a degree of protection against all variants to date, they only blunt but do not defeat new escape variants (e.g., delta variant) ( Lopez Bernal et al, 2021 ; Wadman, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Selection and Validation of siRNAs Preventing Uptake and Replication of SARS-CoV-2

Friedrich

Pfeifer

Binder

et al. 2022

Front. Bioeng. Biotechnol.

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In 2019, the novel highly infectious severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak rapidly led to a global pandemic with more than 346 million confirmed cases worldwide, resulting in 5.5 million associated deaths (January 2022). Entry of all SARS-CoV-2 variants is mediated by the cellular angisin-converting enzyme 2 (ACE2). The virus abundantly replicates in the epithelia of the upper respiratory tract. Beyond vaccines for immunization, there is an imminent need for novel treatment options in COVID-19 patients. So far, only a few drugs have found their way into the clinics, often with modest success. Specific gene silencing based on small interfering RNA (siRNA) has emerged as a promising strategy for therapeutic intervention, preventing/limiting SARS-CoV-2 entry into host cells or interfering with viral replication. Here, we pursued both strategies. We designed and screened nine siRNAs (siA1-9) targeting the viral entry receptor ACE2. SiA1, (siRNA against exon1 of ACE2 mRNA) was most efficient, with up to 90% knockdown of the ACE2 mRNA and protein for at least six days. In vitro, siA1 application was found to protect Vero E6 and Huh-7 cells from infection with SARS-CoV-2 with an up to ∼92% reduction of the viral burden indicating that the treatment targets both the endosomal and the viral entry at the cytoplasmic membrane. Since the RNA-encoded genome makes SARS-CoV-2 vulnerable to RNA interference (RNAi), we designed and analysed eight siRNAs (siV1-8) directly targeting the Orf1a/b region of the SARS-CoV-2 RNA genome, encoding for non-structural proteins (nsp). As a significant hallmark of this study, we identified siV1 (siRNA against leader protein of SARS-CoV-2), which targets the nsp1-encoding sequence (a.k.a. ‘host shutoff factor’) as particularly efficient. SiV1 inhibited SARS-CoV-2 replication in Vero E6 or Huh-7 cells by more than 99% or 97%, respectively. It neither led to toxic effects nor induced type I or III interferon production. Of note, sequence analyses revealed the target sequence of siV1 to be highly conserved in SARS-CoV-2 variants. Thus, our results identify the direct targeting of the viral RNA genome (ORF1a/b) by siRNAs as highly efficient and introduce siV1 as a particularly promising drug candidate for therapeutic intervention.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Selection and Validation of siRNAs Preventing Uptake and Replication of SARS-CoV-2

Friedrich

Pfeifer

Binder

et al. 2022

Front. Bioeng. Biotechnol.

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“…Principally, existing literature has not tested the efficacy of PAD-4 inhibitors in inflammatory conditions, such as COVID-19 in human models. With the continuous discovery of SARS-CoV-2 variants, including but not limited to B.1.1.7 (Alpha), B.1.351 (Beta), P.1 (Gamma), B.1.617.1 (Kappa) B.1.617.2 (Delta), B.1.526 (Iota), B.1.351, A.23.1, and most recently, the highly convoluted B.1.1.529 (Omicron) (Callaway, 2021) [ 85 , 86 , 87 , 88 ], SARS-CoV-2 treatment and vaccination are both constantly challenged. Although specific mutations in the spike protein, including the B.1.1.7 and B.1.351 variants, are generally effectively neutralized by existing vaccines [ 85 ], the response of vaccines to other variants, including the P.1 andB.1.617.2 display significantly reduced neutralization of SARS-CoV-2, with other variants such as the B.1.1.529 posing as novel challenges toward herd immunity.…”

Section: Discussionmentioning

confidence: 99%

PAD Inhibitors as a Potential Treatment for SARS-CoV-2 Immunothrombosis

et al. 2021

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Since the discovery of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in December 2019, the virus’s dynamicity has resulted in the evolution of various variants, including the delta variant and the more novel mu variant. With a multitude of mutant strains posing as challenges to vaccine efficacy, it is critical that researchers embrace the development of pharmacotherapeutics specific to SARS-CoV-2 pathophysiology. Neutrophil extracellular traps and their constituents, including citrullinated histones, display a linear connection with thrombotic manifestations in COVID-19 patients. Peptidylarginine deiminases (PADs) are a group of enzymes involved in the modification of histone arginine residues by citrullination, allowing for the formation of NETs. PAD inhibitors, specifically PAD-4 inhibitors, offer extensive pharmacotherapeutic potential across a broad range of inflammatory diseases such as COVID-19, through mediating NETs formation. Although numerous PAD-4 inhibitors exist, current literature has not explored the depth of utilizing these inhibitors clinically to treat thrombotic complications in COVID-19 patients. This review article offers the clinical significance of PAD-4 inhibitors in reducing thrombotic complications across various inflammatory disorders like COVID-19 and suggests that these inhibitors may be valuable in treating the origin of SARS-CoV-2 immunothrombosis.

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“…The COVID-19 pandemic recently has been more dominated by variants of concern (VOCs) that have emerged in different countries around the globe [1][2][3][4][5]. Mutations in the RBDs of these VOCs have been characterized in detail, and it was found that some mutations (e.g., E484K present in B.1.351 and P.1 variants) reduce recognition by antibodies induced by the wt SARS-CoV-2 strain [6][7][8], while other mutations (N501Y in B.1.1.7, B.1.351 and P.1 variants or L452R and E484Q in B.1.617.1 variant) primarily enhance affinity for the ACE2 receptor (Table 1) [9,10] likely being responsible for the enhanced infectivity of the latter strains.…”

Section: Introductionmentioning

confidence: 99%

Induction of Broadly Cross-Reactive Antibodies by Displaying Receptor Binding Domains of SARS-CoV-2 on Virus-like Particles

et al. 2022

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The impact of the COVID-19 pandemic has been reduced since the application of vaccination programs, mostly shown in the reduction of hospitalized patients. However, the emerging variants, in particular Omicron, have caused a steep increase in the number of infections; this increase is, nevertheless, not matched by an increase in hospitalization. Therefore, a vaccine that induces cross-reactive antibodies against most or all variants is a potential solution for the issue of emerging new variants. Here, we present a vaccine candidate which displays receptor-binding domain (RBD) of SARS-CoV-2 on virus-like particles (VLP) that, in mice, not only induce strong antibody responses against RBD but also bind RBDs from other variants of concern (VOCs). The antibodies induced by wild-type (wt) RBD displayed on immunologically optimized Cucumber mosaic virus incorporated tetanus toxin (CuMVTT) VLPs bind to wt as well as RBDs of VOCs with high avidities, indicating induction of strongly cross-reactive IgG antibodies. Interestingly, similar cross-reactive IgA antibodies were induced in immunized mice. Furthermore, these cross-reactive antibodies demonstrated efficacy in neutralizing wt (Wuhan) as well as SARS-CoV-2 VOCs (Beta, Delta, and Gamma). In summary, RBDs displayed on VLPs are capable of inducing protective cross-reactive IgG and IgA antibodies in mice, indicating that it may be possible to cover emerging VOCs with a single vaccine based on wt RBD.

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SARS-CoV-2 variants: A double-edged sword?

Cited by 20 publications

References 32 publications

Selection and Validation of siRNAs Preventing Uptake and Replication of SARS-CoV-2

Selection and Validation of siRNAs Preventing Uptake and Replication of SARS-CoV-2

PAD Inhibitors as a Potential Treatment for SARS-CoV-2 Immunothrombosis

Induction of Broadly Cross-Reactive Antibodies by Displaying Receptor Binding Domains of SARS-CoV-2 on Virus-like Particles

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