“…SARS-CoV-2 can adapt to and acquire resistance against potent virus-directed antivirals such as remdesivir (RDV) in vitro (Stevens et al, 2022; Szemiel et al, 2021), a replication bottleneck that induces the emergence SARS-CoV-2 variants in vivo (Heyer et al, 2022). To investigate whether SARS-CoV-2 can acquire resistance to iBETs, we serially passaged it in Calu-3 cells under escalating two-fold concentrations of JQ-1 (Sup.…”
Section: Resultsmentioning
confidence: 99%
“…Immune selection of SARS-CoV-2 has led to the emergence of VOCs bearing an arsenal of mutations in the spike and other viral proteins, which confer immune evasion capabilities and transmission superiority (Tuekprakhon et al, 2022;Willett et al, 2022). SARS-CoV-2 adaptation to virus-directed antivirals such as remdesivir (RDV) has been reported in vitro (Stevens et al, 2022;Szemiel et al, 2021) and in vivo (Heyer et al, 2022).…”
Section: Discussionmentioning
confidence: 99%
“…Immune selection of SARS-CoV-2 has led to the emergence of VOCs bearing an arsenal of mutations in the spike and other viral proteins, which confer immune evasion capabilities and transmission superiority (Tuekprakhon et al, 2022; Willett et al, 2022). SARS-CoV-2 adaptation to virus-directed antivirals such as remdesivir (RDV) has been reported in vitro (Stevens et al, 2022; Szemiel et al, 2021) and in vivo (Heyer et al, 2022). Here, as early as passage one (P1) under JQ-1 selection, SARS-CoV-2 RNA copies and infectious titers increased in the supernatant and reached a plateau that was maintained across 14 passages despite the subsequent two-fold escalations of JQ-1 concentrations.…”
Inhibitors of bromodomain and extra-terminal proteins (iBETs), including JQ-1, have been suggested as potential therapeutics against SARS-CoV-2 infection. However, molecular mechanisms underlying JQ-1-induced antiviral activity and its susceptibility to viral antagonism remain incompletely understood. iBET treatment transiently inhibited infection by SARS-CoV-2 variants and SARS-CoV, but not MERS-CoV. Our functional assays confirmed JQ-1-mediated downregulation of ACE2 expression and multi-omics analysis uncovered induction of an antiviral NRF-2-mediated cytoprotective response as an additional antiviral component of JQ-1 treatment. Serial passaging of SARS-CoV-2 in the presence of JQ-1 resulted in predominance of ORF6-deficient variants. JQ-1 antiviral activity was transient in human bronchial airway epithelial cells (hBAECs) treated prior to infection and absent when administered therapeutically. We propose that JQ-1 exerts pleiotropic effects that collectively induce a transient antiviral state that is ultimately nullified by an established SARS-CoV-2 infection, raising questions on their clinical suitability in the context of COVID-19.
“…SARS-CoV-2 can adapt to and acquire resistance against potent virus-directed antivirals such as remdesivir (RDV) in vitro (Stevens et al, 2022; Szemiel et al, 2021), a replication bottleneck that induces the emergence SARS-CoV-2 variants in vivo (Heyer et al, 2022). To investigate whether SARS-CoV-2 can acquire resistance to iBETs, we serially passaged it in Calu-3 cells under escalating two-fold concentrations of JQ-1 (Sup.…”
Section: Resultsmentioning
confidence: 99%
“…Immune selection of SARS-CoV-2 has led to the emergence of VOCs bearing an arsenal of mutations in the spike and other viral proteins, which confer immune evasion capabilities and transmission superiority (Tuekprakhon et al, 2022;Willett et al, 2022). SARS-CoV-2 adaptation to virus-directed antivirals such as remdesivir (RDV) has been reported in vitro (Stevens et al, 2022;Szemiel et al, 2021) and in vivo (Heyer et al, 2022).…”
Section: Discussionmentioning
confidence: 99%
“…Immune selection of SARS-CoV-2 has led to the emergence of VOCs bearing an arsenal of mutations in the spike and other viral proteins, which confer immune evasion capabilities and transmission superiority (Tuekprakhon et al, 2022; Willett et al, 2022). SARS-CoV-2 adaptation to virus-directed antivirals such as remdesivir (RDV) has been reported in vitro (Stevens et al, 2022; Szemiel et al, 2021) and in vivo (Heyer et al, 2022). Here, as early as passage one (P1) under JQ-1 selection, SARS-CoV-2 RNA copies and infectious titers increased in the supernatant and reached a plateau that was maintained across 14 passages despite the subsequent two-fold escalations of JQ-1 concentrations.…”
Inhibitors of bromodomain and extra-terminal proteins (iBETs), including JQ-1, have been suggested as potential therapeutics against SARS-CoV-2 infection. However, molecular mechanisms underlying JQ-1-induced antiviral activity and its susceptibility to viral antagonism remain incompletely understood. iBET treatment transiently inhibited infection by SARS-CoV-2 variants and SARS-CoV, but not MERS-CoV. Our functional assays confirmed JQ-1-mediated downregulation of ACE2 expression and multi-omics analysis uncovered induction of an antiviral NRF-2-mediated cytoprotective response as an additional antiviral component of JQ-1 treatment. Serial passaging of SARS-CoV-2 in the presence of JQ-1 resulted in predominance of ORF6-deficient variants. JQ-1 antiviral activity was transient in human bronchial airway epithelial cells (hBAECs) treated prior to infection and absent when administered therapeutically. We propose that JQ-1 exerts pleiotropic effects that collectively induce a transient antiviral state that is ultimately nullified by an established SARS-CoV-2 infection, raising questions on their clinical suitability in the context of COVID-19.
“…Mpro and RdRp mutations were classified as potential drug-resistance mutations if they met one of the following three criteria: (1) they were associated with 2.5-fold or higher reductions in susceptibility in either a biochemical assay or in cell culture; (2) they were selected during an in vitro passage experiment; or (3) they were selected in a person receiving an Mpro or RdRp inhibitor. Figure 3 illustrates that as of September 2022, 42 mutations at 28 positions were reported to be possibly associated with reduced susceptibility to Mpro inhibitors nirmatrelvir or ensitrelvir [22] , [23] , [24] , [25] , [26] , [27] , [28] , [29] , [30] , [31] , [32] , [33] , [34] , [35] , and 11 mutations at 9 positions were reported to be possibly associated with reduced susceptibility to the RdRp inhibitor remdesivir [36] , [37] , [38] , [39] , [40] , [41] , [42] , [43] . Figure 3 SARS-CoV-2 Mpro (A) and RdRp (B) resistance mutations.…”
“…These include a quantitative model of the in-host evolutionary dynamics of coronaviruses under the pressure of a targeted antiviral drug, accompanied by structural-bioinformatic studies of M pro variants in complex with its natural substrate and inhibitors. Evolutionary studies with remdesivir-treated 64 and untreated 65,66 patients have recently been reported. For deepening the knowledge of the evolutionary process of in-host DAA evasion and the resulting impact on druggability, we further propose continuous time-resolved sequencing of SARS-CoV-2 samples collected from COVID-19 patients, who are treated with protease inhibitors, during their treatment phase.…”
Section: Sars-cov-2 M Pro Variants In the Context Of Historical Antiv...mentioning
The current coronavirus pandemic is being combated worldwide by nontherapeutic measures and massive vaccination programs. Nevertheless, therapeutic options such as SARS-CoV-2 main-protease (Mpro) inhibitors are essential due to the ongoing evolution toward escape from natural or induced immunity. While antiviral strategies are vulnerable to the effects of viral mutation, the relatively conserved Mpro makes an attractive drug target: Nirmatrelvir, an antiviral targeting its active site, has been authorized for conditional or emergency use in several countries since December 2021, and a number of other inhibitors are under clinical evaluation. We analyzed recent SARS-CoV-2 genomic data and discovered accelerated mutational dynamics in an eight-residue long consecutive region (R188-G195) near the active site of Mpro since early December 2021. The herein described increased mutational variability in close proximity to an antiviral-drug binding site may suggest the onset of the development of antiviral resistance. This emerging diversity urgently needs to be further monitored and considered in ongoing drug development and lead optimization.
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