PI3K‐α/mTOR/BRD4 inhibitor alone or in combination with other anti‐virals blocks replication of SARS‐CoV‐2 and its variants of concern including Delta and Omicron

Abstract

Dear Editor, We demonstrated that SF2523, a dual small molecule inhibitor of PI3K-α/mTOR/BRD4 pathways, can inhibit the replication of SARS-CoV-2 and its emerging variants of concern (VOCs), including Delta and Omicron. Further, we also found that SF2523 acts synergistically with remdesivir (RDV) and MU-UNMC-2 (a small molecule entry inhibitor of SARS-CoV-2). 1 The ongoing COVID-19 pandemic due to the emergence of a novel coronavirus SARS-CoV-2 remains a significant health concern globally. Several vaccine candidates and anti-virals received emergency use authorization. However, these vaccines/anti-virals safety, efficacy and durability remain unknown, especially for the individuals with comorbid conditions, and VOCs, such as Delta, Omicron, BA.2 and Deltacron, which have evolved mutations in the receptor-binding domain of SARS-CoV-2 spike protein may even evade antibodies induced by vaccines or natural infection. 2 Similarly, recently FDA-approved Molnupiravir and PAXLOVID remain sensitive towards VOCs. 3 The indepth understanding of the molecular mechanism of the SARS-CoV-2 lifecycle revealed the interaction of several host factors with viral proteins essential for the reproduction of progeny viruses, such as bromodomain, containing extra-terminal domain proteins (BETs), and the mTOR pathway. 4 Recent studies identified 67 potential interactions between host and viral proteins essential for the SARS-CoV-2 lifecycle, like BRD2/BRD4 with the E protein of SARS-CoV-2, 4 and suggested that BRD2 inhibition downregulates ACE2 expression, blocks the entry of SARS-CoV-2 into host cells and controls hyperactive immune response in COVID-19 patients through downregulation Interferon stimulated genes (ISGs). 5 Targeted therapies that exploit host-virus interaction are likely to be least impacted by the VOCs of SARS-CoV-2 andThis is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Binding of the SARS-CoV-2 envelope E protein to human BRD4 is essential for infection

“…BRD4 is known to mediate immune and inflammatory responses to viral infection and was recently reported to regulate COVID-19-mediated cytokine storm and cardiac damage ( Mills et al., 2021 ). Furthermore, BET inhibitors were shown to downregulate the expression of viral host entry factors, such as angiotensin-converting enzyme 2 (ACE2), thereby limiting SARS-CoV-2 replication in vitro ( Gilham et al., 2021 ; Qiao et al., 2020 ), and have potent anti-viral activity ( Acharya et al., 2022 ; Qiao et al., 2020 ; Samelson et al., 2022 ). To examine the importance of the BRD4-E interaction for the SARS-CoV-2 life cycle, we infected the human lung bronchial epithelial cell line Calu-3 with a Delta variant of SARS-CoV-2 (pangolin linage B.1.617.2) and monitored infection by immunofluorescence ( Figures 4 A and 4B).…”

Combining antiviral drugs with BET inhibitors is beneficial in combatting SARS‐CoV‐2 infection

“…Recently, we showed in vitro efficacy of SF2523 as a monotherapy and combined with remdesivir (RDV) or the newly developed inhibitor MU‐UNMC‐2. We found that SF2523, an inhibitor of PI3K‐α/mTOR/BRD4, effectively blocks the replication of SARS‐CoV‐2 and its VOCs, including delta and omicron 15 . Furthermore, SF2523 acts in synergy with the antiviral drug RDV and MU‐UNMC‐2, a small molecule inhibitor that blocks the entry of SARS‐CoV‐2 18 .…”

“…LARP1 downregulation by mTOR inhibitors blocks MERS virus replication and has an immunosuppressive function 14 . We have shown that BRD2/BRD4 and mTOR are critical host factors responsible for the pathogenesis of SARS‐CoV‐2 based on the activity of the small molecule SF2523 15 . SF2523 is a potent inhibitor of PI3Kα (IC 50 = 34 nM), PI3Kγ (IC 50 = 158 nM), DNA‐PK (IC 50 = 9 nM), BRD4 (IC 50 = 241 nM), and mTOR (IC 50 = 280 nM).…”

Promoting autophagy to mitigate coronavirus disease pathology in the elderly

“…As this demographic often faces decreased vaccine-provided immunity, coronavirus disease 2019 treatments must be developed. We discuss a recent study by Acharya et al (2022) that found that SF2523 induced autophagy, reducing SARS-CoV-2 replication. Furthermore, across varying dosages, SF2523 was shown to have a synergistic effect with remdesivir or MU-UNMC.…”