Acharya Arpan, Pandey Kabita, Thurman Michellie, Challagundala Kishore B, Vann Kendra R, Kutateladze Tatiana G, Morales Guillermo A, Durden Donald L, Byrareddy Siddappa N
bioRxiv. 2021 Mar 5:2021.03.02.433604. doi: 10.1101/2021.03.02.433604.
Pathogenic viruses like SARS-CoV-2 and HIV hijack the host molecular machinery to establish infection and survival in infected cells. This has led the scientific community to explore the molecular mechanisms by which SARS-CoV-2 infects host cells, establishes productive infection, and causes life-threatening pathophysiology. Very few targeted therapeutics for COVID-19 currently exist, such as remdesivir. Recently, a proteomic approach explored the interactions of 26 of 29 SARS-CoV-2 proteins with cellular targets in human cells and identified 67 interactions as potential targets for drug development. Two of the critical targets, the bromodomain and extra-terminal domain proteins (BETs): BRD2/BRD4 and mTOR, are inhibited by the dual inhibitory small molecule SF2523 at nanomolar potency. SF2523 is the only known mTOR PI3K-α/(BRD2/BRD4) inhibitor with potential to block two orthogonal pathways necessary for SARS-CoV-2 pathogenesis in human cells. Our results demonstrate that SF2523 effectively blocks SARS-CoV-2 replication in lung bronchial epithelial cells , showing an IC value of 1.5 µM, comparable to IC value of remdesivir (1.1 µM). Further, we demonstrated that the combination of doses of SF2523 and remdesivir is highly synergistic: it allows for the reduction of doses of SF2523 and remdesivir by 25-fold and 4-fold, respectively, to achieve the same potency observed for a single inhibitor. Because SF2523 inhibits two SARS-CoV-2 driven pathogenesis mechanisms involving BRD2/BRD4 and mTOR signaling, our data suggest that SF2523 alone or in combination with remdesivir could be a novel and efficient therapeutic strategy to block SARS-CoV-2 infection and hence be beneficial in preventing severe COVID-19 disease evolution.
Evidence of designed chemotype (SF2523) targeting PI3K-α/mTOR/BRD4 inhibits SARS-CoV-2 infection and is highly synergistic with remdesivir.
像严重急性呼吸综合征冠状病毒2（SARS-CoV-2）和人类免疫缺陷病毒（HIV）这样的致病病毒会劫持宿主分子机制，以便在受感染细胞中建立感染并存活。这促使科学界探索SARS-CoV-2感染宿主细胞、建立有效感染并导致危及生命的病理生理学的分子机制。目前针对2019冠状病毒病（COVID-19）的靶向治疗药物非常少，比如瑞德西韦。最近，一种蛋白质组学方法探究了29种SARS-CoV-2蛋白中的26种与人类细胞中细胞靶点的相互作用，并确定了67种相互作用作为药物开发的潜在靶点。两个关键靶点，即含溴结构域和额外末端结构域蛋白（BETs）：BRD2/BRD4和雷帕霉素靶蛋白（mTOR），被双抑制小分子SF2523以纳摩尔效力抑制。SF2523是唯一已知的具有阻断人类细胞中SARS-CoV-2发病机制所需的两条正交途径潜力的mTOR磷脂酰肌醇-3-激酶-α/（BRD2/BRD4）抑制剂。我们的结果表明，SF2523能有效阻断SARS-CoV-2在肺支气管上皮细胞中的复制，显示出1.5微摩尔的半数抑制浓度（IC）值，与瑞德西韦的IC值（1.1微摩尔）相当。此外，我们证明了SF2523和瑞德西韦的剂量组合具有高度协同性：它能分别将SF2523和瑞德西韦的剂量降低25倍和4倍，以达到单一抑制剂所观察到的相同效力。由于SF2523抑制了两种由SARS-CoV-2驱动的涉及BRD2/BRD4和mTOR信号传导的发病机制，我们的数据表明，单独使用SF2523或与瑞德西韦联合使用可能是一种新型且有效的治疗策略，以阻断SARS-CoV-2感染，从而有利于预防严重COVID-19疾病的进展。
靶向磷脂酰肌醇-3-激酶-α/雷帕霉素靶蛋白/含溴结构域蛋白4（PI3K-α/mTOR/BRD4）的设计化学型（SF2523）的证据抑制了SARS-CoV-2感染，且与瑞德西韦具有高度协同性。
