SRX3177, a CDK4/6-PI3K-BET inhibitor, in combination with an RdRp inhibitor, Molnupiravir, or an entry inhibitor MU-UNMC-2, has potent antiviral activity against the Omicron variant of SARS-CoV-2

IF 4.5 2区 医学 Q1 PHARMACOLOGY & PHARMACY
Kabita Pandey , Arpan Acharya , Dhananjaya Pal , Prashant Jain , Kamal Singh , Donald L. Durden , Tatiana G. Kutateladze , Aniruddha J. Deshpande , Siddappa N. Byrareddy
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Abstract

Despite considerable progress in developing vaccines and antivirals to combat COVID-19, the rapid mutations of the SARS-CoV-2 genome have limited the durability and efficacy of the current vaccines and therapeutic interventions. Hence, it necessitates the development of novel therapeutic approaches or repurposing existing drugs that target either viral life cycle, host factors, or both. Here, we report that SRX3177, a potent triple-activity CDK4/6-PI3K-BET inhibitor, blocks replication of the SARS-CoV-2 Omicron variant with IC50 values at sub-micromolar concentrations without any impact on the cell proliferation of Calu-3 cells at and below its IC50 concentration. When SRX3177 is combined with EIDD-1931 (active moiety of a small-molecule prodrug Molnupiravir) or MU-UNMC-2 (a SARS-CoV-2 entry inhibitor) at a fixed doses matrix, a synergistic effect was observed, leading to the significant reduction in the dose of the individual compounds to achieve similar inhibition of SARS-CoV-2 replication. Herein, we report that the combination of SRX3177/MPV or SRX3177/UM-UNMC-2 has the potential for further development as a combinational therapy against SARS-CoV-2 and in any future outbreak of beta coronavirus.

SRX3177 是一种 CDK4/6-PI3K-BET 抑制剂,与 RdRp 抑制剂 Molnupiravir 或入口抑制剂 MU-UNMC-2 联合使用,对 SARS-CoV-2 的 Omicron 变体具有很强的抗病毒活性。
尽管在开发抗 COVID-19 疫苗和抗病毒药物方面取得了很大进展,但 SARS-CoV-2 基因组的快速变异限制了现有疫苗和治疗干预措施的持久性和有效性。因此,有必要针对病毒生命周期、宿主因素或两者开发新的治疗方法或重新利用现有药物。在这里,我们报告了一种强效的三重活性 CDK4/6-PI3K-BET 抑制剂 SRX3177,它能阻断 SARS-CoV-2 Omicron 变体的复制,其 IC50 值为亚微摩浓度,在其 IC50 浓度及以下不会对 Calu-3 细胞的增殖产生任何影响。当 SRX3177 与 EIDD-1931(小分子原药 Molnupiravir 的活性分子)或 MU-UNMC-2(SARS-CoV-2 进入抑制剂)以固定剂量基质结合使用时,观察到了协同效应,从而显著降低了单个化合物的剂量,以达到类似的抑制 SARS-CoV-2 复制的效果。研究结果表明,SRX3177/MPV 或 SRX3177/UM-UNMC-2 有可能被进一步开发为抗击 SARS-CoV-2 和未来任何β冠状病毒爆发的联合疗法。
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来源期刊
Antiviral research
Antiviral research 医学-病毒学
CiteScore
17.10
自引率
3.90%
发文量
157
审稿时长
34 days
期刊介绍: Antiviral Research is a journal that focuses on various aspects of controlling viral infections in both humans and animals. It is a platform for publishing research reports, short communications, review articles, and commentaries. The journal covers a wide range of topics including antiviral drugs, antibodies, and host-response modifiers. These topics encompass their synthesis, in vitro and in vivo testing, as well as mechanisms of action. Additionally, the journal also publishes studies on the development of new or improved vaccines against viral infections in humans. It delves into assessing the safety of drugs and vaccines, tracking the evolution of drug or vaccine-resistant viruses, and developing effective countermeasures. Another area of interest includes the identification and validation of new drug targets. The journal further explores laboratory animal models of viral diseases, investigates the pathogenesis of viral diseases, and examines the mechanisms by which viruses avoid host immune responses.
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