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

被引：2

作者：

Pandey, Kabita ^{[1
]}

Acharya, Arpan ^{[1
]}

Pal, Dhananjaya ^{[5
,6
]}

Jain, Prashant ^{[2
]}

Singh, Kamal ^{[3
,4
]}

Durden, Donald L. ^{[5
,6
]}

Kutateladze, Tatiana G. ^{[7
]}

Deshpande, Aniruddha J. ^{[2
]}

Byrareddy, Siddappa N. ^{[1
]}

机构：

[1] Univ Nebraska Med Ctr, Dept Pharmacol & Expt Neurosci, Omaha, NE 68131 USA

[2] Sanford Burnham Prebys Med Discovery Inst, NCI, Designated Canc Ctr, Canc Genome & Epigenet Program, La Jolla, CA 92127 USA

[3] Univ Missouri, Bond Life Sci Ctr, Columbia, MO USA

[4] Univ Missouri, Dept Vet Pathobiol, Columbia, MO USA

[5] Levine Canc Inst, Mol Targeted Therapeut Lab, Charlotte, NC 28204 USA

[6] Univ Calif San Diego, Moores Canc Ctr, Dept Pediat, Div Hematol & Oncol, La Jolla, CA 92037 USA

[7] Univ Colorado, Sch Med, Dept Pharmacol, Aurora, CO 80045 USA

来源：

ANTIVIRAL RESEARCH | 2024年 / 227卷

关键词：

Triple inhibitor; SRX3177; RdRp inhibitor; Entry inhibitor; Combinatorial; SARS-CoV-2; Omicron; MU-UNMC-2;

D O I：

10.1016/j.antiviral.2024.105904

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

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 tripleactivity 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/UMUNMC-2 has the potential for further development as a combinational therapy against SARS-CoV-2 and in any future outbreak of beta coronavirus.

引用

页数：7