The Repurposed Drugs Suramin and Quinacrine Cooperatively Inhibit SARS-CoV-2 3CLpro In Vitro

Viruses

DaniloS. Olivier¹  Ian Gering²  MonikaA. Coronado²  RaphaelJ. Eberle²  Dieter Willbold²  MarcosS. Amaral³  RaghuvirK. Arni⁴ 

[1] Campus Cimba, Federal University of Tocantins, Araguaína, TO 77824-838, Brazil;Institute of Biological Information Processing (IBI-7: Structural Biochemistry), Forschungszentrum Jülich, 52428 Jülich, Germany;Institute of Physics, Federal University of Mato Grosso do Sul, Campo Grande, MS 79070-900, Brazil;Multiuser Center for Biomolecular Innovation, IBILCE, Universidade Estadual Paulista (UNESP), São Jose do Rio Preto, SP 15054-000, Brazil;

关键词: SARS-CoV-2;    COVID-19;    3CL^pro;    main protease;    repurposing approved drugs;    suramin;   

DOI  :  10.3390/v13050873

来源: DOAJ

【 摘 要 】

Since the first report of a new pneumonia disease in December 2019 (Wuhan, China) the WHO reported more than 148 million confirmed cases and 3.1 million losses globally up to now. The causative agent of COVID-19 (SARS-CoV-2) has spread worldwide, resulting in a pandemic of unprecedented magnitude. To date, several clinically safe and efficient vaccines (e.g., Pfizer-BioNTech, Moderna, Johnson & Johnson, and AstraZeneca COVID-19 vaccines) as well as drugs for emergency use have been approved. However, increasing numbers of SARS-Cov-2 variants make it imminent to identify an alternative way to treat SARS-CoV-2 infections. A well-known strategy to identify molecules with inhibitory potential against SARS-CoV-2 proteins is repurposing clinically developed drugs, e.g., antiparasitic drugs. The results described in this study demonstrated the inhibitory potential of quinacrine and suramin against SARS-CoV-2 main protease (3CL^pro). Quinacrine and suramin molecules presented a competitive and noncompetitive inhibition mode, respectively, with IC₅₀ values in the low micromolar range. Surface plasmon resonance (SPR) experiments demonstrated that quinacrine and suramin alone possessed a moderate or weak affinity with SARS-CoV-2 3CL^pro but suramin binding increased quinacrine interaction by around a factor of eight. Using docking and molecular dynamics simulations, we identified a possible binding mode and the amino acids involved in these interactions. Our results suggested that suramin, in combination with quinacrine, showed promising synergistic efficacy to inhibit SARS-CoV-2 3CL^pro. We suppose that the identification of effective, synergistic drug combinations could lead to the design of better treatments for the COVID-19 disease and repurposable drug candidates offer fast therapeutic breakthroughs, mainly in a pandemic moment.

【 授权许可】

Unknown