The Repurposed Drugs Suramin and Quinacrine Cooperatively Inhibit SARS-CoV-2 3CL(pro) In Vitro

Autor(es)

Eberle, Raphael J. ^{[1, 2]} ; Olivier, Danilo S. ^[3] ; Amaral, Marcos S. ^[4] ; Gering, Ian ^[1] ; Willbold, Dieter ^{[1, 2, 5]} ; Arni, Raghuvir K. ^[6] ; Coronado, Monika A. ^{[1, 6]}

Afiliação do(s) autor(es)

^[1] Forschungszentrum Julich, Inst Biol Informat Proc IBI Struct Biochem 7, D-52428 Julich - Germany

^[2] Heinrich Heine Univ Dusseldorf, Inst Phys Biol, Univ Str, D-40225 Dusseldorf - Germany

^[3] Fed Univ Tocantins, Campus Cimba, BR-77824838 Araguaina, TO - Brazil

^[4] Univ Fed Mato Grosso do Sul, Inst Phys, BR-79070900 Campo Grande, MS - Brazil

^[5] Forchungszentrum Julich, JuStruct Julich Ctr Struct Biol, D-52428 Julich - Germany

^[6] Univ Estadual Paulista UNESP, IBILCE, Multiuser Ctr Biomol Innovat, BR-15054000 Sao Jose Do Rio Preto, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: Viruses-Basel; v. 13, n. 5 MAY 2021.
• Citações Web of Science: 1

Resumo

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. (AU)

• Processo FAPESP: 16/12904-0 - Mecanismos e Interações Moleculares de Moléculas Bioativas com a Protease NS3 do Zika Vírus.
• Beneficiário: Monika Aparecida Coronado
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 19/05614-3 - Identificação de moléculas bioativas que inibem a atividades dos vírus Chikungunya e Mayaro
• Beneficiário: Raphael Josef Eberle
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Pós-Doutorado
• Processo FAPESP: 18/12659-0 - Mecanismos e Interações Moleculares de Moléculas Bioativas com a Protease NS3 do Zika Vírus - De novo drug design -
• Beneficiário: Monika Aparecida Coronado
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Pós-Doutorado
• Processo FAPESP: 18/07572-3 - Explorando a protease nsP2 dos vírus Chikungunya e Mayaro: estruturas e inibição.
• Beneficiário: Raphael Josef Eberle
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado