Repurposing the Ebola and Marburg Virus Inhibitors Tilorone, Quinacrine, and Pyronaridine: In Vitro Activity against SARS-CoV-2 and Potential Mechanisms

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Puhl, Ana C. ^[1] ; Fritch, Ethan J. ^[2] ; Lane, Thomas R. ^[1] ; Tse, V, Longping ; Yount, Boyd L. ^[3] ; Sacramento, Carolina Q. ^{[4, 5]} ; Fintelman-Rodrigues, Natalia ^{[4, 5]} ; Tavella, Tatyana Almeida ^[6] ; Costa, Fabio Trindade Maranhao ^[6] ; Weston, Stuart ^[7] ; Logue, James ^[7] ; Frieman, Matthew ^[7] ; Premkumar, Lakshmanane ^[2] ; Pearce, Kenneth H. ^[8] ; Hurst, Brett L. ^{[9, 10]} ; Andrade, Carolina Horta ^{[11, 6]} ; Levi, James A. ^[12] ; Johnson, Nicole J. ^[12] ; Kisthardt, Samantha C. ^[12] ; Scholle, Frank ^[12] ; Souza, Thiago Moreno L. ^{[4, 5]} ; Moorman, Nathaniel John ^{[2, 8, 13]} ; Baric, Ralph S. ^{[2, 13, 3]} ; Madrid, Peter B. ^[14] ; Ekins, Sean ^[1]

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^[1] Collaborat Pharmaceut Inc, Raleigh, NC 27606 - USA

^[2] Univ N Carolina, Sch Med, Dept Microbiol & Immunol, Chapel Hill, NC 27599 - USA

^[3] Tse, Longping, V, Univ N Carolina, Dept Epidemiol, Sch Med, Chapel Hill, NC 27599 - USA

^[4] Fundacao Oswaldo Cruz Fiocruz, Inst Oswaldo Cruz IOC, Lab Imunofarmacol, BR-21040900 Rio De Janeiro, RJ - Brazil

^[5] Fiocruz MS, Ctr Desenvolvimento Tecnol Saude CDTS, BR-21040900 Rio De Janeiro - Brazil

^[6] Univ Estadual Campinas, UNICAMP, Dept Genet Evolut Microbiol & Immunol, Lab Trop Dis Prof Dr Luiz Jacinto Silva, BR-13083970 Sao Paulo - Brazil

^[7] Univ Maryland, Dept Microbiol & Immunol, Sch Med, Baltimore, MD 21201 - USA

^[8] Univ N Carolina, Eshelman Sch Pharm, Ctr Integrat Chem Biol & Drug Discovery Chem Biol, Chapel Hill, NC 27599 - USA

^[9] Utah State Univ, Inst Antiviral Res, Logan, UT 84322 - USA

^[10] Utah State Univ, Dept Anim Dairy & Vet Sci, Logan, UT 84322 - USA

^[11] Univ Fed Goias, Fac Farm, LabMol Lab Mol Modeling & Drug Design, BR-74605170 Goiania, Go - Brazil

^[12] North Carolina State Univ, Dept Biol Sci, Raleigh, NC 27695 - USA

^[13] Univ N Carolina, Rapidly Emerging Antiviral Drug Discovery Initiat, Chapel Hill, NC 27599 - USA

^[14] SRI Int, 333 Ravenswood Ave, Menlo Pk, CA 94025 - USA

• Tipo de documento: Artigo Científico
• Fonte: ACS OMEGA; v. 6, n. 11, p. 7454-7468, MAR 23 2021.
• Citações Web of Science: 0

Resumo

Severe acute respiratory coronavirus 2 (SARS-CoV-2) is a newly identified virus that has resulted in over 2.5 million deaths globally and over 116 million cases globally in March, 2021. Small-molecule inhibitors that reverse disease severity have proven difficult to discover. One of the key approaches that has been widely applied in an effort to speed up the translation of drugs is drug repurposing. A few drugs have shown in vitro activity against Ebola viruses and demonstrated activity against SARS-CoV-2 in vivo. Most notably, the RNA polymerase targeting remdesivir demonstrated activity in vitro and efficacy in the early stage of the disease in humans. Testing other small-molecule drugs that are active against Ebola viruses (EBOVs) would appear a reasonable strategy to evaluate their potential for SARS-CoV-2. We have previously repurposed pyronaridine, tilorone, and quinacrine (from malaria, influenza, and antiprotozoal uses, respectively) as inhibitors of Ebola and Marburg viruses in vitro in HeLa cells and mouse-adapted EBOV in mice in vivo. We have now tested these three drugs in various cell lines (VeroE6, Vero76, Caco-2, Calu-3, A549-ACE2, HUH-7, and monocytes) infected with SARS-CoV-2 as well as other viruses (including MHV and HCoV 229E). The compilation of these results indicated considerable variability in antiviral activity observed across cell lines. We found that tilorone and pyronaridine inhibited the virus replication in A549-ACE2 cells with IC50 values of 180 nM and IC50 198 nM, respectively. We used microscale thermophoresis to test the binding of these molecules to the spike protein, and tilorone and pyronaridine bind to the spike receptor binding domain protein with K-d values of 339 and 647 nM, respectively. Human C-max for pyronaridine and quinacrine is greater than the IC50 observed in A549-ACE2 cells. We also provide novel insights into the mechanism of these compounds which is likely lysosomotropic. (AU)

• Processo FAPESP: 19/27626-3 - Identificação de novos tratamentos antimaláricos através de uma abordagem de "reposicionamento de fármacos" centrada no alvo
• Beneficiário: Tatyana Almeida Tavella
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado
• Processo FAPESP: 17/18611-7 - Desenvolvimento de novas ferramentas para busca e validação de alvos moleculares para terapia contra Plasmodium vivax
• Beneficiário: Fabio Trindade Maranhão Costa
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 20/05369-6 - Estratégia acelerada por inteligência artificial para reposicionamento de fármacos contra COVID-19
• Beneficiário: Fabio Trindade Maranhão Costa
• Modalidade de apoio: Auxílio à Pesquisa - Regular