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Antimalarial drugs inhibit the replication of SARS-CoV-2: An in vitro evaluation.

ABSTRACT: In December 2019, a new severe acute respiratory syndrome coronavirus (SARS-CoV-2) causing coronavirus diseases 2019 (COVID-19) emerged in Wuhan, China. African countries see slower dynamic of COVID-19 cases and deaths. One of the assumptions that may explain this later emergence in Africa, and more particularly in malaria endemic areas, would be the use of antimalarial drugs. We investigated the in vitro antiviral activity against SARS-CoV-2 of several antimalarial drugs. Chloroquine (EC50 = 2.1 ?M and EC90 = 3.8 ?M), hydroxychloroquine (EC50 = 1.5 ?M and EC90 = 3.0 ?M), ferroquine (EC50 = 1.5 ?M and EC90 = 2.4 ?M), desethylamodiaquine (EC50 = 0.52 ?M and EC90 = 1.9 ?M), mefloquine (EC50 = 1.8 ?M and EC90 = 8.1 ?M), pyronaridine (EC50 = 0.72 ?M and EC90 = 0.75 ?M) and quinine (EC50 = 10.7 ?M and EC90 = 38.8 ?M) showed in vitro antiviral effective activity with IC50 and IC90 compatible with drug oral uptake at doses commonly administered in malaria treatment. The ratio Clung/EC90 ranged from 5 to 59. Lumefantrine, piperaquine and dihydroartemisinin had IC50 and IC90 too high to be compatible with expected plasma concentrations (ratio Cmax/EC90 < 0.05). Based on our results, we would expect that countries which commonly use artesunate-amodiaquine or artesunate-mefloquine report fewer cases and deaths than those using artemether-lumefantrine or dihydroartemisinin-piperaquine. It could be necessary now to compare the antimalarial use and the dynamics of COVID-19 country by country to confirm this hypothesis.

SUBMITTER: Gendrot M

PROVIDER: S-EPMC7477610 | biostudies-literature | 2020 Sep - Oct

REPOSITORIES: biostudies-literature

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Antimalarial drugs inhibit the replication of SARS-CoV-2: An in vitro evaluation.

Gendrot Mathieu M Andreani Julien J Boxberger Manon M Jardot Priscilla P Fonta Isabelle I Le Bideau Marion M Duflot Isabelle I Mosnier Joel J Rolland Clara C Bogreau Hervé H Hutter Sébastien S La Scola Bernard B Pradines Bruno B

Travel medicine and infectious disease 20200908

In December 2019, a new severe acute respiratory syndrome coronavirus (SARS-CoV-2) causing coronavirus diseases 2019 (COVID-19) emerged in Wuhan, China. African countries see slower dynamic of COVID-19 cases and deaths. One of the assumptions that may explain this later emergence in Africa, and more particularly in malaria endemic areas, would be the use of antimalarial drugs. We investigated the in vitro antiviral activity against SARS-CoV-2 of several antimalarial drugs. Chloroquine (EC<sub>50 ...[more]

PMID: 32916297

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Project description:The SARS-CoV-2 pandemic, and the likelihood of future coronavirus pandemics, has rendered our understanding of coronavirus biology more essential than ever. Small molecule chemical probes offer to both reveal novel aspects of virus replication and to serve as leads for antiviral therapeutic development. The RNA-biased amiloride scaffold was recently tuned to target a viral RNA structure critical for translation in enterovirus 71, ultimately uncovering a novel mechanism to modulate positive-sense RNA viral translation and replication. Analysis of CoV RNA genomes reveal many conserved RNA structures in the 5'-UTR and proximal region critical for viral translation and replication, including several containing bulge-like secondary structures suitable for small molecule targeting. Following phylogenetic conservation analysis of this region, we screened an amiloride-based small molecule library against a less virulent human coronavirus, OC43, to identify lead ligands. Amilorides inhibited OC43 replication as seen in viral plaque assays. Select amilorides also potently inhibited replication competent SARS-CoV-2 as evident in the decreased levels of cell free virions in cell culture supernatants of treated cells. Reporter screens confirmed the importance of RNA structures in the 5'-end of the viral genome for small molecule activity. Finally, NMR chemical shift perturbation studies of the first six stem loops of the 5'-end revealed specific amiloride interactions with stem loops 4, 5a, and 6, all of which contain bulge like structures and were predicted to be strongly bound by the lead amilorides in retrospective docking studies. Taken together, the use of multiple orthogonal approaches allowed us to identify the first small molecules aimed at targeting RNA structures within the 5'-UTR and proximal region of the CoV genome. These molecules will serve as chemical probes to further understand CoV RNA biology and can pave the way for the development of specific CoV RNA-targeted antivirals.

Dataset Information

Antimalarial drugs inhibit the replication of SARS-CoV-2: An in vitro evaluation.

Publications

Antimalarial drugs inhibit the replication of SARS-CoV-2: An in vitro evaluation.

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