Quinine Inhibits Infection of Human Cell Lines with SARS-CoV-2.

Maximilian Große,Ekkehard Brysch,Sascha Rheber,Mirjam Layer,Ramona Businger,Maria Fröba,Dan Hu,Janina Auth,Pia Rauch,Christian Setz,Ulrich Schubert,Natalia Ruetalo,Michael Schindler

doi:10.3390/v13040647

Maximilian Große, Ekkehard Brysch + Show 11 more

Open Access

https://doi.org/10.3390/v13040647

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Abstract

While vaccination campaigns are ongoing worldwide, there is still a tremendous medical need for efficient antivirals against SARS-CoV-2 infection. Among several drug candidates, chloroquine (CQN) and hydroxychloroquine (H-CQN) were tested intensively, and any contentious therapeutic effect of both has been discussed controversially in the light of severe side effects and missing efficacy. Originally, H-CQN descended from the natural substance quinine, a medicinal product used since the Middle Ages, which actually is regulatory approved for various indications. We hypothesized that quinine also exerts anti-SARS-CoV-2 activity. In Vero cells, quinine inhibited SARS-CoV-2 infection more effectively than CQN, and H-CQN and was less toxic. In human Caco-2 colon epithelial cells as well as the lung cell line A549 stably expressing ACE2 and TMPRSS2, quinine also showed antiviral activity. In consistence with Vero cells, quinine was less toxic in A549 as compared to CQN and H-CQN. Finally, we confirmed our findings in Calu-3 lung cells, expressing ACE2 and TMPRSS2 endogenously. In Calu-3, infections with high titers of SARS-CoV-2 were completely blocked by quinine, CQN, and H-CQN in concentrations above 50 µM. The estimated IC50s were ~25 µM in Calu-3, while overall, the inhibitors exhibit IC50 values between ~3.7 to ~50 µM, dependent on the cell line and multiplicity of infection (MOI). Conclusively, our data indicate that quinine could have the potential of a treatment option for SARS-CoV-2, as the toxicological and pharmacological profile seems more favorable when compared to its progeny drugs H-CQN or CQN.

Highlights

In order to analyze if quinine displays antiviral activity against SARS-CoV-2, first, Vero B4 cells were infected with SARS-CoV-2PR1 and treated with quinine, either as Q-L
Quinine displays an even higher efficacy in the inhibition of SARS-CoV-2 replication than H-CQN or CQN: at 10 μM quinine, the replication was reduced by up to 90%, whereas 10 μM H-CQN led to a reduction of ~50%
The natural substance quinine exerts antiviral activity against SARS-CoV-2 that was comparable to its chemical derivatives, H-CQN and CQN, in TMPRSS2+

Summary

Introduction

Infection with SARS-CoV-2 can cause the multi-organ disease COVID-19 (Coronavirus disease 2019), resulting, among other pathologies, in the acute respiratory distress syndrome (ARDS), a clinical condition of acute lung injury with severe hypoxemia [1]. Of all SARS-CoV-2-infected people, 80% remain asymptomatic or develop only mild symptoms, while others require hospitalization [2]. As of 11.03.2021, over 118 million COVID-19 cases have been confirmed that have caused over 2.6 million deaths worldwide, according to Johns Hopkins University reports [3]. While vaccination campaigns are ongoing, the only antiviral therapeutic option approved in the U.S for late-stage hospitalized patients remains remdesivir, a nucleotide analog originally developed to cure Ebola infection [4]. Some repurposed drugs were in clinical development: favipiravir, an inhibitor of a viral RNA-dependent

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