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

Abstract

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 (3CLpro). 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 3CLpro 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 3CLpro. 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.

A Review of the Current Landscape of SARS-CoV-2 Main Protease Inhibitors: Have We Hit the Bullseye Yet?

“…A catalytic water molecule is also important and makes a strong hydrogen bond with His41 [ 5 ]. Although some allosteric binding sites have been identified for the SARS-CoV-2 M-pro [ 6 , 7 , 8 , 9 ], most of the inhibitors crystallized within the M-pro bind to the active site [ 10 ]. One strategy used to find SARS-CoV-2 M-pro inhibitors, especially at the beginning of the pandemic, was drug repositioning [ 2 , 11 , 12 , 13 ].…”

Discovery of potential anti-SARS-CoV-2 drugs based on large-scale screening in vitro and effect evaluation in vivo

“…Quinacrine is an effective phospholipase A2 inhibitor and an antimalarial drug, harboring antiviral activity to Ebola virus, Marburg virus, dengue virus type 2, Zika virus, and SARS-CoV-2 (Balasubramanian et al, 2017;Puhl et al, 2021). Raphael et al reported that quinacrine can inhibit SARS-CoV-2 3CL pro (Eberle et al, 2021). Our study revealed that quinacrine may act at multiple stages of SARS-CoV-2 replication, including S-mediated entry and postentry.…”

Structural biology of SARS-CoV-2: open the door for novel therapies

“…There are several other drugs that target RdRp, such as suramin, 247 a poly-sulfonated trypan blue derivative that effectively inhibits a variety of viruses including SARS-CoV-2. 26 In the RdRp-suramin complex (Fig. 6i ), two suramin molecules occupy the catalytic cavity, which in turn blocks the RNA template-primer strand from binding to the active site and blocks NTP substrate entry into the catalytic site.…”

“…However, the emergence of multiple mutants caused by various competitive processes originating from molecule aspect (such as reading frame shifts, replication errors, etc., of virus itself), organism aspect (such as gene re-edit and recombination induced by host adaptive immune response), and population aspect (such as natural selection), 25 making it critical to identify alternative targets and develop more broad-spectrum antiviral drugs. 26 Structural biology can be used to study the pathogenic mechanism of viruses, but also provides theoretical information for drug development and optimization. For this purpose, we summarize the representative structures of SARS-CoV-2 and discuss the development of drugs, antibodies, vaccines, and other therapeutic agents for targeting these proteins or the virus.…”