Structural basis for repurposing a 100-years-old drug suramin for treating COVID-19

Yin, Wanchao; Luan, Xiaodong; Li, Zhihai; Zhang, Leike; Zhou, Ziwei; Gao, Minqi; Wang, Xiaoxi; Zhou, Fulai; Shi, Jingjing; You, Erli; Liu, Mingliang; Wang, Qingxia; Wang, Qingxing; Jiang, Yi; Jiang, Hualiang; Xiao, Gengfu; Yu, Xuekui; Zhang, Shuyang; Xu, H. Eric

doi:10.1101/2020.10.06.328336

Cited by 6 publications

(4 citation statements)

References 33 publications

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“…As target proteins for quinacrine, ACE2 (SARS-CoV-2 receptor) and furin were identified [ 28 ]. Suramin was reported to bind to SARS-CoV-2 nsp12 (RdRp), acting as a potent inhibitor of the RdRp by blocking the binding of RNA to enzymes [ 58 ].…”

Section: Resultsmentioning

confidence: 99%

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

Eberle

Olivier

Amaral

et al. 2021

Viruses

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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.

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Section: Resultsmentioning

confidence: 99%

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

Eberle

Olivier

Amaral

et al. 2021

Viruses

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“…1) and RNA-dependent RNA polymerase Structure of SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) bound to suramin (PDB ID: 7D4F) (Fig. 1) (Yin et al, 2020), were obtained from the RCSB protein databank (https:/www.rscb.org/pdb). The proteins receptor structures were prepared by 3D protonation and energy minimization using Molecular Operating Environment software (MOE 2014.0901) Ligx option.…”

Section: Molecular Dockingmentioning

confidence: 99%

Phytochemical and in silico studies for potential constituents from Centaurium spicatum as candidates against the SARS-CoV-2 main protease and RNA-dependent RNA polymerase

Allam

Abouelela

Assaf

et al. 2021

Natural Product Research

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“…This is of particular interest in the currently selected example, as the 100-year-old drug suramin was subject to several successful repurposing strategies, where some targets are intracellular, beyond cell walls . Moreover, it even shows promise against the current SARS-CoV-2 infection by inhibiting key interactions during viral reproduction, , however, its affinity to lipid bilayers is not explored. To this end, linear dichroism (LD) measurements were used, a technique suitable to study systems that are either intrinsically oriented or can be oriented by external forces.…”

Section: Introductionmentioning

confidence: 99%

Controlling Peptide Function by Directed Assembly Formation: Mechanistic Insights Using Multiscale Modeling on an Antimicrobial Peptide–Drug–Membrane System

et al. 2021

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Owing to their potential applicability against multidrug-resistant bacteria, antimicrobial peptides (AMPs) or host defense peptides (HDPs) gain increased attention. Besides diverse immunomodulatory roles, their classical mechanism of action mostly involves membrane disruption of microbes. Notably, their unbalanced overexpression has also been associated with host cell cytotoxicity in various diseases. Relatedly, AMPs can be subject to aggregate formation, either via self-assembly or together with other compounds, which has demonstrated a modulation effect on their biological functions, thus highly relevant both for drug targeting projects and understanding their in vivo actions. However, the molecular aspects of the related assembly formation are not understood. Here, we focused in detail on an experimentally studied AMP−drug system, i.e., CM15−suramin, and performed all-atom and coarse-grain (CG) simulations. Results obtained for all systems were in close line with experimental observations and indicate that the CM15−suramin aggregation is an energetically favorable and dynamic process. In the presence of bilayers, the peptide−drug assembly formation was highly dependent on lipid composition, and peptide aggregates themselves were also capable of binding to the membranes. Interestingly, longer CG simulations with zwitterionic membranes indicated an intermediate state in the presence of both AMP−drug assemblies and monomeric peptides located on the membrane surface. In sharp contrast, larger AMP−drug aggregates could not be detected with a negatively charged membrane, rather the AMPs penetrated its surface in a monomeric form, in line with previous in vitro observations. Considering experimental and theoretical results, it is promoted that in biological systems, cationic AMPs may often form associates with anionic compounds in a reversible manner, resulting in lower bioactivity. This is only mildly affected by zwitterionic membranes; however, membranes with a negative charge strongly alter the energetic preference of AMP assemblies, resulting in the dissolution of the complexes into the membrane. The phenomenon observed here at a molecular level can be followed in several experimental systems studied recently, where peptides interact with food colors, drug molecules, or endogenous compounds, which strongly indicates that reversible associate formation is a general phenomenon for these complexes. These results are hoped to be exploited in novel therapeutic strategies aiming to use peptides as drug targets and control AMP bioactivity by directed assembly formation.

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Structural basis for repurposing a 100-years-old drug suramin for treating COVID-19

Cited by 6 publications

References 33 publications

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

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

Phytochemical and in silico studies for potential constituents from Centaurium spicatum as candidates against the SARS-CoV-2 main protease and RNA-dependent RNA polymerase

Controlling Peptide Function by Directed Assembly Formation: Mechanistic Insights Using Multiscale Modeling on an Antimicrobial Peptide–Drug–Membrane System

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