Suramin Inhibits Chikungunya Virus Replication by Interacting with Virions and Blocking the Early Steps of Infection

Abstract

Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus that can cause a debilitating disease that is primarily characterized by persistent joint pain. CHIKV has been emerging globally, while neither a vaccine nor antiviral medication is available. The anti-parasitic drug suramin was previously shown to inhibit CHIKV replication. In this study we aimed to obtain more detailed insight into its mechanism of action. We found that suramin interacts with virions and can inhibit virus binding to cells. It also appeared to inhibit post-attachment steps of the infection process, likely by preventing conformational changes of the envelope glycoproteins required for fusion and the progression of infection. Suramin-resistant CHIKV strains were selected and genotyping and reverse genetics experiments indicated that mutations in E2 were responsible for resistance. The substitutions N5R and H18Q were reverse engineered in the E2 glycoprotein in order to understand their role in resistance. The binding of suramin-resistant viruses with these two E2 mutations was inhibited by suramin like that of wild-type virus, but they appeared to be able to overcome the post-attachment inhibitory effect of suramin. Conversely, a virus with a G82R mutation in E2 (implicated in attenuation of vaccine strain 181/25), which renders it dependent on the interaction with heparan sulfate for entry, was more sensitive to suramin than wild-type virus. Using molecular modelling studies, we predicted the potential suramin binding sites on the mature spikes of the chikungunya virion. We conclude that suramin interferes with CHIKV entry by interacting with the E2 envelope protein, which inhibits attachment and also interferes with conformational changes required for fusion.

Suramin Inhibits SARS-CoV-2 Infection in Cell Culture by Interfering with Early Steps of the Replication Cycle

“…This is in agreement with other studies that also reported on the inhibition of virus binding or entry by suramin (16,23,27). Several studies have suggested that negatively charged suramin molecules can bind to positive charges on virions (22,28,29). Our data suggest that the antiviral effect of suramin is primarily due to inhibition of an early step in the SARS-CoV-2 replication cycle, and we suspect that this is due to binding of the compound to SARS-CoV-2 virions, interfering with their binding to the cell receptor and possibly also inhibiting fusion.…”

Antiviral Strategies against Arthritogenic Alphaviruses

“…Suramin, an anti-trypanosomiasis drug ( Figure 2 ), has also been reported to inhibit the replication of different CHIKV isolates and related alphaviruses in vitro and in vivo [ 17 , 18 , 19 ]. Suramin proved to interact directly with the viral particles of SFV and CHIKV and hence prevented viral attachment to the host cells [ 20 ]. Moreover, suramin showed the ability to interfere with the conformational changes of viral envelope glycoproteins required for the fusion step [ 20 ].…”

“…Suramin proved to interact directly with the viral particles of SFV and CHIKV and hence prevented viral attachment to the host cells [ 20 ]. Moreover, suramin showed the ability to interfere with the conformational changes of viral envelope glycoproteins required for the fusion step [ 20 ].…”

Nitrogen-Based Heterocyclic Compounds: A Promising Class of Antiviral Agents against Chikungunya Virus

“…A series of thioguanine-coumarins derivatives were studied, and the methoxylated coumarins [54] (21, 22 and 23) exhibited the best activities against CHIKV compared to the benzouracil coumarins (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19). EC 50 values were below 13.9 µM with a significant selectivity window covering SI values between 9.37 and 21.7, whereas the molecular lipophilicity of 20, 21, 22 and 23 were between 2.97 and 3.77.…”

“…Some compounds with a broad antiviral activity such as ribavirin, harringtonine, and interferon-alfa (IFN-α) showed great efficiency against CHIKV only in vitro [ 9 ]. On the other hand, the use of chloroquine exhibited a dose-dependent and time-dependent inhibitory effect on CHIKV replication in vitro, but clinical studies have failed to prove its effectiveness in infected patients [ 10 , 11 ].…”