Wednesday, November 23, 2016

Suramin: a possible answer for Ebola

The Chikungunya virus (referred to as CHIKV here) is a virus whose infections cause flu like symptoms and arthritis. Even though the mortality rate of CHIKV is as low as 0.1%, its infection rates are significantly high. On a more serious note, a recent outbreak of the Ebola (referred to as EBOV here) virus in western Africa has gotten immense attention. With over 28,000 cases and 11000 deaths, the most recent outbreak is the biggest in history. This creates more and more interest in finding possible ways to prevent infections with the virus. The primary literature I read looks at how Suramin, a competitive viral inhibitor, prevents the two viruses that are discussed above from infecting host cells.

CHIKV enters host cells by by initially binding to receptors on host cells. Ebola virus enters host cells through the action of a single protein on the viral surface as both a receptor binding and fusion protein. Both viruses use the glycosaminoglycans (GAGs) located on the cell surface as receptors to facilitate their entry into the host cells. The primary literature tries to see if the drug Suramin, a competitive inhibitor of GAGs, inhibits infections by Chikungunya and Ebola viruses by blocking host cell entry.


Figure 1: Virion structures of Chikungunya virus which is spherical (left) and Ebola virus with filamentous (right). 

For the purposes of this study, initially lentiviral particles were pseudotyped - modified with the desired receptor and fusion proteins to mimic the viruses of interest. This was done in order to mitigate the hazardous nature of handling the Ebola virus by minimizing contact with the virus. But later, to validate the results obtained from pseudotyped lentiviruses, the researchers perform experiments with the actual viruses.

The first thing the researchers  looked at was the toxicity of the drug. The results showed that at lower concentrations, Suramin was not toxic to two of the three cell lines used in the study: HEK 293T and HUH7 cells. But as the concentration increased (higher than 50 ug/ml)  the drug affected the viability of these cell lines. After examining the toxicity of the drug, the next thing to look at was if Suramin inhibits infections by CHIKV and Ebola virus pseudotyped lentiviruses. As a control, VSV-G pseudotyped lentiviruses, that are known to infect the host cell types, were used. The results of this experiments show that infections of HEK 293T cells by CHIKV and Ebola virus were inhibited upon treatment with Suramin while infection with the VSV-G pseudotyped control was still successful unless the drug concentrations are too high.

This paper also reports that Suramin blocks CHIKV infection at early time points. To come to this conclusion, the authors used a replication assay. This was done by attaching a luciferase gene to a non structural protein of the CHIKV virion and that was used to track the replication of the viruses. And as expected a significant decrease in rate of replication was observed as the cells were treated with logarithmically increasing dosage of Suramin. Then, the researchers did a similar assay but with a slight modification. They infected cells with CHIKV-Luci and a control VSV-Luci and treated each plate at different time points after infection with 10 ug/ml suramin. The plates treated at early time points after infection exhibited a decrease in the rate of replication while the late time point infections were minimally affected. This leads to the conclusion that Suramin treatment inhibits viral replication at early time points further confirming that the drug is an entry inhibitor. Finally the authors tried to make sure the results obtained using EBOV pseudotyped held consistent when the assay was repeated with Ebola viruses. This replication assay showed that the tissue culture infectious dose (TCID50) of the virus decreased as an increasing dosage of Suramin was administered to Ebola virus infected Huh7 cells.

The drug Suramin, therefore, is able to inhibit Chikungunya and Ebola replication likely by inhibiting their entry to their host cells. As stated above there is no serious harm caused by the Chikungunya virus. Ebola virus, on the other hand, causes a hemorrhagic fever that can, at worst case, be fatal. And the recent outbreak in west Africa has shown how serious infection with this virus can be. Thus a drug like Suramin that can inhibit Ebola virus replication is of a great importance.

A shortcoming of Suramin treatments for chikungunya and Ebola viruses is its side effects. It has been known that the drug may cause undesirable effects such as vomiting, urticaria (an allergic reaction with the formation of red swellings on the skin),  kidney damage, blood dyscrasias (a pathologic condition of the blood, usually referring to a disorder of the cellular elements of the blood) and more. Taking this into consideration, the use for Suramin against a mild virus as Chikungunya may be considered unwise. But given the serious nature of Ebola infection, Suramin may come as  reasonable.

Primary Article:
Henß et. al. “Suramin is a potent inhibitor of Chikungunya and Ebola virus cell entry”. Published - 31/8/2016. Virology Journal
Sources for Images Used

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