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Miltefosine is a US Food and Drug administration (FDA) approved drug used to treat visceral leishmaniasis, commonly known as kala-azar, or black fever, which is a vector-borne disease transmitted by the bite of female sandflies infected with the Leishmania parasite. Miltefosine acts against the Leishmania parasite by more than one mechanism. We are studying one of these mechanisms, focusing on miltefosine’s inhibitory activity against the activation of a molecule called Akt.

Repurposing

Anti-viral drugs are effective in treating, as well as preventing transmission of the disease, especially when there is no vaccine available. Our earlier work looking at microRNA modulation after chikungunya virus infection indicated that Pi3-Akt kinase signaling may be important for the virus at early stages of virus infection. In this follow up study, various inhibitors of this signaling pathway were used to test their effect on chikungunya replication.

Repurposing of FDA-approved drugs is desirable as it significantly reduces the cost and time needed to develop a new drug application for treatment.

These experiments demonstrated that suppression of activation of an important enzyme called Akt, reduced Chikungunya replication. Once this link was identified, the next step was to find an FDA-approved drug that has similar activity. Miltefosine, is an Akt-activation inhibitor that is used to treat lesihmaniasis.

Repurposing of FDA-approved drugs is desirable as it significantly reduces the cost and time needed to develop a new drug application for treatment. The cost of developing a new drug from concept phase to use in humans can run into billions of dollars.

It can also significantly cut the cost and time by leveraging the knowledge gained by the track record of the current usage of the drug in humans with respect to toxicity, formulation, metabolism by the body, and how long it remains in the system to be effective. A lot of this information about miltefosine is already available, which can help in repurposing it as an anti-chikungunya drug.

Miltefosine as an anti-chikungunya drug

In our study, miltefosine inhibited chikungunya replication in cell cultures treated either before or after infection with chikungunya. Upon infection, chikungunya normally causes rapid cell death, and within three days of infection all cells infected die of the infection. We found that cells treated with miltefosine not only survived the infection, but continued to replicate.

We found that cells treated with miltefosine not only survived the infection, but continued to replicate.

Chikungunya virus outbreaks have affected millions around the globe. In spite of a decade of efforts, an effective vaccine against chikungunya is still elusive. Repurposing of miltefosine to treat chikungunya infection can reduce the disease morbidity by directly suppressing chikungunya replication.

Chikungunya spreads via mosquito bites, however, the level of virus in blood circulation needs to be sufficiently high enough for that to occur. Anti-chikungunya activity of miltefosine can reduce the virus burden in the blood circulation, and thereby, indirectly reduce the chances of virus transmission by mosquitoes.

The next steps

The anti-chikungunya activity of miltefosine will need to be further tested in preclinical models of chikungunya infection. Animal studies will show if miltefosine can be effective against chikungunya in physiologically relevant conditions and will be an important step to take miltefosine forward as an anti-chikungunya drug.

Miltefosine may also reduce the chronic arthritis burden in chikungunya infected patients.

We will also need to determine the specific dosing for treating chikungunya infection. Miltefosine has some side effects, including gastric toxicity causing nausea and vomiting, and it cannot be used during pregnancy. Many of these observations have been made with the current twenty-eight day long treatment regimen. Anti-chikungunya effect may need a shorter treatment period to match acute-infection period of the virus, which is typically a week or two.

It will be interesting to see if miltefosine can reduce the persistent arthralgia (joint pain) that follows the resolution of the acute-illness. Chronic arthralgia following chikungunya infection has been suggested to be due to persistent virus infection, and if that is the case, then miltefosine may also reduce the chronic arthritis burden in chikungunya infected patients.