IIT Mandi team has found that the FDA-approved drug for malaria (hydroxychloroquine or HCQ) binds to the protease enzyme of the Zika virus and stops the virus from replicating and surviving. When tested on placental cells infected with Zika virus, the malarial drug significantly reduced the viral load. Since the drug is approved for use in pregnant women, researchers intend testing the drug to prevent vertical transmission.
Researchers at Indian Institute of Technology (IIT) Mandi have found a drug (hydroxychloroquine or HCQ) that is already being used for treating malaria to be effective in inhibiting Zika virus growth and replication. Also, the drug was able to significantly reduce viral load in placental cells. Zika virus is known to damage and kill the placental cells (which act as a barrier to protect the developing foetus from disease-causing organisms) leading to foetal infection. The drug might therefore help in preventing vertical transmission of Zika virus from the placenta to the foetus.
Since, the HCQ drug is already approved for use in pregnancy, positive results in human trials will mean that it can be given to pregnant women infected with Zika to reduce the risk of vertical transmission. Some foetuses infected with Zika virus are born with a small head (microcephaly).
As the Zika virus protease structure is already available in the literature, a team led by Dr. Rajanish Giri from IIT Mandi identified the druggable site on the protease enzyme. The Zika protease enzyme is a good target for drug action as inhibition of the protease stops Zika virus growth. The team then screened FDA-approved drugs and identified five compounds based on their binding to the active site of the enzyme. The malarial drug HCQ was one of the five compounds selected.
Besides binding to the active site of the protease enzyme, the binding of the malarial drug to the active site was found to be stable. Based on these results, in vitro tests were carried out using purified viral enzyme to assess the ability of the drug to inhibit enzyme activity. “We found 92 microMolar of the drug was sufficient to inhibit the enzyme activity,” says Dr. Giri.
“Inhibiting the protease activity leads to stoppage of virus replication and survival. This will eventually result in reducing the viral load,” says Ankur Kumar from IIT Mandi and first author of a paper published in the journal ACS Omega.
In an earlier study, Prof. Indira U. Mysorekar from the Department of Obstetrics and Gynaecology, Washington University School of Medicine used the malarial drug in Zika-infected animals to test its effectiveness in reducing vertical transmission. The drug significantly reduced the viral load in the placenta and foetus of the mice.
“The HCQ drug acts on Zika virus through multiple mechanisms. We exploited the autophagy pathway to reduce the viral load in placental cells. The drug also inhibits the protease enzyme activity to limit its growth,” says Prof. Mysorekar, who is a co-author of the latest paper.
The placenta acts as a barrier and prevents any pathogens from reaching the foetus through a form of garbage recycling system that removes some components of cells, termed autophagy. When the placenta is infected with Zika virus, the autophagy gets ramped up thus allowing the virus to enter the foetus. But in the presence of the drug, the ramping up of autophagy is prevented thus inhibiting the virus from infecting the foetus. Through in vitro and mice studies, Prof. Mysorekar’s team had earlier shown how the drug prevents the Zika virus, which has infected the placental cells, from infecting the foetus.
Besides autophagy, the drug inhibits Zika infection of placental cells by binding to the enzyme. “The drug modulating the autophagy process is important in placental cells, while inhibiting the protease enzyme activity could help stop the growth and kill the virus in other sites of the body,” says Prof. Mysorekar.
The team will carry out more tests to determine the efficacy of the drug in humans. It is currently working to find the optimal dosage required to kill the virus in humans. Since the malarial drug is already approved for use in humans, pregnant women included, the team is planning to carry out trials on humans to assess the ability of the drug to reduce viral load and cut vertical transmission. “The HCQ drug is readily available, cheap and safe for use in pregnant women. So it should be used in humans if the trials provide encouraging results,” says Prof. Mysorekar.