Understanding Enzyme in Hepatitis C Could Lead to Better Medicines

NS3 enzyme interacts with RNA and helps the pathogen replication process.

Scientists may be one step closer to understanding the functions of the NS3 enzyme in hepatitis C virus (HCV), and therefore may soon be able to develop a drug that targets the enzyme and leaves patients cured and without any side effects to report.

Approximately 140 million people are infected with HCV worldwide, according to the World Health Organization. The disease is subtle until it turns chronic and leaves patients suffering from severe symptoms, decreasing their quality of life and, in some cases, leading to death.

One of the molecules involved in the reproduction mechanism of the virus in the body is a helicase, NS3, an enzyme that interacts with the RNA by climbing onto it and helping the pathogen’s replication process.

“By knowing in detail how this helicase works, in the future we could try to block the viral replication, and thus stop the disease from proliferating in the body,” explained Giovanni Bussi, SISSA professor and study co-author.

NS3 does the work of polymerases, molecules that build a replica of the RNA strand. It achieves this by “opening” and preparing the RNA to the action of the second enzyme.

“NS3 crawls along the RNA strand contracting and extending like a caterpillar and, as it does so, it releases the part of the virus to which the polymerase then attaches,” said Andrea Perez-Villa, SISSA student and first author of the paper. “We decided to analyze this protein because, unlike others, it is only present in the hepatitis C virus. This way, any drug capable of targeting its interaction with the RNA would not damage other proteins, for example, those belonging to the body being attacked by the virus. This means that, theoretically, the drug would have no side effects.”

The research was based on a computer simulation, according to Perez-Villa. Thus far, some images of NS3 have been collected, but not enough to fully understand and reconstruct the whole process. Perez-Villa and Bussi created a model of the protein and had it interact with the viral RNA.

“During the process, ATP, the ‘fuel’ utilized by proteins, is consumed. Therefore our simulation also reproduced the system’s interaction with ATP and subsequently with ADP, a waste product together with phosphate, after ATP had been utilized,” Bussi said. “So for the first time, we provided a detailed description of the process, which will serve as a guide for future steps forward, whether theoretical or experimental.”