Channel Blockers Show Promise of New HCV Treatment

Amesh Adalja, MD

Viruses create pores to facilitate replication

Recently-published research has reported exploitable weakness in virus replication that could result in new broad-spectrum antivirals. The antivirals have the potential to revolutionize how infectious diseases like HCV are treated.

Researchers at the Morgridge Institute virology group found for the first time that during replication viruses form pores inside areas in the cell that are supposed to be sealed off. By compromising the cellular walls, the virus is free to operate across many parts of the cell to start and control the replication process.

“One of the reasons why viruses are such a threat and so prolific is the fact that there really are no broad-spectrum antiviral agents available,” Amesh Adalja, MD, Senior Scholar, Johns Hopkins Center for Health Security, said. “The fact that a common replication pathway for positive sense RNA viruses that uses host membrane pores was discovered could lead to the development of antivirals targeting this large group of viruses.”

The role of ERO1

According to the announcement, lead author Masaki Nishikiori used molecular genetic and biochemical approaches to understand the capacity of a virus to create and use pores punched through the cell membrane. Nishikiori used bromovirus in yeast cells that allowed the virus to replicate. This provided a highly controlled system to manipulate and assess both virus and host cell contributions.

Nishikiori found that an enzyme called ERO1, contained only inside the organelle on the opposite side of a cell membrane, is essential in the viral replication process. Changes in ERO1 can either increase or reduce viral replication.

The problem was finding out how an enzyme that’s sealed away from the virus behind a solid membrane barrier be used to activate viral growth. This is what ultimately led to the discovery that a key viral protein can drill across the membrane, making it possible for ERO1 to influence virus replication on the other side.

Channel inhibitors offer hope for new treatments

“When the viral protein creates this pore, it allows oxidants generated by ERO1 to leach from the organelle interior into the cytoplasm and create a plume of oxidizing power,” Nishikori said.

According to an article published in the Journal of Virology, clinically approved ion channel inhibitors already offer hope of reducing the high cost of conventional DAA HCV therapy. Although several related drugs typically used to treat allergies and as neuroleptics may be potent HCV cell entry inhibitors, Nishikiori’s research finally offers insight into the mechanism of their antiviral mode of action.

This opens up drug repurposing for HCV and likely many other severe human pathogens. But Adalja isn’t so sure.

“Hepatitis C has currently undergone a revolution in treatment with several extremely effective direct-acting agents available,” Adalja said. “However, for other positive sense RNA viruses, such as many that cause the common cold, this could lead to new treatments.”

Adalja believes the finding should be pursued in tandem with looking for other direct-acting antivirals.

“Also, this finding is specific to positive-sense RNA viruses, and there are many other virus classes that cause human infections for which this finding may not be applicable and where a DAA approach may be better,” Adalja said.

The study, "Organelle luminal dependence of (+)strand RNA virus replication reveals a hidden druggable target," was published online in Science Advances last month.

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