New antivirals against herpes

Researchers at Harvard Medical School in Boston, United States, have revealed How a new class of antivirals works against herpes virusesby identifying in detail the structure and behavior of viral enzymes when they interact with these drugs.

The discovery, published this Monday in the magazine cellcould open the door to the development of new treatments against resistant strains herpes simplex virus (HSV) and other DNA-based viruses.

The study, led by professors Jonathan Abraham and Joseph Loparo, used cryogenic electron microscopy (cryo-EM) and optical tweezers to observe in real time how antivirals known as helicase-primase inhibitors (IHP) block an essential enzyme of HSV-1 during the replication of its genome. The images obtained showed almost atomic resolution and allowed us to visualize for the first time how the drugs bind to the viral proteins and interrupt their functioning.

Abraham has seen many patients with compromised immune systems develop dangerous HSV infections drug resistant. This resistance can develop when the virus is repeatedly treated with the same type of antiviral. But Abraham is also an associate professor of microbiology at HMS and studies how the physical structures of viruses influence infections, diseases and immune responses, putting him in a unique position to study and find solutions to the problem.

“As a doctor, it is discouraging that medicine can cure a patient with cancer, but they require immunosuppression that leaves them vulnerable to a virus that does not respond to the best drugs available to treat it. As a researcher, this inspires me to learn as much as possible about how the virus works so we can continue to find better options for people suffering from resistant strains of viruses,” he says.

Members of a new class of antivirals are being tested in clinical trials in the US, and one of them has gained approval in Japan. However, how these emerging drugs work is largely unknown. Abraham and his colleagues sought to unlock some of those secrets.

Abraham worked with co-senior author Joseph Loparo, professor of HMS Biological Chemistry and Molecular Pharmacologyto leverage advances in structural biology and imaging techniques to explore the biophysical mechanisms at play as new drugs bind to and inactivate a critical enzyme in the HSV life cycle.

Abraham’s lab focused on revealing the structural details of how drugs bind to viral proteinwhile Loparo’s lab worked to capture real-time details about how the binding process works to block the viral protein.

“A real strength of this study is the combination of high-resolution atomistic imaging of the viral proteins bound by the inhibitors and real-time imaging of the viral proteins in action,” says Loparo.

A dangerous and tenacious viral enemy

Herpes viruses can cause infections such as chickenpox, shingles, and mononucleosis; have been related to cancers, autoimmune diseases and other diseases; and tend to remain dormant for life. Among them, HSV-1 It is known to cause cold sores, but can also cause serious brain infections in healthy adults and serious illness in immunocompromised people.

Currently approved antiviral drugs focus on the DNA polymerase of the virusa protein that copies the viral genome. However, strains of the virus resistant to these drugs have emerged. There are already alternatives in development, including a class of drugs known as inhibitors of helicase-primase (IHP). These target the viral helicase-primase, an enzyme that, like polymerase, is essential for herpes viruses to reproduce.

The viral helicase unwinds the viral genome, pushing and unzipping intertwined strands of DNA to convert it into single-stranded DNA. This exposes the information encoded in the genome so that the polymerase can reproduce it.

Meanwhile, the viral primase triggers the creation of a molecule of RNA which serves as a starting point for the new copy of the genome to attach, like the piece at the bottom of a jacket zipper that allows the slider to engage with the teeth of the zipper.

High resolution images

Until now, no research had been able to reveal the structures of the HSV enzymeslike helicase-primase. One reason is that they are very flexible, constantly moving and changing shape. The existence of an effective inhibitor – HPI drugs – now allows scientists to lock the enzymes into a single static form that can be visualized. Without it, Abraham and his colleagues said, their discoveries would not have been possible.

The team used cryogenic electron microscopy (cryo-EM) to visualize at near-atomic resolution the physical structure of HSV-1 helicase-primase when bound to various inhibitors.

The researchers also used cryo-EM to visualize how the viral helicase-primase interacts with the viral polymerase during DNA replication. The structure of this larger complex could help identify new drug target sites by revealing the physical and chemical properties of places where a potential drug could bind and interfere with replication.