Going Viral – Meet the Scientist Working to Outsmart the Smartest Viruses – Georgia State University News

In 1999, when Plemper first arrived at Minnesotas Mayo Clinic as a postdoctoral researcher, he decided to study measles (Morbillivirus) virus. Measles is so contagious it sickens an astounding nine of 10 people exposed, and a measles carrier can infect others up to four days before a rash first appears. Most of measles victims are children, and before widespread vaccination, measles routinely killed a million people a year. Even with vaccination, measles still causes 100,000 deaths annually, with outbreaks around the world, including an outbreak in 31 U.S. states in 2019.

The measles virus genome is composed of negative polarity RNA (ribonucleic acid) strands and the virus is a member of the paramyxovirus family, which also includes parainfluenza viruses and mumps virus pathogens that tend to target mostly children. To develop effective antivirals for measles, Plemper first needed to understand the virus at the molecular level.

Viruses have a very complex protein machinery with many moving parts, he explains.

He began to analyze the viruss structure, focusing in particular on its densely packed glycoproteins, molecules made of sugars and proteins that live on the outer membrane of the virus, and the viral polymerase complex, which plays a critical role in virus replication. He wanted to know how glycoproteins on the virus membrane fused with the membranes of a cell, how the virus then manages to enter the cells interior and how it effectively replicates its genome. He was looking for critical hinge points in viral function, aspects of its machinery that were so essential that interrupting them could prevent the entire system from running. If they were that essential, they might be broadly conserved across a number of different viral pathogens in that family. That would allow him to develop broad-spectrum drugs that targeted whole classes of pathogens and not just one disease.

He had another requirement as well: the compound must be orally bioavailable, meaning it can be taken by mouth and therefore started early after infection. The drug also must be well tolerated. This is particularly critical in medicines given to children. The medicines must be exceptionally safe.

So he set about studying measles, using electron microscopes to examine its subterranean world of spikes, rings and tubular structures, and learning how these shifted during its life cycle.

Richard is very good at studying protein structures and is passionately intense in his studies of viruses. At times he had to go to extra lengths to justify his stellar work on measles, largely because disease caused by measles is not a big threat in the United States, recalls Paul Spearman, the Albert B. Sabin professor and director of Infectious Diseases at Cincinnati Childrens Hospital Medical Center.

(When Spearman was division chief for infectious diseases at Emory University, he had recruited Plemper as a young assistant professor).

However, it turns out working on measles is important for a number of reasons, He says. Measles virus can teach us a lot about how viruses function in ways that are applicable to the study of other viruses. Measles also remains an important public health threat globally, so antivirals against measles are very much needed.

Plemper also did something else that reflected his ability to plan ahead. He began to assemble a library of small molecules and established an automated facility in his lab that would allow him to quickly screen for activity against many viruses.

This was the beginning of a great intellectual journey, explains his colleague Benhur Lee, professor of microbiology at the Icahn School of Medicine at Mount Sinai.

Lee calls himself the virus whisperer and has coauthored papers with Plemper. Some molecules in the screens, for instance, turned out to be pan-reactive, inhibiting almost everything, which could be toxic to human cells. Plemper methodically deleted all non-developable pan-reactive molecules and began to curate a large library of drug-like molecules that might one day be used to create antiviral drugs. It was methodical, obsessive work that took several years to complete.

It was Richards years of optimization and work on this library of molecules that laid the groundwork for todays successes, says Lee.

By 2018, Plemper and his team had discovered a novel drug target unique to the viral polymerase that was critical for the replication of the measles virus. With this new understanding, he could begin to zero in on possible therapeutics. In 2020, the team announced the discovery of a broad spectrum, oral drug that could target many different paramyxoviruses.

Arriving at the discovery was not easy in total, they tested 141,936 different compounds in the laboratory. The new compound, called GHP88309, is able to bind to and inhibit paramyxovirus polymerases, which are protein complexes essential to viral replication. This means it could likely treat not only measles, but also parainfluenza viruses and related paramyxoviruses of the henipavirus group, which are usually found in Australia and Asia and can cause fatal encephalitis. There is no approved treatment option some of these viruses today.

To test the compound, they first studied its impact on measles-infected human organoid lung tissue. Organoids are three-dimensional tissue cultures that are derived from stem cells. They can be designed to act much like an organ or simply to produce certain types of cells. Plemper and his team designed tissue that recreated the lining of the lungs, known as the epithelium. By testing it in this tissue they could verify its activity, potency and safety. The compound was found to be highly potent, with very low toxicity, in this lung tissue. It broadly inhibited measles, parainfluenza viruses and other viruses.

Then they tested it in animals, where it led to complete recovery from a lethal paramyxovirus infection human parainfluenza virus type 3 (HPIV3).

Every year, up to 14 percent of adults who get stem cell transplants in the United States suffer from life-threatening HPIV3 infections, says Plemper. The research teams work was published in the prestigious journal Nature Microbiology. GHP88309 is undergoing rigorous testing for safety and Plemper is working with the universitys Office of Technology Transfer and Commercialization to help advance it toward the clinic.The road ahead is long but based on the exciting results the group has obtained, Plemper expects the compound will advance to clinical trials in human patients.

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Going Viral - Meet the Scientist Working to Outsmart the Smartest Viruses - Georgia State University News