With measles rearing its head in places long devoid of infections, scientists and clinicians are searching for new ways to combat the virus in those that have no immunity and become afflicted with the disease. As such, investigators at the Georgia State University Institute for Biomedical Sciences have just published new findings that show targeting specific areas of the measles virus polymerase, a protein complex that copies the viral genome, can effectively fight the virus and be used as an approach to developing new antiviral drugs to treat the serious infectious. Results from the new study were published recently in PLOS Pathogens through an article titled “Bipartite interface of the measles virus phosphoprotein X domain with the large polymerase protein regulates viral polymerase dynamics.”
While an effective measles vaccine exists, there has been a steady decline in the number of people being vaccinated against the measles virus. Most new cases were among unvaccinated individuals, making the development of an effective treatment strategy complementing vaccination a public health priority. There are no antivirals licensed to treat measles. The new study identified a novel protein interface in the polymerase complex that is pivotal for the regulation of polymerase activity, providing a new objective for target-based antiviral drug discovery.
“We have advanced current understanding of the underlying mechanism of viral RNA-dependent RNA polymerase advancement along the encapsulated genome—a poorly understood and not well-characterized mechanism—by identifying and characterizing the dynamic interactions between its constituents,” explained lead study investigator Venice Du Pont, a doctoral candidate working at the Institute for Biomedical Sciences.
In the current study, the research team proposed a novel model of dynamic binding and dissociation interacting proteins in the viral polymerase complex, describing how the polymerase negotiates and regulates advancement along the viral genome. This insight has revealed a vulnerability that could be exploited as a target for small-molecule antiviral drugs.
“Measles virus (MeV) is a highly contagious, re-emerging, major human pathogen. Replication requires a viral RNA-dependent RNA polymerase (RdRP) consisting of the large (L) polymerase protein complexed with the homo-tetrameric phosphoprotein (P),” the authors wrote. “In addition, P mediates interaction with the nucleoprotein (N)-encapsidated viral RNA genome. The nature of the P:L interface and RdRP negotiation of the ribonucleoprotein template are poorly understood.”
The researchers went on to explain that “based on biochemical interface mapping, swapping of the central P tetramerization domain (OD) for yeast GCN4, and functional assays, we demonstrate that the MeV P-to-L interface is bipartite, comprising a coiled-coil microdomain proximal to the OD and an unoccupied face of the triangular prism-shaped C-terminal P X-domain (P-XD), which is distinct from the known P-XD face that binds N-tail. Mixed null-mutant P tetramers regained L-binding competence in a ratio-dependent manner and fully reclaimed bioactivity in minireplicon assays and recombinant MeV, demonstrating that the individual L-binding interface elements are physically and mechanistically distinct. P-XD binding competence to L and N was likewise trans-complementable, which, combined with mathematical modeling, enabled the mechanistic characterization of P through two- and stoichiometrically-controlled three-way complementations.”
Measles is a highly contagious virus that can lead to serious health complications and death. It begins with a fever, cough, runny nose, and red eyes followed by a rash of tiny, red spots that starts at the head and spreads to the rest of the body. Although declared eliminated in the United States in 2000, the Centers for Disease Control and Prevention says the U.S. is experiencing the greatest number of measles cases reported since the early 1990s. The reemergence of this infection has placed an undue burden on the public health system and puts many people at risk for serious disease.
The research team was optimistic about their recent findings and are looking toward the next steps in order to ramp up the development of much-needed therapeutics.
“In recent years, enormous progress has been made to successfully target protein-protein interfaces for therapeutic purpose with chemical fragment libraries,” concluded senior study investigator Richard Plemper, PhD, a professor in the Institute for Biomedical Sciences. “The newly identified interface in the paramyxovirus polymerase machinery meets key criteria of a druggable target and is very likely mechanistically conserved in highly pathogenic paramyxoviruses closely related to measles virus such as the zoonotic Nipah virus, against which we have currently no treatment option.”
