With influenza contributing to an estimated 290,000 to 650,000 deaths each year [1], the demand for effective interventions has never been greater. Recent structural studies have made extraordinary contributions to our understanding of the viral ribonucleoprotein complex. This ternary complex is essential for the virus’s encapsidation and viral RNA replication. Scientists highlighted a penumbral sliding mechanism at play within this complex. This discovery might lead to previously unimagined antiviral approaches and foster the creation of a non-seasonal flu vaccine.
The study, published in Science by Ruchao Peng and colleagues, delves deep into the structure and function of the ribonucleoprotein complex in influenza. This complex takes on a right-handed, antiparallel double-helix structure, fundamental to the virus’s replication machinery. The research reveals that as the viral polymerase copies RNA, the double-helix structure slides strand-against-strand, a process known as the helical strand-sliding model.
Structure and Mechanism of Influenza’s Ribonucleoprotein Complex
The helical strand-sliding model is key to maintaining the overall architecture of the ribonucleoprotein complex. This model allows polymerase to access the outside of the helix. It thoroughly engages the performance strand while the two strands pass underneath each other. This complex molecular machine is important to elucidating how influenza replicates itself and how it can be effectively inhibited by antiviral therapeutic agents.
Within the ribonucleoprotein complex, the researchers showed there is a highly conserved tail-loop interface that represents a novel target for small molecule antiviral drugs. They then did a virtual screening of 30 million compounds against this novel interface. This joint effort brought them to identify three promising candidate compounds, which they named 1, 5, and 23. The preliminary results confirm that compounds 1 and 5 inhibited the replication of H1N1 virus within MDCK cells. Moreover, they accomplished this without inducing cytotoxicity at the concentration tested below 100 uM.
“Molecular basis of influenza ribonucleoprotein complex assembly and processive RNA synthesis” – Ruchao Peng et al
Promising Antiviral Candidates
Of the 29 candidate compounds, compound 23 demonstrated moderate antiviral activity (EC50 at low micromolar concentrations) but was cytotoxic above 50 µM. These results indicate that one size does not fit all. Although these compounds are among the most powerful blockers yet of H1N1 replication, it’s still an important step forward in treating dangerous strains of influenza.
These compounds offer exciting potential beyond short-term therapy. They might help enable the development of a non-seasonal flu vaccine, preventing an even broader array of influenza strains. Many researchers are seeking to better understand these promising compounds. They aim to develop a vaccine that does not need to be updated each year, addressing difficulties encountered with existing seasonal vaccines.
Comprehensive Analysis of Influenza D Particles
Aside from exploring the ribonucleoprotein complex, scientists studied Influenza D nonstructural segment particles. They digitally reconstructed and traced the outlines of these particles using digital micrographs, discovering a jaw-dropping 516,476 particles in their analysis. This deep dataset of viral interactors gives researchers an unprecedented glimpse into the virus’s structural makeup and opens the door to possible future vaccines.
The study resulted in a high-resolution 5.1 Å reconstruction where four NP subunits were resolved. It generated sub-nanometer maps on seven additional conformations of the ribonucleoprotein complex. Providing this level of detail is helping the scientific community understand how influenza works at a molecular scale.
“Non-seasonal flu vaccine slides closer to reality” – Science X Network