Ebola virus (EBOV), a virulent infectious virus, was first discovered in 1976 in the Ebola River region of southern Sudan and the Democratic Republic of the Congo (DRC), causing widespread concern and attention in the medical community. The Ebola virus can cause Ebola hemorrhagic fever in humans and other primates, and its cause, Ebola hemorrhagic fever (EBHF), is the world's most lethal virus today, with a mortality rate of between 50% and 90% of those infected.
As one of the most terrifying viruses in the world, some people die within 48 hours of being infected with the Ebola virus, and they all "die a horrible death", as the virus spreads rapidly and multiplies in the body, attacking multiple organs, causing them to become deformed, necrotic, and slowly being broken down. The patient first suffered internal bleeding, then bleeding from all seven organs, continued to vomit the necrotic tissue from the organs out of his mouth, and finally died from extensive internal bleeding and brain damage.
On September 12, 2023, researchers from the Chinese Academy of Sciences published a research paper entitled "Molecular mechanism of de novo replication by the Ebola virus polymerase" in Nature.
Non-segmented negative-strand RNA viruses (nsNSVs), including Ebola virus, rabies virus, human respiratory syncytial virus, and pneumovirus, cause respiratory infections, hemorrhagic fevers, and encephalitis in humans and animals and pose an enormous health and economic burden worldwide.
The Ebola virus genome is approximately 19 kb long and contains seven reading frames, and its viral RNA genome is encapsidated by a nucleoprotein (NP), which further binds to the polymerase protein (L), viral auxiliary protein (VP35), and transcriptional activation protein (VP30) to form a ribonucleoprotein complex (RNP). In viral particles, RNP further binds to nucleocapsid-associated protein (VP24) and is surrounded by matrix protein (VP40), which further forms intact viral particles with viral surface spike glycoprotein (GP).
The replication and transcription of its viral genome is executed by the polymerase L protein, a promising target for the development of anti-Ebola drugs.
In this study, the team used the polymerase L protein of the Ebola virus as a representative of the virus and demonstrated through enzymatic experiments that ab initio replication of the polymerase L protein is controlled by the Ebola genome-specific 3' leading sequence and that the formation of at least three base pairs can efficiently drive the elongation process of RNA synthesis independently of the specific RNA sequence. The study then determined the high-resolution structure of the Ebola virus polymerase L-VP35-RNA complex and found that the 3' leading RNA binds in the template entry channel with a unique, stable bent conformation. Further mutagenesis work confirmed that the bent conformation of the RNA is required for the ab initio replication activity of the RNA and revealed key residues of the polymerase L protein that stabilize the RNA conformation.
These findings provide a new mechanistic understanding of RNA synthesis by the polymerase of non-segmented negative-stranded RNA viruses (nsNSV) and reveal important targets for antiviral drug development.