User:Violettemoonlight/Rabies virus

Rabies Virus Proteins
Rabies virus causes around 55,000 deaths across the world and has a death rate of nearly 100%. These statistics coupled with the fact that there is currently no specific treatment, or antiviral drug makes research on the virus of vital importance for the scientific community in order to possibly lower the current death rate. The rabies virus phosphoprotein and polymerase are both important targets for antivirals and are currently used to create the vaccine used for domestic and wild animals. A lot of research is being done to better understand the specific roles and functions of the L-P protein because there is significant evidence already that it could be one of the most important proteins to target for future drugs.

There are five proteins that are coded for by the rabies virus genome—phosphoprotein (P), polymerase (L), matrix protein (M), nucleoprotein (N), and glycoprotein (G). These five proteins are transcribed into mRNA in different quantities. The protein transcribed the most is the nucleoprotein, then the phosphoprotein, then the matrix protein, then the glycoprotein and finally the polymerase. Of those proteins, the ones that may be the most important for the functions of the virus are the L-P protein complex. These two proteins are required for the production of all of the proteins utilized by the rabies virus and they interact with many of the other proteins to complete the functions needed by the virus to infect cells, replicate and complete other vital functions. When the structure of the L-P protein was analyzed using UCSF Chimera, it was found that it contained two zinc molecules as well as 2 five-membered rings. The secondary structures were also analyzed, and it was found that there were three different kinds-coil, helix and strand.

The phosphoprotein (P) consists of 297 amino acids, has a total mass of 33 k-Da and is a type I interferon antagonist. It is in a viral ribonucleoprotein made up of RNA surrounded by nucleoproteins (N), which form a structure that is ring-like. Each nucleoprotein surrounds nine nucleotides of the RNA and the nucleoproteins in conjunction with the phosphoprotein are important for initiating synthesis of the RNA. The phosphoprotein is largely responsible for preventing the immune system from destroying the virus before it can take hold. It has been found that it stops production of interferons by disrupting the interferon regulatory factor-3 (IRF-3) and, therefore, prevents the normal function of the interferons, which allows it to continue to infect the host. The phosphoprotein is also very important for replication. It is a required cofactor of the viral polymerase (L) and is also a chaperone for the nucleoprotein (N), which is responsible for the encapsidation of viral RNA. It is thought that the P protein consists of only a few repeating units.

The polymerase (L) consists of 2,127 amino acids, has a total mass of 242 k-Da and interacts with the phosphoprotein to form the RNA-dependent RNA polymerase complex. L and P bind to each other and according to current research, the major L binding site is somewhere in the first 19 residues of the P protein. Other research found that the amino acid sequence numbered 1929 to 1933 is the sequence that is important for the L protein to bind with the P protein. It has been found that the L protein initiates synthesis and works optimally if it works together with the P protein. The region from 1900-1930, which contains part of the sequence that is important for L and P protein binding, and the region from 1870 to 1890 are hydrophilic regions and are also highly conserved among rabies virus strains. The 1929 to 1933 sequence is also of importance because it is involved with RNA synthesis of the virus and thus could possibly be a target for new drugs. The carboxy-terminal domain of L must be present in order for L to bind to P. The L protein also has a catalytic center while the P protein is believed to not have a catalytic center. There is evidence that for the rabies virus, the L protein can be expressed even if the P protein is not expressed. This is different from many other related viruses, which require both to be expressed and present. One of the domains in the L protein is responsible for speeding up the reaction that results in the capping of the RNA and thus could possibly be another good target for an antiviral drug. The nucleoproteins (N), which it was previously mentioned aid the P protein, also interact with the L protein and this is necessary for initiation. The interactions between the L protein and the M protein have also been noted to be of importance to its function. Research has shown that there are interactions between the two proteins in relation to the balance of transcription and translation. The polymerase is an enzyme and can aid in initiation, elongation, capping, methylation, polyadenylation and RNA polymerization.

Interestingly, the rabies virus vaccine that was created using the SAD-B19 complex, which includes the L-P protein, was utilized in the creation of a vaccine for SARS-CoV-2. The S1 protein from SARS-CoV-2 was inserted into the rabies virus vaccine vector to create a new vaccine that was shown to be effective in protecting against COVID-19. Rabies virus has also been used to create a vaccine against Ebola, called FiloRab1, and it was found to be 100% effective for nonhuman primates.