Disease
Polio or poliomyelitis is a disabling and life-threatening diseased caused by the poliovirus. This virus spreads from person to person and can infect a person’s spinal cord, resulting in paralysis. Most people that get infected with the poliovirus will not develop any visible symptoms. However, about one in four people with poliovirus infection will have flu-like symptoms that include: sore throat, fever, tiredness, nausea, headache, and stomach pain. These symptoms usually last from two to five days before disappearing. A smaller fraction of people infected with virus will develop more serious symptoms that affect the brain and spinal cord such as: paresthesia, meningitis, and paralysis. This last symptom is the most associated with polio because it can lead to permanent disability and death. Between 2 and 10% of people who develop paralysis will die because the virus affects the diaphragm and other muscles that aid in respiration. Even young children who seem to completely recover from this virus can develop muscle pain or weakness and paralysis as adults, usually 15 to 40 years later. This is called post-polio syndrome.
The U.S has been polio-free since 1979, poliovirus 2 was eradicated globally in 1999, and there has not been a case of poliovirus 3 since 2012. However, according to the WHO (World Health Organization) poliovirus 1 only affects two countries as of 2020, Pakistan and Afghanistan. There is a vaccine for this virus called the Inactivated polio vaccine (IPV), for best protection children should get four doses of this vaccine.
Viral RNA Classification
The poliovirus comes in three different serotypes: poliovirus 1 (PV1), poliovirus 2 (PV2), or poliovirus 3 (PV3). These viruses are non-enveloped, single-stranded positive-sense RNA. The poliovirus is a member of the picornavirus family which includes a significant number of pathogens for humans and livestock. This virus is very small and consists of an icosahedral protein coat.
RNA-dependent RNA polymerases(RdRps)are one of the most versatile enzymes of RNA viruses that are vital for genome replication as well as for carrying out transcription. They have such a name due to their function where they use RNA template to synthesize mRNA which will later be translated into proteins and spread virus among the host. The core structural features of these polymerases are conserved, however, there is some divergence among their sequences. The structure of the RNA-dependent RNA polymerases resembles a cupped right hand which also consists of fingers, palm and thumb subdomains. In most cases catalysis involves several conserved aspartate residues together with divalent metal ions.
These RdRps are such a great target for antiviral drugs because they are in charge of viral genome replication as well as viral genome transcription, meaning these proteins allow viruses to grow in number and spread to other cells or parts of the body. Therefore, if there are drugs that target these enzymes, viruses would not be able to survive inside a host.
The Poliovirus RNA-Dependent RNA polymerase is a 53kDa polymerase which together with other host proteins carries out viral RNA replication on the host cell cytoplasm. The poliovirus RdRp’s shape is common to that of other polymerases, with a palm subdomain which contains a core structure very similar to other polymerases, and different structures of the fingers and thumb from those of other polymerases.
The palm subdomain contains five of the amino acid sequence motifs of RNA-dependent RNA polymerases, referred to as A, B, C, D, and E. The thumb subdomain is composed of mostly residues C-terminal of the palm subdomain and is largely alpha helical. The core structure comprises motifs A-D, and it consists of two alpha helices that pack beneath a four-stranded antiparallel beta sheet. The strands of the antiparallel beta sheet are composed of residues from motifs A, C, and part of D, while the alpha helices are composed of residues from motif B and the remainder of motif D. Motif E packs between the pal and thumb subdomains. Near the end of the beta strand of motif A just before the helix is a completely conserved aspartate residue that is expected to coordinate catalytically essential metal ions.
The fingers subdomain of the poliovirus RdRp is composed of two polypeptide segments, a larger segment that precedesmotif A and a smaller segment composed of residues between motifs A and B of the palm subdomain.This fingers subdomain is composed of two polypeptide segments, an N-terminal of the palm subdomain and the second between motifs A and B. The thumb subdomain is composed primarily ofthe C-terminal-most 80 amino acid residues. The thumb subdomain of this polymerase begins with a beta strand that interacts with the edge of the beta strands of motif E to from a short three-stranded antiparallel beta sheet. The remainder of the thumb is composed of a series of five alpha helices. The first three from a three-helix bundle, the fourth is positioned at the top of the thumb subdomain and the fifth is positioned along the front edge of the beta strand of the thumb subdomain.
