Disease
Ebola virus (EBOV) causes Ebola virus disease (EVD), a fatal hemorrhagic disease discovered in 1976.[1] Sources of infection are mainly linked with “hunting wildlife, exposure to animal carcasses found in the forest, or contact with the putative virus reservoir, bats”.[2]
EVD pathogenesis in humans consists of three phases with symptoms normally occurring after an incubation period of 2-21 days.[3] In the first phase, symptoms during the first few days include nonspecific fever, headache, and myalgia.[4] This is followed by a “gastrointestinal phase” characterized by symptoms including diarrhea, vomiting, abdominal discomfort, and dehydration.[5] The final and advanced phase of the illness consist of kidney and liver function failure, often resulting in “metabolic compromise, convulsion, shock, and death due to mucosal bleeding, bloody diarrhea, and multi-organ failure within 16 days after the first symptoms appear”.[6]
Since EBOV's discovery, there have been 20 known outbreaks restricted primarily to African countries with minor spread to neighboring countries.[7] The most recent outbreak of Ebola occurred during a three-month span in the Democratic Republic of the Congo this year, the country’s 4th in the past three years.[1] Since its start in February, there was a total of eleven confirmed cases with six recoveries and six deaths and one probable case emanating from four health zones in North Kivu.[2] There is also an ongoing outbreak in Guinea, West Africa which started in the same month as the outbreak in the DRC.[3]
There is currently no vaccine for EVD, but there are currently eight vaccine candidates in human clinical trials that all target the Ebola virus glycoprotein (GP), one of the nine known proteins to be expressed by the virus’s genome.[8] However, these vaccines are different from each other in the immune responses they elicit, the antigen delivery system, and their respective side-effect profiles.[9]
RNA Classification
Ebola is part of the Filoviridae family of single-stranded negative-sense RNA viruses of approximately 19 kb.[10] The 19 kb RNA encodes for “glycoproteins (i.e., GP, sGP, ssGP), nucleoproteins, virion proteins (i.e., VP 24, 30, 40) and the RNA-dependent RNA polymerase”.[11] In EBOV, the RNA dependent RNA polymerase in conjunction with NP, VP30, and VP35 form the RNP complex in viral genome transcription and replication.[12] RDRP binds to the 3’ leader promoter and changes EBOV’s negative-sense RNA into positive-sense messenger RNA to produce Ebola proteins that produce new viral particles (virions).[13]
Function of RNA-Dependent RNA Polymerase
RNA-dependent RNA polymerases (RdRp) are critical to the replication of RNA viruses.[14] Due to this protein's importance in the viral life cycle, they are feasible targets for vaccine development.[15] Inhibition of RdRp results in the inhibition of transcription of the viral genome, ultimately resulting in no new production of virions for the virus.
Structural Features of Ebola Virus RNA-Dependent RNA Polymerase
EBOV has a monomeric RNA-dependent RNA polymerase and as such, shares the characteristic right-hand shape of other monomeric RdRp composed of the fingertips, palm, and thumb subdomains. [16] The fingertips subdomain is composed of residues 417-439 and 489-563, the palm subdomain is composed of residues 440-488 and 563-666, and the thumb is made up of residues 667-704.[17]
RNA Transcription and Translation
