Towards Structural Based Drug Development for Ebola Virus Disease

Abstract

Ebola virus disease (EVD), characterized by fatal bleeding and coagulation abnormalities, is caused by infection of Ebola viruses (EBOV) and other members of the family Filoviridae. Ebola viruses have 5 species named after the places of outbreaks: Zaire ebolavirus (ZEBOV), Bundibugyo ebolavirus (BDBV), Reston ebolavirus (RESTV), Sudan ebolavirus (SUDV), and Tai Forest ebolavirus (TAFV). Among them, the Zaire strain is the most lethal. The EBOV genome consists of a linear, non-segmented negative-stranded RNA of 19 kb in length, coding for 7 structural proteins, including nucleoprotein (NP), VP35, VP40, glycoprotein (GP), VP30, VP24, and L protein. Human infection by EBOV is possible through contact with body fluids of virus infected individuals or animals like Primates or fruit bats. There have been over 25 outbreaks since its discovery in 1976. In the most recent largest Ebola outbreak in Western Africa, 28,639 cases and 11,316 deaths were recorded by the World Health Organization (WHO, http://www.who.int/csr/disease/ebola/situationreports/en/). There is no Food and Drug Administration (FDA) approved specific treatment for the EVD. The medical care for patients primarily relies on intensive supportive care. The use of convalescent plasma from patients who have recovered from EVD was among the first specific therapeutic approaches, and later on, human neutralizing antibodies, like ZMappTM, have been tested. However, the source of convalescent plasma is very limited and antibody production is too expensive to meet the demands for large scale applications, especially for those patients in less developed countries most at risk from Ebola outbreaks. Using small interfering RNA (siRNA) targeting Ebola Virus (EBOV) genome is another appealing therapeutic idea. A successful siRNA product, TKM-Ebola, developed by the Tekmira pharmaceuticals corp, has been tried clinically during Ebola crisis. It uses a mixture of three siRNAs to target EBOV VP24 (membrane associated protein), VP35 (polymerase complex protein) and L (RNA dependent RNA polymerase) respectively. It is effective against Ebola virus, however, the TKM-Ebola therapy was discontinued soon after phase I clinical trials due to activation of inflammatory pathways in patients.