Emerging Targets and Novel Approaches to Ebola Virus Prophylaxis and Treatment

Abstract

Ebola is a highly virulent pathogen causing severe hemorrhagic fever with a high case fatality rate in humans and non-human primates (NHPs). Although safe and effective vaccines or other medicinal agents to block Ebola infection are currently unavailable, a significant effort has been put forth to identify several promising candidates for the treatment and prevention of Ebola hemorrhagic fever. Among these, recombinant-virus based vectors have been identified as potent vaccine candidates with some affording both pre-and post-exposure protection from the virus. Recently, Investigational New Drug (IND) applications have been approved by the United States (U.S.) Food and Drug Administration (FDA) and Phase I clinical trials initiated for two small molecule therapeutics, 1) anti-sense phosphorodiamidate morphino oligomers (PMOs: AVI-6002, AVI-6003), and 2) lipid-nanoparticle/small interfering RNA (LNP/siRNA: TKM-Ebola). These potential alternatives to vector-based vaccines require multiple doses to achieve therapeutic efficacy which is not ideal with regard to patient compliance and outbreak scenarios. These concerns have fueled a quest for even better vaccination and treatment strategies. Here, we summarize recent advances in vaccines or post-exposure therapeutics for prevention of Ebola hemorrhagic fever. The utility of novel pharmaceutical approaches to refine and overcome barriers associated with the most promising therapeutic platforms will also be discussed.

Exploitation of Glycobiology in Anti-Adhesion Approaches against Biothreat Agents

“…The glycopolymer field has addressed Ebola inhibition and constructed multi-block glycopolymers with acrylate monomers consisting of mannose, glucose, and fucose residues [60]. The resulting "glycodendronanoparticles" are the most highly branched glycodendrimeric constructs with diameters of up to 32 nm corresponding to 1,620 glycan units.…”

Ebola virus – from neglected threat to global emergency state

“…The VP40 and VP24 proteins establish bonds with the RNP and the inner surface of the viral envelope, respectively. 7,27,28 NP is the most abundant component of the nucleocapsid, with a close bond to the viral genome. It has been shown for the first time that NP is composed of two domains: one hydrophobic (N-terminal) and another hydrophilic (C-terminal).…”

“…The Δ-peptide, unlike the sGP, is retained in the cell for a long period before being released into the extracellular medium: it has been shown that in the extracellular medium it impedes the entry of filoviruses and prevents superinfection of cellular targets, although the mechanism is not yet clear. 27,29 The phenomena of viral replication occur in the cytoplasm of the host cell, while the assembly and release of new viral particles take place in the cytoplasmic membrane. Matrix proteins VP24 and especially VP40, which has great affinity to the cell membranes, play a critical role in the assembly and release of the virus into host cell.…”

“…VP35 also causes inhibition of co-stimulatory molecules (CD4, CD80, CD86 and type II histocompatibility system) and the maturation of dendritic cells. 27,40 The loss of function of the APCs causes massive apoptosis of lymphocytes, although these are not infected by the virus. 40 Simultaneously, the infected cells release large amounts of pro-inflammatory cytokines and chemokines, including interleukins IL-1β , IL-2, II-6, IL-10, tumor necrosis factor (TNF-α), monocyte chemoattractant protein 1 (MCP-1) of macrophages and nitric oxide (NO).…”

“…40 Simultaneously, the infected cells release large amounts of pro-inflammatory cytokines and chemokines, including interleukins IL-1β , IL-2, II-6, IL-10, tumor necrosis factor (TNF-α), monocyte chemoattractant protein 1 (MCP-1) of macrophages and nitric oxide (NO). 27 The systemic inflammatory response causes fever and the recruitment of more APCs to the site of infection; this results in the spread of infected cells to secondary lymphoid organs, lungs, liver, and other sites of viral replication. 30,37,38 Hepatocellular necrosis reduces the synthesis of coagulation factors and plasma proteins which in conjunction with TNF-α synthesized by macrophages appears to explain the severe coagulation changes observed in Ebola infection.…”