Perspectives towards antiviral drug discovery against Ebola virus

Abstract

Ebola virus disease (EVD), caused by Ebola viruses, resulted in more than 11 500 deaths according to a recent 2018 WHO report. With mortality rates up to 90%, it is nowadays one of the most deadly infectious diseases. However, no Food and Drug Administration-approved Ebola drugs or vaccines are available yet with the mainstay of therapy being supportive care. The high fatality rate and absence of effective treatment or vaccination make Ebola virus a category-A biothreat pathogen. Fortunately, a series of investigational countermeasures have been developed to control and prevent this global threat. This review summarizes the recent therapeutic advances and ongoing research progress from research and development to clinical trials in the development of small-molecule antiviral drugs, small-interference RNA molecules, phosphorodiamidate morpholino oligomers, full-length monoclonal antibodies, and vaccines. Moreover, difficulties are highlighted in the search for effective countermeasures against EVD with additional focus on the interplay between available in silico prediction methods and their evidenced potential in antiviral drug discovery.

Keywords: Ebola virus; advancement; antiviral; discovery; drugs; in silico methods; therapeutic.

Figure 1

Few drug candidates to treat Ebola virus disease

Figure 2

Stepwise drug discovery process from target identification, hit‐to‐lead optimization, and clinical trials along with the progress in the development of small‐molecule inhibitors against EBOV. ADMET, absorption, distribution, metabolism, excretion, and toxicity; HTS, high through‐put screen; PDB, protein data bank; PK, pharmacokinetics; QSAR, quantitative structure‐activity relationship; R&D, research and development; SAR, structure‐activity relationship

Figure 3

Detailed comprehensive workflow toward efficient anti‐EBOV drug discovery. ADMET, absorption, distribution, metabolism, excretion, and toxicity; CoMFA, comparative molecular field analysis; CoMSIA, comparative molecular similarity indices analysis; GBSA, generalized born surface area; MM, molecular mechanics; PAINS, filters for removal of pan assay interference compounds; PBSA, Poisson‐Boltzmann surface area; PCA, principal component analysis; PDB, protein data bank; QM; quantum mechanics; QSAR, quantitative structure‐activity relationship; Rg, radius gyration; RMSD, root‐mean‐square deviation; RMSF, root‐mean‐square fluctuation