Ebola virus (EBOV) infection: Therapeutic strategies

Abstract

Within less than a year after its epidemic started (in December 2013) in Guinea, Ebola virus (EBOV), a member of the filoviridae, has spread over a number of West-African countries (Guinea, Sierra Leone and Liberia) and gained allures that have been unprecedented except by human immunodeficiency virus (HIV). Although EBOV is highly contagious and transmitted by direct contact with body fluids, it could be counteracted by the adequate chemoprophylactic and -therapeutic interventions: vaccines, antibodies, siRNAs (small interfering RNAs), interferons and chemical substances, i.e. neplanocin A derivatives (i.e. 3-deazaneplanocin A), BCX4430, favipiravir (T-705), endoplasmic reticulum (ER) α-glucosidase inhibitors and a variety of compounds that have been found to inhibit EBOV infection blocking viral entry or by a mode of action that still has to be resolved. Much has to be learned from the mechanism of action of the compounds active against VSV (vesicular stomatitis virus), a virus belonging to the rhabdoviridae, that in its mode of replication could be exemplary for the replication of filoviridae.

Keywords: 3-Deazaneplanocin A; 3-Deazaneplanocin A (PubChem CID: 73087); Amiodarone (PubChem CID: 2157); BCX-1777 (PubChem CID: 11493192); BCX4430; BCX4430 (PubChem CID: 69211190); Chloroquine (PubChem CID: 2719); Clomifene (PubChem CID: 1548953); Dronedarone (PubChem CID: 208898); Ebola; FGI-103 (PubChem CID: 5477931); Favipiravir; Favipiravir (PubChem CID: 492405); Filoviridae; LJ 001 (PubChem CID: 49777349); NSC62914 (PubChem CID: 66662); VSV (vesicular stomatitis virus); Verapamil (PubChem CID: 2520); dUY11 (PubChem CID: 24771429).

Graphical abstract

Fig. 1

Numbers of confirmed and probable Ebola cases reported weekly from Guinea, Sierra Leone, and Liberia from January 5, 2014, to September 14, 2014 .

Fig. 2

Structure of Ebola virus. An ebolavirus particle and its characteristic filamentous shape are shown. The negative-strand RNA genome is found in the center of particles in an encapsidated form as the nucleocapsid, together with the polymerase complex. Embedded in the virus membrane are trimeric glycoprotein spikes. Beneath the membrane is the matrix protein, which facilitates morphogenesis and budding of virus particles .

Fig. 3

Structure of 3-deazaneplanocin A , and neplanocin A (D-like and L-like) analogs .

Fig. 4

Structures of BCX4430 and BCX-1777 .

Fig. 5

Structure of favipiravir (T-705) .

Fig. 6

Metabolic pathways of T-705 (favipiravir) .

Fig. 7

Endoplasmic reticulum (ER) glucosidase inhibitors: IHVR11029, IHVR17028 and IHVR19029 .

Fig. 8

The FGI (Functional Genetics Inc.) compounds: FGI 103 and FGI 106 .

Fig. 9

Antioxidant NSC62914 .

Fig. 10

Viral entry inhibitors, benzylpiperazine adamantine diamides 3.0 and 3.47 and benzodiazepine derivative (compound 7) .

Fig. 11

Viral entry inhibitors: LJ 001 and dUY11 .

Fig. 12

Selective estrogen receptor modulators (SERMS): clomiphene and toremifene .

Fig. 13

Ion channel blockers amiodarone, dronedarone and verapamil .

Fig. 14

CMLDBU3402, an indoline alkaloid-type compound .

Fig. 15

(−)-Epigallocatechin gallate.

Fig. 16

Miscellaneous compounds preventing cathepsin L cleavage of viral glycoproteins derived from SARS coronavirus, Hendra, Nipah or EBOV. Chemical structures of the small molecules identified by pseudovirus inhibition assay. Four small molecules showed inhibition of both EBOV and SARS-CoV pseudotyped virus entry. (A) Compound 5182554 {N-(3,4-dichlorophenyl)-N′-[3-(trifluoromethyl)phenyl]urea}; (B) compound 7910528 [N-(3,4-dichlorophenyl)-2-oxo-2,3-dihydro-1,3-benzoxazole-6-sulfonamide]; (C) compound 7914021 [N-(3-chlorophenyl)-N′-(4-cyanophenyl)urea]; (D and E) compound 5705213 {methyl-N-[4,6-bis(isopropylamino)-1,3,5-triazin-2-yl]-N-cyanoglycinate}. (D) and (E) its derivative 7402683 {methyl-N-[4-(tert-butylamino)-6-(ethylamino)-1,3,5-triazin-2-yl]-N-cyanoglycinate} .

Fig. 17

Chloroquine.