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Novel amodiaquine derivatives potently inhibit Ebola virus infection.

ABSTRACT: Ebola virus disease is a severe disease caused by highly pathogenic Ebolaviruses. Although it shows a high mortality rate in humans, currently there is no licensed therapeutic. During the recent epidemic in West Africa, it was demonstrated that administration of antimalarial medication containing amodiaquine significantly lowered mortality rate of patients infected with the virus. Here, in order to improve its antiviral activity, a series of amodiaquine derivatives were synthesized and tested for Ebola virus infection. We found that multiple compounds were more potent than amodiaquine. The structure-activity relationship analysis revealed that the two independent parts, which are the alkyl chains extending from the aminomethyl group and a halogen bonded to the quinoline ring, were keys for enhancing antiviral potency without increasing toxicity. When these modifications were combined, the antiviral efficacy could be further improved with the selectivity indexes being over 10-times higher than amodiaquine. Mechanistic evaluation demonstrated that the potent derivatives blocked host cell entry of Ebola virus, like the parental amodiaquine. Taken together, our work identified novel potent amodiaquine derivatives, which will aid in further development of effective antiviral therapeutics.

SUBMITTER: Sakurai Y

PROVIDER: S-EPMC6374029 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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Novel amodiaquine derivatives potently inhibit Ebola virus infection.

Sakurai Yasuteru Y Sakakibara Norikazu N Toyama Masaaki M Baba Masanori M Davey Robert A RA

Antiviral research 20181103

Ebola virus disease is a severe disease caused by highly pathogenic Ebolaviruses. Although it shows a high mortality rate in humans, currently there is no licensed therapeutic. During the recent epidemic in West Africa, it was demonstrated that administration of antimalarial medication containing amodiaquine significantly lowered mortality rate of patients infected with the virus. Here, in order to improve its antiviral activity, a series of amodiaquine derivatives were synthesized and tested fo ...[more]

PMID: 30395872

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Project description:Background:Ebola viral disease is a severe and mostly fatal disease in humans caused by Ebola virus. This virus belongs to family Filoviridae and is a single-stranded negative-sense virus. There is no single treatment for this disease which puts forth the need to identify new therapy to control and treat this fatal condition. Curcumin, one of the bioactives of turmeric, has proven antiviral property. Objective:The current study evaluates the inhibitory activity of curcumin, bisdemethoxycurcumin, demethoxycurcumin, and tetrahydrocurcumin against Zaire Ebola viral proteins (VPs). Materials and Methods:Molecular simulation of the Ebola VPs followed by docking studies with ligands comprising curcumin and related compounds was performed. Results:The highest binding activity for VP40 is -6.3 kcal/mol, VP35 is -8.3 kcal/mol, VP30 is -8.0 kcal/mol, VP24 is -7.7 kcal/mol, glycoprotein is -7.1 kcal/mol, and nucleoprotein is 6.8 kcal/mol. Conclusion:Bisdemethoxycurcumin shows better binding affinity than curcumin for most VPs. Metabolite tetrahydrocurcumin also shows binding affinity comparable to curcumin. These results indicate that curcumin, curcuminoids, and metabolite tetrahydrocurcumin can be potential lead compounds for developing a new therapy for Ebola viral disease. SUMMARY:Curcumin, bisdemethoxycurcumin, and demethoxycurcumin are active constituents of turmeric. Tetrahydrocurcumin is the major metabolite of curcumin formed in the body after consumption and absorption of curcuminoidsCurcuminoids have proven antiviral activityBisdemethoxycurcumin showed maximum inhibition of Ebola viral proteins (VPs) among the curcuminoids in the docking procedure with a docking score as high as -8.3 kcal/molTetrahydrocurcumin showed inhibitory activity against Ebola VPs close to that of curcumin's inhibitory action. Abbreviations Used: EBOV: Ebola virus, GP: Glycoprotein, NP: Nucleoprotein, NPT: Isothermal-isobaric Ensemble, amount of substance (N), pressure (P) and temperature (T) conserved, NVE: Canonical ensemble, amount of substance (N), volume (V) and temperature (T) conserved, VP: Viral protein.

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Novel amodiaquine derivatives potently inhibit Ebola virus infection.

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Novel amodiaquine derivatives potently inhibit Ebola virus infection.

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