Monoterpenoid-based inhibitors of filoviruses targeting the glycoprotein-mediated entry process.

Autor: Sokolova AS; N.N.Vorozhtsov Novosibirsk Institute of Organic Chemistry SB RAS, 630090, Novosibirsk, Lavrent'ev Av., 9, Russia. Electronic address: asokolova@nioch.nsc.ru., Yarovaya OI; N.N.Vorozhtsov Novosibirsk Institute of Organic Chemistry SB RAS, 630090, Novosibirsk, Lavrent'ev Av., 9, Russia; Novosibirsk State University, 630090, Novosibirsk, Pirogova St., 1, Russia., Zybkina AV; State Research Center of Virology and Biotechnology VECTOR, Rospotrebnadzor, 630559, Koltsovo, Novosibirsk Region, Russia., Mordvinova ED; N.N.Vorozhtsov Novosibirsk Institute of Organic Chemistry SB RAS, 630090, Novosibirsk, Lavrent'ev Av., 9, Russia; State Research Center of Virology and Biotechnology VECTOR, Rospotrebnadzor, 630559, Koltsovo, Novosibirsk Region, Russia., Shcherbakova NS; State Research Center of Virology and Biotechnology VECTOR, Rospotrebnadzor, 630559, Koltsovo, Novosibirsk Region, Russia., Zaykovskaya AV; State Research Center of Virology and Biotechnology VECTOR, Rospotrebnadzor, 630559, Koltsovo, Novosibirsk Region, Russia., Baev DS; N.N.Vorozhtsov Novosibirsk Institute of Organic Chemistry SB RAS, 630090, Novosibirsk, Lavrent'ev Av., 9, Russia., Tolstikova TG; N.N.Vorozhtsov Novosibirsk Institute of Organic Chemistry SB RAS, 630090, Novosibirsk, Lavrent'ev Av., 9, Russia; Novosibirsk State University, 630090, Novosibirsk, Pirogova St., 1, Russia., Shcherbakov DN; State Research Center of Virology and Biotechnology VECTOR, Rospotrebnadzor, 630559, Koltsovo, Novosibirsk Region, Russia., Pyankov OV; State Research Center of Virology and Biotechnology VECTOR, Rospotrebnadzor, 630559, Koltsovo, Novosibirsk Region, Russia., Maksyutov RA; State Research Center of Virology and Biotechnology VECTOR, Rospotrebnadzor, 630559, Koltsovo, Novosibirsk Region, Russia., Salakhutdinov NF; N.N.Vorozhtsov Novosibirsk Institute of Organic Chemistry SB RAS, 630090, Novosibirsk, Lavrent'ev Av., 9, Russia.
Jazyk: angličtina
Zdroj: European journal of medicinal chemistry [Eur J Med Chem] 2020 Dec 01; Vol. 207, pp. 112726. Date of Electronic Publication: 2020 Aug 20.
DOI: 10.1016/j.ejmech.2020.112726
Abstrakt: In this study, we screened a large library of (+)-camphor and (-)-borneol derivatives to assess their filovirus entry inhibition activities using pseudotype systems. Structure-activity relationship studies revealed several compounds exhibiting submicromolar IC 50 values. These compounds were evaluated for their effect against natural Ebola virus (EBOV) and Marburg virus. Compound 3b (As-358) exhibited the good antiviral potency (IC 50  = 3.7 μM, SI = 118) against Marburg virus, while the hydrochloride salt of this compound 3b·HCl had a strong inhibitory effect against Ebola virus (IC 50  = 9.1 μM, SI = 31) and good in vivo safety (LD 50  > 1000 mg/kg). The results of molecular docking and in vitro mutagenesis analyses suggest that the synthesized compounds bind to the active binding site of EBOV glycoprotein similar to the known inhibitor toremifene.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2020 Elsevier Masson SAS. All rights reserved.)
Databáze: MEDLINE
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