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

Anastasiya S Sokolova; Olga I Yarovaya; Anastasiya V Zybkina; Ekaterina D Mordvinova; Nadezhda S Shcherbakova; Anna V Zaykovskaya; Dmitriy S Baev; Tatyana G Tolstikova; Dmitriy N Shcherbakov; Oleg V Pyankov; Rinat A Maksyutov; Nariman F Salakhutdinov

doi:10.1016/j.ejmech.2020.112726

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

Eur J Med Chem. 2020 Dec 1:207:112726. doi: 10.1016/j.ejmech.2020.112726. Epub 2020 Aug 20.

Affiliations

¹ N.N.Vorozhtsov Novosibirsk Institute of Organic Chemistry SB RAS, 630090, Novosibirsk, Lavrent'ev Av., 9, Russia. Electronic address: asokolova@nioch.nsc.ru.
² 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.
³ State Research Center of Virology and Biotechnology VECTOR, Rospotrebnadzor, 630559, Koltsovo, Novosibirsk Region, Russia.
⁴ 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.
⁵ N.N.Vorozhtsov Novosibirsk Institute of Organic Chemistry SB RAS, 630090, Novosibirsk, Lavrent'ev Av., 9, Russia.

PMID: 32905862
DOI: 10.1016/j.ejmech.2020.112726

Abstract

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 IC₅₀ 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 (IC₅₀ = 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 (IC₅₀ = 9.1 μM, SI = 31) and good in vivo safety (LD₅₀ > 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.

Keywords: Borneol; Camphor; Ebola virus; Glycoprotein; Marburg virus; Mutagenesis study.

MeSH terms

Animals
Antiviral Agents / chemistry*
Antiviral Agents / pharmacology*
Antiviral Agents / toxicity
Ebolavirus / drug effects*
Ebolavirus / physiology
HEK293 Cells
Hemorrhagic Fever, Ebola / drug therapy
Humans
Marburg Virus Disease / drug therapy
Marburgvirus / drug effects*
Marburgvirus / physiology
Mice, Inbred ICR
Molecular Docking Simulation
Monoterpenes / chemistry*
Monoterpenes / pharmacology*
Monoterpenes / toxicity
Virus Internalization

Substances

Antiviral Agents
Monoterpenes