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.
Anastasiya S Sokolova  1 ,  Olga I Yarovaya  2 ,  Anastasiya V Zybkina  3 ,  Ekaterina D Mordvinova  4 ,  Nadezhda S Shcherbakova  3 ,  Anna V Zaykovskaya  3 ,  Dmitriy S Baev  5 ,  Tatyana G Tolstikova  2 ,  Dmitriy N Shcherbakov  3 ,  Oleg V Pyankov  3 ,  Rinat A Maksyutov  3 ,  Nariman F Salakhutdinov  5
Affiliations
  • 1. N.N.Vorozhtsov Novosibirsk Institute of Organic Chemistry SB RAS, 630090, Novosibirsk, Lavrent'ev Av., 9, Russia. Electronic address: [email protected].
  • 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.
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