TY - JOUR

T1 - (+)-fenchol and (−)-isopinocampheol derivatives targeting the entry process of filoviruses

AU - Sokolova, Anastasiya S.

AU - Baev, Dmitriy S.

AU - Mordvinova, Ekaterina D.

AU - Yarovaya, Olga I.

AU - Volkova, Natalia V.

AU - Shcherbakov, Dmitriy N.

AU - Okhina, Alina A.

AU - Rogachev, Artem D.

AU - Shnaider, Tatiana A.

AU - Chvileva, Anastasiya S.

AU - Nikitina, Tatiana V.

AU - Tolstikova, Tatyana G.

AU - Salakhutdinov, Nariman F.

N1 - This work was supported by grant No. 22-73-00168 from the Russian Science Foundation. The authors would like to acknowledge the Multi-Access Chemical Research Center SB RAS for spectral and analytical measurements. The cultivation of human adult fibroblasts was performed at the multi-access center Collection of Pluripotent Human and Mammalian Cell Cultures for Biological and Biomedical Research at the ICG SB RAS (https://ckp.icgen.ru/cells/; http://www.biores.cytogen.ru/brc_cells/collections/ICG_SB_RAS_CELL). The microscopic analysis was conducted at the Multi-Access Center for Microscopy of Biological Subjects (ICG SB RAS, Novosibirsk, Russia). The MD simulations were performed with support from the Ministry of Science and Higher Education of the Russian Federation within a government contract for SRF SKIF and Boreskov Institute of Catalysis (project FWUR-2024-0040). The English language was corrected and certified by shevchuk-editing.com. This work was supported by grant No. 22-73-00168 from the Russian Science Foundation. The authors would like to acknowledge the Multi-Access Chemical Research Center SB RAS for spectral and analytical measurements. The cultivation of human adult fibroblasts was performed at the multi-access center Collection of Pluripotent Human and Mammalian Cell Cultures for Biological and Biomedical Research at the ICG SB RAS ( https://ckp.icgen.ru/cells/ ; http://www.biores.cytogen.ru/brc_cells/collections/ICG_SB_RAS_CELL ). The microscopic analysis was conducted at the Multi-Access Center for Microscopy of Biological Subjects (ICG SB RAS, Novosibirsk, Russia). The MD simulations were performed with support from the Ministry of Science and Higher Education of the Russian Federation within a government contract for SRF SKIF and Boreskov Institute of Catalysis (project FWUR-2024-0040). The English language was corrected and certified by shevchuk-editing.com

PY - 2024/9/5

Y1 - 2024/9/5

N2 - The increasing frequency of filovirus outbreaks in African countries has led to a pressing need for the development of effective antifilovirus agents. In continuation of our previous research on the antifilovirus activity of monoterpenoid derivatives, we synthesized a series of (+)-fenchol and (−)-isopinocampheol derivatives by varying the type of heterocycle and linker length. Derivatives with an N-alkylpiperazine cycle proved to be the most potent antiviral compounds, with half-maximal inhibitory concentration (IC50) 1.4–20 μМ against Lenti-EboV-GP infection and 11.3–47 μМ against Lenti-MarV-GP infection. Mechanism-of-action experiments revealed that the compounds may exert their action by binding to surface glycoproteins (GPs). It was demonstrated that the binding of the synthesized compounds to the Marburg virus GP is less efficient as compared to the Ebola virus GP. Furthermore, it was shown that the compounds possess lysosomotropic properties. Thus, the antiviral activity may be due to dual effects. This study offers new antiviral agents that are worthy of further exploration.

AB - The increasing frequency of filovirus outbreaks in African countries has led to a pressing need for the development of effective antifilovirus agents. In continuation of our previous research on the antifilovirus activity of monoterpenoid derivatives, we synthesized a series of (+)-fenchol and (−)-isopinocampheol derivatives by varying the type of heterocycle and linker length. Derivatives with an N-alkylpiperazine cycle proved to be the most potent antiviral compounds, with half-maximal inhibitory concentration (IC50) 1.4–20 μМ against Lenti-EboV-GP infection and 11.3–47 μМ against Lenti-MarV-GP infection. Mechanism-of-action experiments revealed that the compounds may exert their action by binding to surface glycoproteins (GPs). It was demonstrated that the binding of the synthesized compounds to the Marburg virus GP is less efficient as compared to the Ebola virus GP. Furthermore, it was shown that the compounds possess lysosomotropic properties. Thus, the antiviral activity may be due to dual effects. This study offers new antiviral agents that are worthy of further exploration.

KW - Ebola virus

KW - Fenchol

KW - Glycoprotein

KW - Isopinocampheol

KW - Lysosomotropic compounds

KW - Marburg virus

UR - https://www.scopus.com/record/display.uri?eid=2-s2.0-85196192293&origin=inward&txGid=f95a6084360124c4c559c80a060314af

UR - https://www.mendeley.com/catalogue/0f7530d4-1c56-34aa-8dab-86d9afc430d3/

U2 - 10.1016/j.ejmech.2024.116596

DO - 10.1016/j.ejmech.2024.116596

M3 - Article

C2 - 38889610

VL - 275

JO - European Journal of Medicinal Chemistry

JF - European Journal of Medicinal Chemistry

SN - 0223-5234

M1 - 116596

ER -