Identification of novel chemical compounds targeting filovirus VP40-mediated particle production

Shuzo Urata; Olaposi Idowu Omotuyi; Ayako Izumisawa; Takeshi Ishikawa; Satoshi Mizuta; Yasuteru Sakurai; Tatsuaki Mizutani; Hiroshi Ueda; Yoshimasa Tanaka; Jiro Yasuda

doi:10.1016/j.antiviral.2022.105267

Identification of novel chemical compounds targeting filovirus VP40-mediated particle production

Antiviral Res. 2022 Mar:199:105267. doi: 10.1016/j.antiviral.2022.105267. Epub 2022 Feb 25.

Authors

Affiliations

¹ Department of Emerging Infectious Diseases, Institute of Tropical Medicine (NEKKEN), Nagasaki University, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan; National Research Center for the Control and Prevention of Infectious Diseases (CCPID), Nagasaki University, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan. Electronic address: shuzourata@nagasaki-u.ac.jp.
² Department of Pharmacology and Therapeutic Innovation, Graduate School of Biomedical Sciences, Nagasaki University, 1-14 Bunkyo-machi, Nagasaki, 852-8521, Japan.
³ National Research Center for the Control and Prevention of Infectious Diseases (CCPID), Nagasaki University, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan.
⁴ Graduate School of Biomedical Sciences and Program for Nurturing Global Leaders in Tropical and Emerging Communicable Diseases, Nagasaki University, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan.
⁵ Center for Bioinformatics and Molecular Medicine, Graduate School of Biomedical Sciences, Nagasaki University, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan.
⁶ Department of Emerging Infectious Diseases, Institute of Tropical Medicine (NEKKEN), Nagasaki University, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan; National Research Center for the Control and Prevention of Infectious Diseases (CCPID), Nagasaki University, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan.
⁷ Center for Medical Innovation Nagasaki University, 1-7-1 Sakamoto, Nagasaki, 852-8588, Japan.
⁸ Department of Emerging Infectious Diseases, Institute of Tropical Medicine (NEKKEN), Nagasaki University, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan; National Research Center for the Control and Prevention of Infectious Diseases (CCPID), Nagasaki University, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan; Graduate School of Biomedical Sciences and Program for Nurturing Global Leaders in Tropical and Emerging Communicable Diseases, Nagasaki University, 1-12-4 Sakamoto, Nagasaki, 852-8523, Japan. Electronic address: j-yasuda@nagasaki-u.ac.jp.

PMID: 35227759
DOI: 10.1016/j.antiviral.2022.105267

Abstract

The central role of Ebola virus (EBOV) VP40 in nascent virion assembly and budding from infected host cells makes it an important therapeutic target. The mechanism of dimerization, following oligomerization of VP40 leading to the production of virus-like particles (VLP) has never been investigated for the development of therapeutic candidates against Ebola disease. Molecular dynamics-based computational screening targeted VP40 dimer with 40,000,000 compounds selected 374 compounds. A novel in vitro screening assay selected two compounds, NUSU#1 and NUSU#2. Conventional VLP assays consistently showed that both compounds inhibited EBOV VP40-mediated VLP production. Intriguingly, NUSU#1 inhibited the VP40-mediated VLP production in other ebolavirus species and the Marburg virus, but did not inhibit Lassa virus Z-mediated VLP production. These results strongly suggested that the selected compounds are potential lead drug candidates against Filovirus disease via disruption of VP40-mediated particle production.

Keywords: Anti-Ebolavirus compound; Ebola virus VP40; Viral particle production.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Ebolavirus* / chemistry
Hemorrhagic Fever, Ebola*
Humans
Marburgvirus*
Viral Matrix Proteins / chemistry
Virus Release

Substances

Viral Matrix Proteins