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A biaryl sulfonamide derivative as a novel inhibitor of filovirus infection

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Title: A biaryl sulfonamide derivative as a novel inhibitor of filovirus infection
Authors: Isono, Mao Browse this author
Furuyama, Wakako Browse this author
Kuroda, Makoto Browse this author →KAKEN DB
Kondoh, Tatsunari Browse this author
Igarashi, Manabu Browse this author →KAKEN DB
Kajihara, Masahiro Browse this author →KAKEN DB
Yoshida, Reiko Browse this author →KAKEN DB
Manzoor, Rashid Browse this author
Okuya, Kosuke Browse this author
Miyamoto, Hiroko Browse this author
Feldmann, Heinz Browse this author
Marzi, Andrea Browse this author
Sakaitani, Masahiro Browse this author
Nanbo, Asuka Browse this author →KAKEN DB
Takada, Ayato Browse this author →KAKEN DB
Keywords: Ebolavirus
Entry inhibitor
Membrane fusion
Issue Date: Nov-2020
Publisher: Elsevier
Journal Title: Antiviral research
Volume: 183
Start Page: 104932
Publisher DOI: 10.1016/j.antiviral.2020.104932
Abstract: Ebolaviruses and marburgviruses, members of the family Filoviridae, are known to cause fatal diseases often associated with hemorrhagic fever. Recent outbreaks of Ebola virus disease in West African countries and the Democratic Republic of the Congo have made clear the urgent need for the development of therapeutics and vaccines against filoviruses. Using replication-incompetent vesicular stomatitis virus (VSV) pseudotyped with the Ebola virus (EBOV) envelope glycopmtein (GP), we screened a chemical compound library to obtain new drug candidates that inhibit filoviral entry into target cells. We discovered a biaryl sulfonamide derivative that suppressed in vitro infection mediated by GPs derived from all known human-pathogenic filoviruses. To determine the inhibitory mechanism of the compound, we monitored each entry step (attachment, internalization, and membrane fusion) using lipophilic tracer-labeled ebolavirus-like particles and found that the compound efficiently blocked fusion between the viral envelope and the endosomal membrane during cellular entry. However, the compound did not block the interaction of GP with the Niemann-Pick Cl protein, which is believed to be the receptor of filoviruses. Using replication-competent VSVs pseudotyped with EBOV GP, we selected escape mutants and identified two EBOV GP amino acid residues (positions 47 and 66) important for the interaction with this compound. Interestingly, these amino acid residues were located at the base region of the GP trimer, suggesting that the compound might interfere with the GP conformational change required for membrane fusion. These results suggest that this biaryl sulfonamide derivative is a novel fusion inhibitor and a possible drug candidate for the development of a pan-filovirus therapeutic.
Rights: © 2020. This manuscript version is made available under the CC-BY-NC-ND 4.0 license
Type: article (author version)
Appears in Collections:人獣共通感染症国際共同研究所 (International Institute for Zoonosis Control) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)
国際連携研究教育局 : GI-CoRE (Global Institution for Collaborative Research and Education : GI-CoRE) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

Submitter: 高田 礼人

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