A biaryl sulfonamide derivative as a novel inhibitor of filovirus infection

Isono, Mao; Furuyama, Wakako; Kuroda, Makoto; Kondoh, Tatsunari; Igarashi, Manabu; Kajihara, Masahiro; Yoshida, Reiko; Manzoor, Rashid; Okuya, Kosuke; Miyamoto, Hiroko; Feldmann, Heinz; Marzi, Andrea; Sakaitani, Masahiro; Nanbo, Asuka; Takada, Ayato

A biaryl sulfonamide derivative as a novel inhibitor of filovirus infection

Isono, Mao; Furuyama, Wakako; Kuroda, Makoto et al.

Antiviral research, 2020, 183, 104932

Permalink : https://hdl.handle.net/2115/83372

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アクセス権	open access
URI	https://hdl.handle.net/2115/83372
タイトル	A biaryl sulfonamide derivative as a novel inhibitor of filovirus infection
著者	Isono, Mao ; Furuyama, Wakako ; Kuroda, Makoto ; Kondoh, Tatsunari ; Igarashi, Manabu ; Kajihara, Masahiro ; Yoshida, Reiko ; Manzoor, Rashid ; Okuya, Kosuke ; Miyamoto, Hiroko ; Feldmann, Heinz ; Marzi, Andrea ; Sakaitani, Masahiro ; Nanbo, Asuka ; Takada, Ayato
著者名 Isono, Mao
著者名 Furuyama, Wakako
e-Rad_Researcher 80317411 著者名 Kuroda, Makoto
著者名 Kondoh, Tatsunari
e-Rad_Researcher 10374240 著者名 Igarashi, Manabu
e-Rad_Researcher 70711894 著者名 Kajihara, Masahiro
e-Rad_Researcher 80435966 著者名 Yoshida, Reiko
著者名 Manzoor, Rashid
著者名 Okuya, Kosuke
著者名 Miyamoto, Hiroko
著者名 Feldmann, Heinz
著者名 Marzi, Andrea
著者名 Sakaitani, Masahiro
e-Rad_Researcher 60359487 著者名 Nanbo, Asuka
e-Rad_Researcher 10292062 著者名 Takada, Ayato
言語	英語
キーワード	Ebolavirus
	Marburgvirus
	Glycoprotein
	Compound
	Entry inhibitor
	Membrane fusion
発行日	2020-11
出版者	Elsevier
収録物名	Antiviral research
巻(号)	183
ページ	104932
抄録	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.
資源タイプ	学術雑誌論文
出版タイプ	Accepted Manuscript
権利情報	Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International
権利情報	© 2020. This manuscript version is made available under the CC-BY-NC-ND 4.0 license https://creativecommons.org/licenses/by-nc-nd/4.0/
PISSN	0166-3542
関連情報 (isVersionOf)	出版社版DOI https://doi.org/10.1016/j.antiviral.2020.104932