Claudin 5-binding small molecule transiently opens the blood-brain barrier and safely enhances brain drug delivery

Inoue, Saito; Shirakura, Keisuke; Shirono, Atsuya; Taguchi, Jumpei; Ikeda, Yoshiki; Tomita, Satomi; Funatsu, Risa; Muraoka, Kosuke; Hashimoto, Yosuke; Tachibana, Keisuke; Hino, Nobumasa; Doi, Takefumi; Ikemi, Yui; Nunomura, Kazuto; Lin, Bangzhong; Nakagawa, Shinsaku; Tsujikawa, Kazutake; Tanaka, Shota; Obana, Masanori; Fujio, Yasushi; Hosoya, Takamitsu; Takeda, Hiroyuki; Kondoh, Masuo; Okada, Yoshiaki

doi:https://doi.org/10.1016/j.jconrel.2025.114314

Claudin 5-binding small molecule transiently opens the blood-brain barrier and safely enhances brain drug delivery

Inoue, Saito; Shirakura, Keisuke; Shirono, Atsuya et al.

Journal of Controlled Release, 2025, 388, 114314

Number of Access:1,876（2026-08-24 16:05 Counts）

Identifier to cite or link to this item: https://hdl.handle.net/11094/103511

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Title	Claudin 5-binding small molecule transiently opens the blood-brain barrier and safely enhances brain drug delivery
Creator	CreatorName Inoue, Saito
	ORCID 0000-0002-9487-9495 0000-0002-9487-9495 researchmap permalink kshirak kshirak Scopus Author ID 56166869200 56166869200 CreatorName Shirakura, Keisuke
	CreatorName Shirono, Atsuya
	NRID 1000050865855 1000050865855 CreatorName Taguchi, Jumpei
	NRID 1000010633026 1000010633026 CreatorName Ikeda, Yoshiki
	CreatorName Tomita, Satomi
	CreatorName Funatsu, Risa
	CreatorName Muraoka, Kosuke
	CreatorName Hashimoto, Yosuke
	NRID 1000030432446 1000030432446 CreatorName Tachibana, Keisuke
	NRID 1000090469916 1000090469916 ORCID 0000-0002-7072-1183 0000-0002-7072-1183 researchmap permalink crosslinker crosslinker Scopus Author ID 24175680600 24175680600 CreatorName Hino, Nobumasa
	CreatorName Doi, Takefumi
	ORCID 0000-0001-5687-8988 0000-0001-5687-8988 Scopus Author ID 57226317499 57226317499 CreatorName Ikemi, Yui
	ORCID 0000-0002-6444-3244 0000-0002-6444-3244 researchmap permalink nunomurakazuto nunomurakazuto Scopus Author ID 6701473939 6701473939 CreatorName Nunomura, Kazuto
	ORCID 0000-0001-5877-949X 0000-0001-5877-949X researchmap permalink linbangzhong linbangzhong Scopus Author ID 57200092216 57200092216 CreatorName Lin, Bangzhong
	NRID 1000070207728 1000070207728 researchmap permalink read0042859 read0042859 CreatorName Nakagawa, Shinsaku
	NRID 1000010207376 1000010207376 researchmap permalink read0014359 read0014359 Scopus Author ID 7004354760 7004354760 ORCID 0000-0003-1870-9790 0000-0003-1870-9790 CreatorName Tsujikawa, Kazutake
	NRID 1000080880294 1000080880294 researchmap permalink 80880294 80880294 Scopus Author ID 56612561000 56612561000 ORCID 0000-0002-3053-6928 0000-0002-3053-6928 CreatorName Tanaka, Shota
	NRID 1000050745883 1000050745883 researchmap permalink m_o m_o Scopus Author ID 17135691100 17135691100 CreatorName Obana, Masanori
	NRID 1000020359839 1000020359839 ORCID 0000-0003-0828-2930 0000-0003-0828-2930 researchmap permalink yfujio yfujio Scopus Author ID 7006517527 7006517527 CreatorName Fujio, Yasushi
	NRID 1000060273124 1000060273124 CreatorName Hosoya, Takamitsu
	NRID 1000040609393 1000040609393 CreatorName Takeda, Hiroyuki
	NRID 1000050309697 1000050309697 researchmap permalink read0083480 read0083480 Scopus Author ID 26643156500 26643156500 CreatorName Kondoh, Masuo
	NRID 1000050444500 1000050444500 researchmap permalink magic_roundabout magic_roundabout Scopus Author ID 55721995000 55721995000 ORCID 0000-0002-2962-244X 0000-0002-2962-244X CreatorName Okada, Yoshiaki
Subject	Blood–brain barrier
	Claudin 5
	Drug delivery
	Permeability
	Tight junction
Description	Inoue S., Shirakura K., Shirono A., et al. Claudin 5-binding small molecule transiently opens the blood-brain barrier and safely enhances brain drug delivery. Journal of Controlled Release 388, 114314 (2025); https://doi.org/10.1016/j.jconrel.2025.114314.
Abstract	The blood–brain barrier (BBB) protects the brain from harmful substances, but it also limits drug delivery, hindering the treatment of brain diseases. Claudin 5, a tight junction protein in endothelial cells, plays a key role in maintaining the BBB integrity. Although modulation of Claudin 5 is a promising strategy for transiently opening the BBB, the currently available modulators often cause adverse effects due to strong or prolonged activity. Thus, we aimed to develop a moderate Claudin 5 modulator that enables safe and transient opening of the BBB. We identified a Claudin 5-binding small molecule (CL5B), capable of binding Claudin 5 via a high-throughput screening of 9600 compounds using a Claudin 5 antibody and proteoliposomes. CL5B increased endothelial permeability and tracer permeation across the endothelial monolayer by altering the localization of Claudin 5 without affecting its expression. In mice, CL5B transiently opened the BBB for less than 30 min, delivering drugs specifically to the brain. Notably, CL5B-facilitated delivery of methylscopolamine, a drug with limited brain penetration, alleviated seizure symptoms in a mouse epilepsy model. These findings demonstrate that CL5B is a safe BBB modulator that enhances brain drug delivery and holds therapeutic potential for brain diseases.
Publisher	Elsevier B.V.
Source Title	Journal of Controlled Release
Volume (Issue)	388
Page	114314
Date of Issued	2025-10-17
Language	English
Handle URL	https://hdl.handle.net/11094/103511
PISSN	01683659
eISSN	18734995
Relation.isIdenticalTo	DOI (Publisher Version) https://doi.org/10.1016/j.jconrel.2025.114314
Access Rights	open access
CopyRight	This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
oaire:version	Version of Record
Category	学術雑誌論文 Journal Article

Resource Type	journal article
Local Type	Journal Article
DCMI Type	Text
DCTERMS.bibliographicCitation	Journal of Controlled Release. 2025, 388, p. 114314
DC.title	Claudin 5-binding small molecule transiently opens the blood-brain barrier and safely enhances brain drug delivery
DC.creator	Inoue, Saito
	Shirakura, Keisuke
	Shirono, Atsuya
	Taguchi, Jumpei
	Ikeda, Yoshiki
	Tomita, Satomi
	Funatsu, Risa
	Muraoka, Kosuke
	Hashimoto, Yosuke
	Tachibana, Keisuke
	Hino, Nobumasa
	Doi, Takefumi
	Ikemi, Yui
	Nunomura, Kazuto
	Lin, Bangzhong
	Nakagawa, Shinsaku
	Tsujikawa, Kazutake
	Tanaka, Shota
	Obana, Masanori
	Fujio, Yasushi
	Hosoya, Takamitsu
	Takeda, Hiroyuki
	Kondoh, Masuo
	Okada, Yoshiaki
DC.publisher	Elsevier B.V.
DC.language' scheme='DCTERMS.RFC1766	English
DC.type' scheme='DCTERMS.DCMIType	Text
DCTERMS.issued' scheme='DCTERMS.W3CDTF	2025-10-17
DC.identifier	https://doi.org/10.1016/j.jconrel.2025.114314
DC.subject	Blood–brain barrier
	Claudin 5
	Drug delivery
	Permeability
	Tight junction
DC.description	Inoue S., Shirakura K., Shirono A., et al. Claudin 5-binding small molecule transiently opens the blood-brain barrier and safely enhances brain drug delivery. Journal of Controlled Release 388, 114314 (2025); https://doi.org/10.1016/j.jconrel.2025.114314.
DCTERMS.abstract	The blood–brain barrier (BBB) protects the brain from harmful substances, but it also limits drug delivery, hindering the treatment of brain diseases. Claudin 5, a tight junction protein in endothelial cells, plays a key role in maintaining the BBB integrity. Although modulation of Claudin 5 is a promising strategy for transiently opening the BBB, the currently available modulators often cause adverse effects due to strong or prolonged activity. Thus, we aimed to develop a moderate Claudin 5 modulator that enables safe and transient opening of the BBB. We identified a Claudin 5-binding small molecule (CL5B), capable of binding Claudin 5 via a high-throughput screening of 9600 compounds using a Claudin 5 antibody and proteoliposomes. CL5B increased endothelial permeability and tracer permeation across the endothelial monolayer by altering the localization of Claudin 5 without affecting its expression. In mice, CL5B transiently opened the BBB for less than 30 min, delivering drugs specifically to the brain. Notably, CL5B-facilitated delivery of methylscopolamine, a drug with limited brain penetration, alleviated seizure symptoms in a mouse epilepsy model. These findings demonstrate that CL5B is a safe BBB modulator that enhances brain drug delivery and holds therapeutic potential for brain diseases.
DC.rights	This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
DC.format	103511
citation_title	Claudin 5-binding small molecule transiently opens the blood-brain barrier and safely enhances brain drug delivery
citation_author	Inoue, Saito
	Shirakura, Keisuke
	Shirono, Atsuya
	Taguchi, Jumpei
	Ikeda, Yoshiki
	Tomita, Satomi
	Funatsu, Risa
	Muraoka, Kosuke
	Hashimoto, Yosuke
	Tachibana, Keisuke
	Hino, Nobumasa
	Doi, Takefumi
	Ikemi, Yui
	Nunomura, Kazuto
	Lin, Bangzhong
	Nakagawa, Shinsaku
	Tsujikawa, Kazutake
	Tanaka, Shota
	Obana, Masanori
	Fujio, Yasushi
	Hosoya, Takamitsu
	Takeda, Hiroyuki
	Kondoh, Masuo
	Okada, Yoshiaki
citation_publisher	Elsevier B.V.
citation_language	English
citation_date	2025-10-17
citation_journal_title	Journal of Controlled Release
citation_volume	388
citation_firstpage	114314
citation_doi	https://doi.org/10.1016/j.jconrel.2025.114314
citation_public_url	https://hdl.handle.net/11094/103511

Claudin 5-binding small molecule transiently opens the blood-brain barrier and safely enhances brain drug delivery

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