In vitro screening of chemically synthesized dipeptide-antisense oligonucleotide conjugates to identify ligand molecules enhancing their activity

Osawa, Takashi; Kita, Ryosuke; Kasahara, Yuuya; Yamaguma, Harumi; Nakayama, Taisuke; Kamada, Haruhiko; Obika, Satoshi

doi:https://doi.org/10.1016/j.bmc.2024.117814

In vitro screening of chemically synthesized dipeptide-antisense oligonucleotide conjugates to identify ligand molecules enhancing their activity

Osawa, Takashi; Kita, Ryosuke; Kasahara, Yuuya et al.

Bioorganic and Medicinal Chemistry, 2024, 110, 117814

Number of Access:764（2025-08-16 03:18 Counts）

Identifier to cite or link to this item: https://hdl.handle.net/11094/98157

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Title	In vitro screening of chemically synthesized dipeptide-antisense oligonucleotide conjugates to identify ligand molecules enhancing their activity
Creator	NRID 1000000783226 1000000783226 researchmap permalink 66x0qtd 66x0qtd Scopus Author ID 54788169500 54788169500 CreatorName Osawa, Takashi
	CreatorName Kita, Ryosuke
	NRID 1000010740673 1000010740673 researchmap permalink YKasa YKasa CreatorName Kasahara, Yuuya
	CreatorName Yamaguma, Harumi
	NRID 1000090467598 1000090467598 researchmap permalink rican rican CreatorName Nakayama, Taisuke
	NRID 1000000324509 1000000324509 ORCID 0000-0002-2478-3818 0000-0002-2478-3818 researchmap permalink read0067290 read0067290 CreatorName Kamada, Haruhiko
	NRID 1000080243252 1000080243252 ORCID 0000-0002-6842-6812 0000-0002-6842-6812 researchmap permalink read0014368 read0014368 Scopus Author ID 7003800550 7003800550 CreatorName Obika, Satoshi
Subject	Antisense oligonucleotide (ASO)
	Conjugate
	Dipeptide
	Ugi reaction
Description	Osawa T., Kita R., Kasahara Y., et al. In vitro screening of chemically synthesized dipeptide-antisense oligonucleotide conjugates to identify ligand molecules enhancing their activity. Bioorganic and Medicinal Chemistry 110, 117814 (2024); https://doi.org/10.1016/j.bmc.2024.117814.
Abstract	Oligonucleotide therapeutics, particularly antisense oligonucleotides (ASOs), have emerged as promising candidates in drug discovery. However, their effective delivery to the target tissues and cells remains a challenge, necessitating the development of suitable drug delivery technologies for ASOs to enable their practical application. In this study, we synthesized a library of chemically modified dipeptide-ASO conjugates using a recent synthetic method based on the Ugi reaction. We then conducted in vitro screening of this library using luciferase-expressing cell lines to identify ligands capable of enhancing ASO activity. Our findings suggest that N-(4-nitrophenoxycarbonyl)glycine may interact with the thiophosphate moiety of the phosphorothioate-modification in ASO. Through our screening efforts, we identified two ligands that modestly reduced luciferase luminescence in a cell type-selective manner. Furthermore, quantification of luciferase mRNA levels revealed that one of these promising dipeptide-ASO conjugates markedly suppressed luciferase RNA levels through its antisense effect in prostate-derived DU-145 cells compared to the ASOs without ligand modification.
Publisher	Elsevier Ltd
Source Title	Bioorganic and Medicinal Chemistry
Volume (Issue)	110
Page	117814
Date of Issued	2024-08-01
Language	English
Handle URL	https://hdl.handle.net/11094/98157
PISSN	09680896
eISSN	14643391
Relation.isIdenticalTo	DOI (Publisher Version) https://doi.org/10.1016/j.bmc.2024.117814
Access Rights	open access
CopyRight	This article is licensed under a Creative Commons Attribution 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
DCTERMS.bibliographicCitation	Bioorganic and Medicinal Chemistry. 2024, 110, p. 117814
DC.title	In vitro screening of chemically synthesized dipeptide-antisense oligonucleotide conjugates to identify ligand molecules enhancing their activity
DC.creator	Osawa, Takashi
	Kita, Ryosuke
	Kasahara, Yuuya
	Yamaguma, Harumi
	Nakayama, Taisuke
	Kamada, Haruhiko
	Obika, Satoshi
DC.publisher	Elsevier Ltd
DC.language' scheme='DCTERMS.RFC1766	English
DCTERMS.issued' scheme='DCTERMS.W3CDTF	2024-08-01
DC.identifier	https://doi.org/10.1016/j.bmc.2024.117814
DC.subject	Antisense oligonucleotide (ASO)
	Conjugate
	Dipeptide
	Ugi reaction
DC.description	Osawa T., Kita R., Kasahara Y., et al. In vitro screening of chemically synthesized dipeptide-antisense oligonucleotide conjugates to identify ligand molecules enhancing their activity. Bioorganic and Medicinal Chemistry 110, 117814 (2024); https://doi.org/10.1016/j.bmc.2024.117814.
DCTERMS.abstract	Oligonucleotide therapeutics, particularly antisense oligonucleotides (ASOs), have emerged as promising candidates in drug discovery. However, their effective delivery to the target tissues and cells remains a challenge, necessitating the development of suitable drug delivery technologies for ASOs to enable their practical application. In this study, we synthesized a library of chemically modified dipeptide-ASO conjugates using a recent synthetic method based on the Ugi reaction. We then conducted in vitro screening of this library using luciferase-expressing cell lines to identify ligands capable of enhancing ASO activity. Our findings suggest that N-(4-nitrophenoxycarbonyl)glycine may interact with the thiophosphate moiety of the phosphorothioate-modification in ASO. Through our screening efforts, we identified two ligands that modestly reduced luciferase luminescence in a cell type-selective manner. Furthermore, quantification of luciferase mRNA levels revealed that one of these promising dipeptide-ASO conjugates markedly suppressed luciferase RNA levels through its antisense effect in prostate-derived DU-145 cells compared to the ASOs without ligand modification.
DC.rights	This article is licensed under a Creative Commons Attribution 4.0 International License.
DC.format	98157
citation_title	In vitro screening of chemically synthesized dipeptide-antisense oligonucleotide conjugates to identify ligand molecules enhancing their activity
citation_author	Osawa, Takashi
	Kita, Ryosuke
	Kasahara, Yuuya
	Yamaguma, Harumi
	Nakayama, Taisuke
	Kamada, Haruhiko
	Obika, Satoshi
citation_publisher	Elsevier Ltd
citation_language	English
citation_date	2024-08-01
citation_journal_title	Bioorganic and Medicinal Chemistry
citation_volume	110
citation_firstpage	117814
citation_doi	https://doi.org/10.1016/j.bmc.2024.117814
citation_public_url	https://hdl.handle.net/11094/98157

In vitro screening of chemically synthesized dipeptide-antisense oligonucleotide conjugates to identify ligand molecules enhancing their activity

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