Construction of a Tm-value prediction model and molecular dynamics study of AmNA-containing gapmer antisense oligonucleotide

Kuroda, Masataka; Kasahara, Yuuya; Hirose, Masako; Yamaguma, Harumi; Oda, Masayuki; Nagao, Chioko; Mizuguchi, Kenji

doi:https://doi.org/10.1016/j.omtn.2024.102272

Construction of a Tm-value prediction model and molecular dynamics study of AmNA-containing gapmer antisense oligonucleotide

Kuroda, Masataka; Kasahara, Yuuya; Hirose, Masako et al.

Molecular Therapy Nucleic Acids, 2024, 35(3), 102272

Number of Access:158（2025-06-08 12:33 Counts）

Identifier to cite or link to this item: https://hdl.handle.net/11094/97644

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Title	Construction of a Tm-value prediction model and molecular dynamics study of AmNA-containing gapmer antisense oligonucleotide
Creator	CreatorName Kuroda, Masataka
	NRID 1000010740673 1000010740673 researchmap permalink YKasa YKasa CreatorName Kasahara, Yuuya
	CreatorName Hirose, Masako
	CreatorName Yamaguma, Harumi
	NRID 1000020318231 1000020318231 CreatorName Oda, Masayuki
	NRID 1000010402463 1000010402463 researchmap permalink c_nagao c_nagao Scopus Author ID 14520710200 14520710200 ORCID 0000-0002-7721-0642 0000-0002-7721-0642 CreatorName Nagao, Chioko
	NRID 1000050450896 1000050450896 ORCID 0000-0003-3021-7078 0000-0003-3021-7078 researchmap permalink kenji_mizuguchi kenji_mizuguchi Scopus Author ID 57191477452 57191477452 CreatorName Mizuguchi, Kenji
Subject	amido-bridged nucleic acid, AmNA
	machine learning
	molecular dynamics, MD
	MT: Bioinformatics
	RNase H-dependent antisense oligonucleotide, gapmer ASO
	Tm value prediction
Description	Kuroda M., Kasahara Y., Hirose M., et al. Construction of a Tm-value prediction model and molecular dynamics study of AmNA-containing gapmer antisense oligonucleotide. Molecular Therapy Nucleic Acids 35, 102272 (2024); https://doi.org/10.1016/j.omtn.2024.102272.
Abstract	RNase H-dependent antisense oligonucleotides (gapmer ASOs) represent a class of nucleic acid therapeutics that bind to target RNA to facilitate RNase H-mediated RNA cleavage, thereby regulating the expression of disease-associated proteins. Integrating artificial nucleic acids into gapmer ASOs enhances their therapeutic efficacy. Among these, amido-bridged nucleic acid (AmNA) stands out for its potential to confer high affinity and stability to ASOs. However, a significant challenge in the design of gapmer ASOs incorporating artificial nucleic acids, such as AmNA, is the accurate prediction of their melting temperature (Tm) values. The Tm is a critical parameter for designing effective gapmer ASOs to ensure proper functioning. However, predicting accurate Tm values for oligonucleotides containing artificial nucleic acids remains problematic. We developed a Tm prediction model using a library of AmNA-containing ASOs to address this issue. We measured the Tm values of 157 oligonucleotides through differential scanning calorimetry, enabling the construction of an accurate prediction model. Additionally, molecular dynamics simulations were used to elucidate the molecular mechanisms by which AmNA modifications elevate Tm, thereby informing the design strategies of gapmer ASOs.
Publisher	Cell Press
Source Title	Molecular Therapy Nucleic Acids
Volume (Issue)	35(3)
Page	102272
Date of Issued	2024-09-10
Language	English
Handle URL	https://hdl.handle.net/11094/97644
eISSN	21622531
Relation.isIdenticalTo	DOI (Publisher Version) https://doi.org/10.1016/j.omtn.2024.102272
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	Molecular Therapy Nucleic Acids. 2024, 35(3), p. 102272
DC.title	Construction of a Tm-value prediction model and molecular dynamics study of AmNA-containing gapmer antisense oligonucleotide
DC.creator	Kuroda, Masataka
	Kasahara, Yuuya
	Hirose, Masako
	Yamaguma, Harumi
	Oda, Masayuki
	Nagao, Chioko
	Mizuguchi, Kenji
DC.publisher	Cell Press
DC.language' scheme='DCTERMS.RFC1766	English
DCTERMS.issued' scheme='DCTERMS.W3CDTF	2024-09-10
DC.identifier	https://doi.org/10.1016/j.omtn.2024.102272
DC.subject	amido-bridged nucleic acid, AmNA
	machine learning
	molecular dynamics, MD
	MT: Bioinformatics
	RNase H-dependent antisense oligonucleotide, gapmer ASO
	Tm value prediction
DC.description	Kuroda M., Kasahara Y., Hirose M., et al. Construction of a Tm-value prediction model and molecular dynamics study of AmNA-containing gapmer antisense oligonucleotide. Molecular Therapy Nucleic Acids 35, 102272 (2024); https://doi.org/10.1016/j.omtn.2024.102272.
DCTERMS.abstract	RNase H-dependent antisense oligonucleotides (gapmer ASOs) represent a class of nucleic acid therapeutics that bind to target RNA to facilitate RNase H-mediated RNA cleavage, thereby regulating the expression of disease-associated proteins. Integrating artificial nucleic acids into gapmer ASOs enhances their therapeutic efficacy. Among these, amido-bridged nucleic acid (AmNA) stands out for its potential to confer high affinity and stability to ASOs. However, a significant challenge in the design of gapmer ASOs incorporating artificial nucleic acids, such as AmNA, is the accurate prediction of their melting temperature (Tm) values. The Tm is a critical parameter for designing effective gapmer ASOs to ensure proper functioning. However, predicting accurate Tm values for oligonucleotides containing artificial nucleic acids remains problematic. We developed a Tm prediction model using a library of AmNA-containing ASOs to address this issue. We measured the Tm values of 157 oligonucleotides through differential scanning calorimetry, enabling the construction of an accurate prediction model. Additionally, molecular dynamics simulations were used to elucidate the molecular mechanisms by which AmNA modifications elevate Tm, thereby informing the design strategies of gapmer ASOs.
DC.rights	This article is licensed under a Creative Commons Attribution 4.0 International License.
DC.format	97644
citation_title	Construction of a Tm-value prediction model and molecular dynamics study of AmNA-containing gapmer antisense oligonucleotide
citation_author	Kuroda, Masataka
	Kasahara, Yuuya
	Hirose, Masako
	Yamaguma, Harumi
	Oda, Masayuki
	Nagao, Chioko
	Mizuguchi, Kenji
citation_publisher	Cell Press
citation_language	English
citation_date	2024-09-10
citation_journal_title	Molecular Therapy Nucleic Acids
citation_volume	35
citation_issue	3
citation_firstpage	102272
citation_doi	https://doi.org/10.1016/j.omtn.2024.102272
citation_public_url	https://hdl.handle.net/11094/97644

Construction of a Tm-value prediction model and molecular dynamics study of AmNA-containing gapmer antisense oligonucleotide

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