Oligonucleotide therapeutics and their chemical modification strategies for clinical applications

Kim, Hyunsook; Kim, Sujeong; Lee, Dayoung; Lee, Dahye; Yoon, Jiyeon; Lee, Hyukjin

doi:10.1007/s40005-024-00669-8

J. Pharm. Investig.

2024

DOI: 10.1007/s40005-024-00669-8

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Oligonucleotide therapeutics and their chemical modification strategies for clinical applications

Hyunsook Kim,

Sujeong Kim,

Dayoung Lee

et al.

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2024

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Cited by 3 publications

References 163 publications

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Oligonucleotides: evolution and innovation

Mohammed,

AlShaer,

Al Musaimi

2024

Med Chem Res

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Oligonucleotides, comprising single or double strands of RNA or DNA, are vital chemical compounds used in various laboratory and clinical applications. They represent a significant class of therapeutics with a rapidly expanding range of uses. Between 1998 and 2023, 19 oligonucleotides have received approval from the U.S. Food and Drug Administration (FDA). Their synthesis methods have undergone significant evolution over time. This review examines several oligonucleotide synthesis techniques, including phosphodiester, phosphotriester, and phosphoramidite approaches. It begins with a discussion of an early synthesis method involving a phosphoryl chloride intermediate, which proved unstable and prone to hydrolysis. The review then transitions to the solid-phase synthesis method, which uses polymer resins as a solid support, emphasizing its advantages over both phosphotriester and phosphoramidite techniques. This is followed by an exploration of recent advancements in oligonucleotide enzymatic synthesis, concluding with a discussion on modifications to bases, sugars, and backbones designed to improve their properties and therapeutic potential.

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Oligonucleotides: evolution and innovation

Mohammed,

AlShaer,

Al Musaimi

2024

Med Chem Res

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Novel synthesis and evaluation of oligonucleotides containing (S)-5′-C-aminopropyl-modified thymidine analogs for RNase H-dependent antisense therapy

Hibino,

Zhou,

Saito

et al. 2024

Results in Chemistry

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modXNA: A Modular Approach to Parametrization of Modified Nucleic Acids for Use with Amber Force Fields

Love,

Galindo-Murillo,

Roe

et al. 2024

J. Chem. Theory Comput.

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Modified nucleic acids have surged as a popular therapeutic route, emphasizing the importance of nucleic acid research in drug discovery and development. Beyond well-known RNA vaccines, antisense oligonucleotides and aptamers can incorporate various modified nucleic acids to target specific biomolecules for various therapeutic activities. Molecular dynamics simulations can accelerate the design and development of these systems with noncanonical nucleic acids by observing intricate dynamic properties and relative stability on the all-atom level. However, modeling these modified systems is challenging due to the time and resources required to parametrize components outside default force field parameters. Here, we present modXNA, a tool to derive and build modified nucleotides for use with Amber force fields. Several nucleic acid systems varying in size and number of modification sites were used to evaluate the accuracy of modXNA parameters, and results indicate the dynamics and structure are preserved throughout the simulations. We detail the protocol for quantum mechanics charge derivation and describe a workflow for implementing modXNA in Amber molecular dynamics simulations, which includes updates and added features to CPPTRAJ.

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Oligonucleotide therapeutics and their chemical modification strategies for clinical applications

Cited by 3 publications

References 163 publications

Oligonucleotides: evolution and innovation

Oligonucleotides: evolution and innovation

Novel synthesis and evaluation of oligonucleotides containing (S)-5′-C-aminopropyl-modified thymidine analogs for RNase H-dependent antisense therapy

modXNA: A Modular Approach to Parametrization of Modified Nucleic Acids for Use with Amber Force Fields

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