Crystallographic studies of chemically modified nucleic acids: a backward glance

Area of Science:

• Biochemistry
• Molecular Biology
• Structural Biology

Background:

• Chemically modified nucleic acids (CNAs) are crucial for therapeutic applications like antisense oligonucleotides and small interfering RNAs (siRNAs).
• CNAs are also vital tools in diagnostics, genomics, nanotechnology, and fundamental research into nucleic acid structure and function.
• Understanding the structural and physicochemical properties of CNAs is essential for their effective development and application.

Purpose of the Study:

• To review two decades of laboratory research on the crystal-structure analyses of CNAs and artificial pairing systems.
• To highlight key insights into conformational changes, pairing strength modulation, and RNA affinity influenced by modifications.
• To demonstrate how crystallographic studies of CNAs provide guiding principles for designing novel analogs with specific properties.

Main Methods:

• Focus on crystal-structure analyses of chemically modified nucleic acids (CNAs).
• Examination of artificial pairing systems involving CNAs.
• Review of research data spanning two decades, emphasizing structural insights.

Main Results:

• Crystal structures reveal how modifications induce conformational distortions in nucleic acids.
• Stereoelectronic effects and hydration significantly modulate pairing strength and RNA affinity.
• Structural data provide guiding principles for designing CNAs with enhanced pairing specificity, nuclease resistance, and cellular uptake.
• Crystallography of CNAs has elucidated fundamental aspects of DNA and RNA structure and function beyond natural nucleic acids.

Conclusions:

• Crystal-structure analyses of CNAs and artificial systems offer profound insights into nucleic acid behavior.
• These studies provide a foundation for designing next-generation CNAs with tailored therapeutic and diagnostic properties.
• Investigating CNAs through crystallography enhances our fundamental understanding of DNA and RNA structure and function.