The RAvIN Platform: A Noncarbohydrate Platform for Oligonucleotide Synthesis

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Drug Discovery

Background:

• Oligonucleotide therapeutics (ONTs) represent a significant advancement in medicine.
• The large-scale synthesis of nucleoside analogues (NAs) for ONTs is a major bottleneck.
• Current methods relying on carbohydrates are often complex and inefficient, limiting exploration of NA chemical space.

Purpose of the Study:

• To develop a streamlined, scalable, and flexible platform for synthesizing diverse NAs.
• To overcome limitations of carbohydrate-based starting materials in NA synthesis.
• To enable broader exploration of chemical modifications for improved oligonucleotide therapeutic properties.

Main Methods:

• Utilized achiral starting materials for NA synthesis.
• Employed a dual organocatalyst, one-pot process.
• Developed RAvIN (rapid access to value-added innovative nucleosides) ketones (RKs) as key intermediates.
• Demonstrated synthesis of an 18-mer all-MOE modified oligonucleotide.

Main Results:

• Achieved scalable synthesis of RKs in 2-4 steps.
• Produced NAs with carbohydrate-like enantiomeric purity.
• RKs readily incorporate natural and analogue nucleobases.
• Successfully synthesized Nusinersen, an all-MOE modified 18-mer ONT, via a non-carbohydrate route.

Conclusions:

• The presented platform significantly improves access to novel nucleoside analogues.
• This method facilitates the development of next-generation oligonucleotide therapeutics with enhanced pharmacokinetic properties.
• The non-carbohydrate approach broadens the chemical space for oligonucleotide drug design and discovery.