Extended Nucleic Acid (exNA): A Novel, Biologically Compatible Backbone that Significantly Enhances Oligonucleotide Efficacy in vivo. Release Time：2023-11-03

Metabolic stabilization of therapeutic oligonucleotides requires both sugar and backbone modifications, where phosphorothioate (PS) is the only backbone chemistry used in the clinic. Recently, Ken Yamada etc. described the discovery, synthesis, and characterization of a novel biologically compatible backbone, extended nucleic acid (exNA) (Fig. 1)1. Upon exNA precursor scale up, exNA incorporation is fully compatible with common nucleic acid synthetic protocols. The novel backbone is orthogonal to PS and shows profound stabilization against 3'- and 5'-exonucleases. Using small interfering RNAs (siRNAs) as an example, they show exNA is tolerated at most nucleotide positions and profoundly improves in vivo efficacy. A combined exNA-PS backbone enhances siRNA resistance to serum 3'-exonuclease by ~32-fold over PS backbone and >1000-fold over the natural phosphodiester backbone, thereby enhancing tissue exposure (~6-fold), tissues accumulation (4- to 20-fold), and potency both systemically and in the brain. The improved potency and durability imparted by exNA opens more tissues and indications to oligonucleotide-driven therapeutic interventions.

Fig 1. Chemical structure of extended Nucleic Acid (exNA) with methyl inserts (permanent structural modulation) and natural epigenetic modification with methyl adduct (removable by endogenous demethylase).

HitGen has an experienced team with almost 10 years of hands-on experience on a series of unconventional natural nucleoside compound modification methods, including stereo- and enantio-selective reactions, and is able to obtain the modified nucleoside compounds in a time and cost-effective manner.

Reference

1.Yamada, Ken, et al. "Extended Nucleic Acid (exNA): A Novel, Biologically Compatible Backbone that Significantly Enhances Oligonucleotide Efficacy in vivo." bioRxiv (2023).