Hexitol Nucleic Acid (HNA): From Chemical Design to Functional Genetic Polymer

Chemically modified nucleic acids have become crucial tools across a diverse range of sciences. They are extensively used not only as diagnostic and therapeutic agents to modulate gene expression or impede protein function by binding a specific RNA sequence or target protein but also in synthetic biology, particularly in the context of artificial genetic polymers (XNAs). In order to enable maximum scope for all in vivo applications, it is pivotal for oligonucleotides to form thermodynamically and metabolically stable helical structures via self- or cross-pairing with natural complements. In this respect, the discovery of hexitol nucleic acid (HNA), consisting of a phosphorylated 1,5-anhydrohexitol backbone and natural nucleobases, has driven many significant advances in these areas, and especially in the last decade, numerous novel approaches have emerged that overstepped the molecular and functional boundaries of extant biopolymers. Herein, we discuss the more recent progress that has been made to synthesize HNA as well as related six-membered nucleic acids [altritol nucleic acid (ANA), FHNA (3′-fluorohexitol nucleic acid), cyclohexene nucleic acid (CeNA), and 2′-fluoro cyclohexene nucleic acid (F-CeNA)] involving optimized and novel chemical and enzymatic methods, and we highlight a number of selected examples of in vitro and in vivo biological and biomedical applications in which such synthetic polymers played a crucial role. Despite most of these efforts are still at their early stages, the influence of these modified nucleic acids in medicine and biotechnology is destined to increase, especially judging from their impressive and unique abilities.