On this occasion of celebrating Professor Derek Horton’s achievements in carbohydrate chemistry in the form of the 2021 Derek Horton’s Award in Industrial Carbohydrate Chemistry, I thought about how sweet it has been to work in the “Sugar Alley” of Carbohydrates (Priebe, W. Glycoconj. J. 2015, 32, 557–558) over the past three decades. I have been involved in chemistry of pentofuranoses, which give rise to chemically modified nucleosides, nucleotides, and oligonucleotides, and hexopyranoses such as N-acetylgalactosamine (GalNAc), which has enabled the delivery of oligonucleotides into liver hepatocytes. The first RNAi therapeutic approved for use in humans is an LNP formulation of a partially chemically modified siRNA. This drug, ONPATTRO® (patisiran), was approved in 2018 and is used to treat polyneuropathy in patients with hereditary ATTR amyloidosis. The approval of ONPATTRO® paved the way for a whole new class of RNA-based medicines and validated LNP-mediated delivery of nucleic acids for human therapeutics including mRNA-based vaccines and vectors used for gene editing. The Ashwell-Morell, or asialoglycoprotein receptor, was discovered in 1965 and fully characterized in 1974. However, the human therapeutic utility of this receptor and its GalNAc ligand for delivery of nucleic acids was fully realized only in 2019. By conjugation of a chemically modified oligonucleotide with triantennary GalNAc, our research group enabled hepatocyte-targeting of siRNAs. This delivery platform has revolutionized the nucleic acid-based therapeutics field. Three GalNAc-conjugated RNAi therapeutics have been approved so far: GIVLAARI® (givosiran, 2019) for treating acute hepatic porphyria, OXLUMO® (lumasiran, 2020) for the treatment of primary hyperoxaluria type 1, and Leqvio® (inclisiran, 2020) for treatment of hypercholesterolemia. We will describe our walk in the Sugar Alley of hexoses, pyranoses, and bicyclic sugars over the past three decades, which has been the molecular basis of the success of RNA therapeutics.

How sweet it is to work in the “Sugar Alley” of RNA therapeutics

ACS Fall 2021

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