KAZUYA OKANO
Deputy General Manager, Juzen Chemical Corporation, Tokyo, Japan

Abstract

The number of approved nucleic acid drugs has increased recently owing to progress in the medicinal chemistry of oligonucleotide therapeutics; the expansion of drug sales is providing new API demand opportunities for CDMO. Nucleic acid drugs utilize various chemically modified nucleotides, to avoid decomposition by nucleases in the human body and improve the RNA binding affinity. The production of modified nucleotides requires organic synthesis technology and sufficient production capacity at CDMO. This study focuses on the synthetic process of modified nucleotides, especially those comprising bridged nucleic acids (BNAs), and explains the progress in BNA research from a process chemistry perspective.

INTRODUCTION

Market demand for nucleic acid drugs
The use of nucleic acid drugs is rapidly growing as a new modality in the pharmaceutical industry (1). The APIs of nucleic acid drugs are synthetic oligonucleotides of 20–40 mers which are used for the treatment of various diseases. The oligonucleotides bind to mRNA in cells via Watson−Crick base-pairing and modulate the function of mRNA to produce a pharmacological effect. Vitravene, the first nucleic acid drug approved in 1998 for the treatment of cytomegalovirus (CMV) retinitis demonstrated the clinical benefit of nucleic acid drugs; however, small-molecule antiretroviral therapy provided a better option for treating CMV, and Vitravene was withdrawn from the market (2). The challenges to nucleic acid drug development continued, it took another six years until Macugen was approved in 2004, and a further nine years until the approval of Kynamro in 2013. However, since the approval of Exondys 51 and Spinraza in 2016, new nucleic acid drugs have been approved annually since 2016, with 16 being approved as of August 2022 (Table 1).

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