Nucleotide in Nucleic Acid Medicine

Nucleic acid and nucleic acid drugs

Nucleic acid is the carrier of life genetic information. It has both the storage function of life information and the active function of biocatalysis. Nucleic acids also have huge commercial drug potential in medicine and therapy. Compared with antibody drugs, nucleic acid drugs do not require complex protein modification and CMC development in the development stage of nucleic acid drugs. The preparation process in the production stage is relatively simple and does not require large-scale mammalian cell fermentation and protein purification. It has the advantages of abundant candidate targets, short development cycle, long-lasting drug effect, and high clinical development success rate. Nucleic acid drugs are treated at the post-transcriptional level and can achieve breakthroughs in special protein targets that are difficult to make drugs. They are expected to overcome diseases that have not yet been treated by drugs and become the third-generation new drugs after small molecule drugs and antibody drugs.

Types of nucleic acid drugs

Nucleic acid drugs mainly include antisense nucleic acid (ASO), small interfering RNA (siRNA), microRNA (miRNA), small activating RNA (saRNA), messenger RNA (mRNA), aptamer, ribozyme, and antibody nucleic acid conjugated drugs (ARC), etc. There are currently 14 small nucleic acid drugs on the global market, including 4 siRNA drugs, 9 ASO drugs, and 1 aptamer drug. About 80% of nucleic acid drugs are on the market after 2015, and most of the indications are genetic diseases.

Figure 1. Action mechanisms of RNAi and representative nucleic acid therapeutics.

Factors restricting the development of nucleic acid drugs

Chemical synthesis and manufacturing in the development of nucleic acid drugs is one of the main factors restricting the development of nucleic acid drugs. In addition, the instability of nucleic acid drugs in the body also limits the development of nucleic acid drugs. Nucleic acid drugs are unstable in the human body, and are easily degraded by nucleases after entering the blood, and are easily cleared by the kidneys, with a short half-life. At the same time, foreign nucleic acid molecules are immunogenic and easily cause an immune response in the human body. The emergence of various new nucleotide synthesis technologies and different chemical modifications of nucleotide molecules have improved the stability and therapeutic effect of nucleic acid drugs in the body, reduced the cost of drug production, and thus made a breakthrough in the development of nucleic acid drugs.

Nucleotide and nucleic acid drugs

Nucleotides are the basic unit of nucleic acid drugs, and nucleic acid drugs are a polymer formed from different numbers of nucleotides. According to the different diseases treated by nucleic acid drugs, there are differences in the sequence of nucleotides. Chemical modification can enhance the stability of nucleic acid drugs and reduce immunogenicity. The chemical modification of nucleic acids includes modification of the ribose, phosphate backbone, bases, and ends of nucleic acid strands of nucleotides(see Fig 2). The most commonly used chemical modification of the phosphate backbone is phosphorothioate. PS is a common chemical modification in the first generation of ASO drugs, and it is still often used in nucleic acid drugs. Common ribose structural modifications include 2’-OME, 2’-OMe, and 2’-F. These modifications can further enhance resistance to nucleases and enhance their ability to bind to complementary nucleotide chains. The modification of the five-membered ring of ribose is called the third-generation chemical modification, including LNA (locked nucleic acid), PNA (peptide nucleic acid), and PMO (phosphoroamidate morpholino oligomer). The modification of nucleotide bases is being tried.

Figure 2. Structures of common chemical modifications used in nucleic acid therapeutics.

At present, most nucleic acid drugs contain modified nucleotides, and in some nucleic acid drugs, the entire nucleic acid chain is composed of modified nucleotides. Fomivirsen is a 21-nucleotide single-stranded DNA, using the first generation of PS chemical modification, which is naked DNA; Eteplirsen is the first approved PMO-modified nucleic acid drug; Mipomersen is 20 nucleotides in length , Uses the chemical modification of PS and 2’MOE; Nusinersen is also a naked oligonucleotide, which is 18 nucleotides in length, which uses the chemical modification of PS and 2’MOE; Givosiran is 21/23 nucleosides Acid length, which uses chemical modification of PS, 2’F and 2’OMe; Lumasiran is 21/23 nucleotide length, which uses chemical modification of PS, 2’F and 2’OMe, and Pegaptanib is the first This is the only Aptamer drug approved by the FDA. It has a length of 28 nucleotides and is modified by PEGylation.

Figure 3. Representative designs for the chemical modification of siRNA.


1. Weng Y, Xiao H, Zhang J, et al. RNAi therapeutic and its innovative biotechnological evolution[J]. Biotechnology advances, 2019, 37(5): 801-825.

2. Wang F, Zuroske T, Watts J K. RNA therapeutics on the rise[J]. Nat Rev Drug Discov, 2020, 19(7): 441-442.

3. Hu B, Zhong L, Weng Y, et al. Therapeutic siRNA: state of the art[J]. Signal transduction and targeted therapy, 2020, 5(1): 1-25.

4. Ambesajir A, Kaushik A, Kaushik J J, et al. RNA interference: A futuristic tool and its therapeutic applications[J]. Saudi journal of biological sciences, 2012, 19(4): 395-403.

5. Cho K J, Kim G W. RNAi Therapeutic Potentials and Prospects in CNS Disease[M]//RNA interference. IntechOpen, 2016.

6. Aagaard L, Rossi J J. RNAi therapeutics: principles, prospects and challenges[J]. Advanced drug delivery reviews, 2007, 59(2-3): 75-86.