Application of nucleoside pharmaceutical intermediates
On July 25, 2022, the State Food and Drug Administration approved the application for registration of new indications for the treatment of coronavirus pneumonia with Azovudine under emergency conditions for the treatment of adult patients with common new coronavirus pneumonia (COVID-19). Azovudine has therefore become the first domestic new small molecule oral drug approved for marketing in China.
Azovudine is a unique nucleoside small molecule drug design, and its structure is very similar to the nucleotide substrate required in the process of virus replication[1].
Introduciton
Nucleosides are N-glycosides formed by condensation of purine or pyrimidine bases with ribose or deoxyribose[2]. Most of the modified nucleoside analogues have good antiviral, anti-tumor and other biological activities, and play a vital role in the treatment of viruses, HIV, tumors, herpes and other major diseases[3]. At present, antiviral nucleoside drugs account for more than half of clinical drugs. After entering the cell, they are usually gradually phosphorylated into nucleoside triphosphate analogues to play an antiviral role (Fig. 1) [4].
Nucleotides are the basic units of nucleic acids composed of sugars, nitrogenous bases and one or more phosphate groups[5]. Nucleotides and their analogues are very important biochemical reagents and raw materials in research fields such as genetic engineering, medicine, and agricultural products[6].
Fig. 1 Action mechanism of nucleoside antiviral drugs[4]
Applicaiton
Ⅰ. Antineoplastic application
In recent years, with the continuous in-depth study of nucleoside transporters, enzymes in nucleoside metabolism and the anticancer mechanism of nucleosides, nucleoside (acid) drugs have been widely used in clinical treatment of various viral diseases and tumors. The anticancer mechanism of active metabolite mainly involves the incorporation of tumor cell DNA or RNA chain to stop its extension, inhibit the synthesis of DNA or RNA, or induce cancer cell apoptosis[7]; It can also indirectly inhibit DNA synthesis by inhibiting nucleotide reductase to down regulate dNTP level; In addition, it can also inhibit the activities of DNA and RNA polymerase, DNA primer enzyme, DNA helicase and RNA reductase.
Ⅱ.Antivirus application
1.COVID-19 treatment
The COVID-19 has a simple structure, including the viral envelope structure and the genetic material RNA in the envelope. Azovudine, the first domestic anti new coronavirus oral drug, blocks the replication of new coronavirus in human body by inhibiting the key enzyme of virus replication. Generally speaking, it is to "cheat" the virus by making a "low-quality" nucleotide, so that it can use this "low-quality material" when replicating itself, to achieve the goal of blocking replication or make the virus itself a "rotten project". With its compact structure and chemical composition, it can easily penetrate the cell membrane to inhibit virus replication (Fig. 2)[8,9].
Fig. 2 Mechanism of Azovudine in the Treatment of New Coronavirus
2. Hepatopathy treatment
Viral hepatitis is the most common hepatitis disease in the world[10,11], among which hepatitis B is the most important viral hepatitis. According to the Guidelines for the Prevention and Treatment of Chronic Hepatitis B (2019 Edition) issued by the Chinese Medical Association, antiviral drugs for hepatitis B are mainly divided into two categories: nucleoside and interferon. Among them, nucleoside antiviral drugs are recommended as the first choice for the treatment of chronic hepatitis B.
3. AIDS treatment
HIV is a retrovirus, whose treatment mainly uses antiretroviral drugs, and requires lifelong medication. Antiretroviral drugs are divided into six categories, namely nucleoside reverse transcriptase inhibitors, non nucleoside reverse transcriptase inhibitors, protease inhibitors, integrase inhibitors, fusion inhibitors and CCR5 inhibitors. Nucleoside reverse transcriptase inhibitors, non nucleoside reverse transcriptase inhibitors and protease inhibitors are the main drugs at present[12].
4. Herpes treatment
At present, anti herpesvirus drugs are mainly nucleoside drugs. These compounds are phosphorylated into triphosphate compounds through viral thymidine kinase to compete with deoxyuridine triphosphate, thereby inhibiting the synthesis of viral DNA. Nucleoside antiherpesvirus drugs include acyclovir, valaciclovir, famciclovir, ganciclovir and valeganciclovir[13].
Ⅲ.Other applications
Nucleoside drugs are mainly used in the field of antineoplastic and antivirus treatment. In addition, they also have important applications in the field of treatment of nervous system diseases. The representative drugs are cytidine series. Cytidine is a kind of endogenous nucleoside naturally produced in vivo and an intermediate product of the main pathway of phospholipid biosynthesis of cell membrane. The repair of nerve cell membrane requires a large amount of citicoline, and supplement of exogenous citicoline can promote the synthesis of phospholipids in nerve cell membrane. At present, citicoline sodium is the largest nerve activator in clinical use among hospital brain protective drugs in China, and has been included in the Chinese Pharmacopoeia.
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Reference：
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