Introducation
Nucleosides, composing of a nucleobase (A, T, C, G or U) and a pentofuranose (ribose or 2-deoxyribose), are the fundamental units of the genetic material (DNA and RNA) for all the living beings. Although nucleosides and ribonucleosides are mostly similar, but ribonucleosides contain uracil instead of thymine (fig.1).
Figure 1 Nucleoside and deoxynucleoside structures.
The importance of nucleosides
Nucleosides are important biological molecules that function as signaling molecules and as precursors to nucleotides needed for DNA and RNA synthesis. Nucleosides and their derivates also take part in various biological processes. It has been believed that the synthesis of nucleosides and their analogues would be “the key to understanding the cellular functions and mechanisms involved in a variety of diseases.” Indeed, nucleoside analogues have been extensively used as drugs for the treatment of cancers, viral/bacterial/fungal infections; as precursors in the preparation of artificial oligonucleotides for therapeutic or diagnostic use; and as tools for investigation of mechanisms of enzyme function in molecular biology .
The application of nucleosides in anticancer area
Nucleoside compounds have many uses and are mainly used in the field of medicine. In the anticancer area, nucleoside anticancer drugs are mainly purine and pyrimidine nucleoside analogs. Purine nucleoside analogs are represented by Hudarabine (F-mAMP) Cladribine (2-CaA), and they are mainly used for the treatment of chronic lymphocytic leukemia and other blood cancers.Among the pyrimidine nucleoside analogs, Cytarabine (Ara-C) is widely used in the treatment of acute myeloid leukemia, and Gemcitabine (dFdC) is used in the treatment of solid tumors of pancreatic cancer, lung cancer, breast cancer, ovarian cancer and bladder cancer. The fluoropyrimidine analogue fluorouracil (5-FU) has a good effect on colon cancer and breast cancer. Nucleoside analogs with anticancer activity are a class of anti-metabolites, which mainly antagonize nucleotide metabolism. The mechanism of cytotoxicity of these compounds has three aspects: the first one is that nucleoside analogues act as pseudo-substrates in biochemical reactions, inhibiting the related enzymes of nucleotide de novo synthesis, interfering with the aNTes library, thereby inhibiting DNA replication; the next one is that Glycoside analogues are incorporated into DNA and RNA to interrupt the extension of DNA and RNA chains; the third is to inhibit nucleic acid synthesis related enzymes, such as DNA polymerase and nucleic acid reductase, etc., thereby inhibiting the synthesis and repair of nucleic acid macromolecules.
The nucleoside antiviral drugs
In the antiviral drugs area, nucleoside compounds account for more than half of the antiviral drugs currently on the market, and they play an important role in in the treatment of viral diseases. Nucleoside drugs, as viral polymerase or reverse transcriptase inhibitors, are gradually phosphorylated into nucleoside triphosphate analogues to exert antiviral effects after entering the cell. The treatment of human immunodeficiency virus (HIV) infection has seen the introduction of no less than eight nucleos(t)ides into clinical practice where they have become the cornerstone of combination therapies. Nucleos(t)ides have become the standard of care for the treatment of hepatitis B virus (HBV) infection and are rapidly emerging as the backbone of future combination regimens for the treatment of hepatitis C virus (HCV) infection. The treatment of many other viral infections such as those caused by cytomegalovirus, herpes simplex virus, Epstein–Barr virus, and varicella zoster virus rely heavily on nucleos(t)ide-based therapies. Consequently, because of the broad utility and success of these molecules in the treatment of viral diseases, efforts continue to search for novel nucleos(t)ides that can have an impact in antiviral clinical practice. This review will focus on recent developments in the field of nucleos(t)ide antiviral drug discovery and development with emphasis on HIV, HBV, HCV, and Dengue virus. Since the 1980s, a large number of high-efficiency and low-toxic nucleoside drugs have emerged, most of which are chemically modified purine and pyrimidine nucleosides, which structure is very similar to natural nucleosides. Due to the mutation and drug resistance of the virus, and the continuous production of new viruses, the existing nucleoside drugs are far from being able to meet the therapeutic needs. Therefore, the broad-spectrum antiviral activity is improved and the selectivity between the host cell and the host cell is improved. Toxic and side effects are an important direction in the research and development of nucleoside antiviral drugs.
References:
1. Hobbs, J. B. (1993). Nucleosides, nucleotides and nucleic acids. In The Chemistry of Natural Products (pp. 259-328). Springer, Dordrecht.
2. Mikhailopulo, I. A. (2007). Biotechnology of nucleic acid constituents-State of the art and perspectives. Current Organic Chemistry, 11(4), 317-335.
3. Mikhailopulo, I. A., & Miroshnikov, A. I. (2011). Biologically important nucleosides: modern trends in biotechnology and application. Mendeleev Communications, 21(2), 57.