Nucleotide drugs can be divided into two major categories. One is a nucleic acid substance having a natural structure, which is a raw material for biosynthesis, or a coenzyme for protein, fat, sugar biosynthesis, degradation, and energy metabolism. The lack of such substances can cause metabolic disorders. Providing this kind of medicine will help improve the body’s material metabolism and energy balance, accelerate the repair of damaged tissues, and promote the recovery of normal physiological functions of hypoxic tissues. The other is analogs or polymers of natural structural bases, nucleosides and nucleotide structure. The nucleotide drug is an important means for humans to treat viruses, tumors and AIDS, as well as clinical drugs of interferon and immunosuppression.
Nucleoside reverse transcriptase inhibitors (NRTIs) are the first antiretroviral drugs. NRTIs are first phosphorylated into a nucleotide analogue of active diphosphate or triphosphate in the cell, competing with the natural substrate of the virus to inhibit HIV reverse transcriptase. Zidovudine and Didanosine are the first antiretroviral drugs that prolong the survival of patients but do not prevent the death of CCD4 cells. The most commonly used NRTIs currently are Tenofovir and Abacavir. Adenosine monophosphate (nucleotide) analogue, Tenofovir is phosphorylated into the active metabolite Tenofovir Diphosphate (TFV-DP), which competitively inhibits HIV reverse transcriptase activity and causes DNA strand termination.
Nucleoside analogues are an important class of anticancer chemotherapeutic agents, including derivatives of various purine and pyrimidine nucleosides. The family of nucleoside analogs is primarily a class of antimetabolites that interfere with DNA synthesis of tumor cells and synthesis of purines, pyrimidines, purine nucleotides, and pyrimidine nucleotides. In recent years, with the continuous research of nucleoside transferons, enzymes in the metabolism of nucleosides and the anticancer mechanism of nucleosides, nucleoside anticancer chemotherapeutic agents have made great progress. The structure of the nucleoside analog is modified by the principle of prodrugs. For example, Fludarabine and Cladribine are highly effective in the treatment of chronic lymphocytic leukemia. Cytarabine is a chemotherapy medication used to treat acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), chronic myelogenous leukemia (CML), etc.
Nucleotides used in drug discovery include two types: reagents used to modify nucleotides and nucleotides with particular properties. Some kinds of nucleotides are used in medical field for their specific properties such as antiviral and cytostatic activities. The nucleoside analog structure is easy to be engineered, and many new nucleoside analogs with drug activity are constantly emerging. The multiple molecular targets in the body allow nucleoside analogs to produce drug activity through multiple pathways. In the middle of the year, the transfer mechanism, pharmacokinetics, metabolic and apoptosis mechanisms of nucleoside analogs have made great progress, which makes nucleoside analogues have broad development prospects. At present, the development direction of nucleoside drugs is to synthesize the prodrugs of existing drugs, improve their bioavailability and reduce toxic and side effects; secondly, carry out structural transformation and synthesize novel nucleoside analogues. Screening out new drugs with high efficiency and low toxicity, and establishing a model through structure-activity relationship to guide the synthesis of drugs is the direction of new drug development.
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