Zenchenko A A, Drenichev M S, Ilyicheva I A, Mikhailov S N
Engelhardt Institute of Molecular Biology, Moscow, 119991 Russia.
Mol Biol (Mosk). 2021 Nov-Dec;55(6):897-926. doi: 10.31857/S0026898421050104.
The emergence of new viruses and resistant strains of pathogenic microorganisms has become a powerful stimulus in the search for new drugs. Nucleosides are a promising class of natural compound, and more than a hundred drugs have already been created based on them, including antiviral, antibacterial and antitumor agents. The review considers the structural and functional features and mechanisms of action of known nucleoside analogs with antiviral, antibacterial, or antiprotozoal activity. Particular attention is paid to the mechanisms that determine the antiviral effect of nucleoside analogs containing hydrophobic fragments. Depending on the structure and position of the hydrophobic substituent, such nucleosides can either block the process of penetration of viruses into cells or inhibit the stage of genome replication. The mechanisms of inhibition of viral enzymes by compounds of nucleoside and non-nucleoside nature have been compared. The stages of creation of antiparasitic drugs, which are based on the peculiarities of metabolic transformations of nucleosides in humans body and parasites, have been considered. A new approach to the creation of drugs is described, based on the use of prodrugs of modified nucleosides, which, as a result of metabolic processes, are converted into an effective drug directly in the target organ or tissue. This strategy makes it possible to reduce the general toxicity of the drug to humans and to increase the effectiveness of its action on cells infected by the virus.
新病毒和致病微生物耐药菌株的出现，已成为研发新药的强大推动力。核苷是一类很有前景的天然化合物，基于核苷已研发出一百多种药物，包括抗病毒、抗菌和抗肿瘤药物。本综述探讨了具有抗病毒、抗菌或抗原虫活性的已知核苷类似物的结构和功能特点及其作用机制。特别关注了决定含疏水片段核苷类似物抗病毒作用的机制。根据疏水取代基的结构和位置，此类核苷可阻断病毒进入细胞的过程，或抑制基因组复制阶段。对核苷类和非核苷类化合物抑制病毒酶的机制进行了比较。考虑了基于核苷在人体和寄生虫体内代谢转化特点研发抗寄生虫药物的各个阶段。描述了一种基于使用修饰核苷前药研发药物的新方法，这些前药在代谢过程中直接在靶器官或组织中转化为有效药物。该策略能够降低药物对人体的总体毒性，并提高其对病毒感染细胞的作用效果。
