Молекулярная биология, 2021, T. 55, № 6, стр. 897-926

Противовирусные и противомикробные производные нуклеозидов: структурные особенности и механизмы действия

А. А. Зенченко a, М. С. Дреничев a*, И. А. Ильичева a, С. Н. Михайлов a

a Институт молекулярной биологии им. В.А. Энгельгардта Российской академии наук
119991 Москва, Россия

* E-mail: mdrenichev@mail.ru

Поступила в редакцию 20.01.2021
После доработки 03.04.2021
Принята к публикации 09.04.2021

Аннотация

Появление новых вирусов и резистентных штаммов патогенных микроорганизмов стало мощным стимулом для поиска новых лекарственных средств. Нуклеозиды – один из перспективных классов природных соединений, на основе которых уже создано более ста лекарственных препаратов, включая противовирусные, антибактериальные и противоопухолевые средства. В обзоре рассмотрены структурно-функциональные особенности и механизмы действия известных аналогов нуклеозидов, обладающих противовирусной, антибактериальной или антипротозойной активностью. Особое внимание уделено механизмам, которые определяют противовирусный эффект аналогов нуклеозидов, содержащих гидрофобные фрагменты. В зависимости от структуры и положения гидрофобного заместителя такие нуклеозиды могут либо блокировать процесс проникновения вирусов в клетки, либо ингибировать стадию репликации их геномов. Проведено сравнение механизмов ингибирования вирусных ферментов соединениями нуклеозидной и ненуклеозидной природы. Рассмотрены стадии создания антипаразитарных препаратов, которые базируются на данных об особенностях метаболических превращений нуклеозидов в организме человека и организме паразита. Описан новый подход к созданию лекарственных препаратов, основанный на использовании пролекарственных форм модифицированных нуклеозидов, которые в результате метаболических процессов конвертируются в эффективный лекарственный препарат непосредственно в целевом органе или ткани. Такая стратегия позволяет уменьшить общую токсичность препарата для человека и увеличить эффективность его действия на клетки, пораженные вирусом.

Ключевые слова: биосинтез нуклеозидов, антибактериальная активность, противовирусная активность, антипротозойная активность, РНК-вирусы, SARS-CoV-2, ферменты-мишени, гидрофобные производные нуклеозидов

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