Abstract
Herpes simplex viruses type 1 (HSV-1) are extremely widespread throughout the world and, similar to other herpesviruses, establish lifelong persistent infection in the host. Reactivating sporadically, HSV-1 elicits recurrences in both immunocompetent and immunocompromised individuals and can cause serious diseases (blindness, encephalitis, generalized infections). The currently available antiherpetic drugs that aimed mainly at suppressing replication of viral DNA are not always effective enough, for example, due to the development of drug resistance. As we showed earlier the newly discovered compound LAS-131 exhibits the strong and highly selective inhibitory activity against HSV‑1, including strain resistant to acyclovir (selective index, SI = 63). The presence of LAS-131 at a concentration of 20 μg/ml leads to a decrease in the titer of HSV-1 (strain L2) by 4 lg in a one round of HSV-1 replication. To establish the step(s) of the virus life cycle that is sensitive to the action of LAS-131, we have applied a widely used approach, that made it possible to determine how long the addition of a compound can be postponed before it loses its antiviral activity (time-of-addition assay), and to compare this indicator with the crucial time of application of inhibitors with a well-known mechanism of action (in cell culture). It has been shown for the first time that LAS-131 retains a pronounced antiviral effect when introduced into the experimental system no later than 9 hours post-infection (p.i.). However, LAS-131 does not affect the release of HSV-1 from the cell. Together with published data on the termination of the synthesis of viral DNA 9-12 h after the adsorption in a cell culture infected with HSV with a high multiplicity (≥1 PFU/cell), our results suggest that LAS-131 interferes the life cycle of HSV-1 during synthesis of viral DNA. Further studies of the mechanism of action are necessary to establish definitely the biological target for this compound,.
Highlights
Herpes simplex viruses type 1 (HSV-1) are extremely widespread throughout the world and, similar to other herpesviruses, establish lifelong persistent infection in the host
The presence of LAS-131 at a concentration of 20 μg/ml leads to a decrease in the titer of HSV-1 by 4 lg in a one round of HSV-1 replication
To establish the step(s) of the virus life cycle that is sensitive to the action of LAS-131, we have applied a widely used approach, that made it possible to determine how long the addition of a compound can be postponed before it loses its antiviral activity, and to compare this indicator with the crucial time of application of inhibitors with a well-known mechanism of action
Summary
Антивирусный эффект нового конъюгата пурина LAS-131 в отношении вируса простого герпеса 1 типа (Herpesviridae: Alphaherpesvirinae: Simplexvirus: Human alphaherpesvirus 1) in vitro. Как было показано нами ранее, новое оригинальное соединение LAS-131 высокоселективно ингибирует репродукцию ВПГ-1 (индекс селективности, SI = 63). Чтобы установить этап(ы) жизненного цикла вируса, чувствительный(ные) к действию LAS-131, мы применили обычно используемый в мировой практике подход (метод варьирования времени добавления препарата, time-of-addition assay), позволяющий установить временнóй период, на который можно отсрочить введение тестируемого соединения без потери его противовирусной активности, и сравнить этот показатель с переломным временем введения ингибиторов с хорошо известным механизмом действия (in vitro). Что LAS-131 сохраняет выраженное противовирусное действие при внесении в экспериментальную систему не позднее 9 ч после инфицирования (p.i.), но не влияет на выход ВПГ-1 из клетки. – концепция и дизайн исследования, написание текста, экспериментальная часть, статистический анализ; Галегов Г.А.
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