Стратегия биокаталитического синтеза модифицированных пептидов-ингибиторов протеиназ

выводы.

1.Предложены два биокаталитических подхода к синтезу пептидил-а-аминоальдегидов. Впервые показана возможность использования аналогов природных аминокислот — (3-аминоспиртов и производных а-аминоальдегидов — в качестве аминокомпонентов в реакциях ферментативного синтеза пептидной связи.

2. Разработаны методы ферментативного синтеза пептидил-р-аминоспиртов и семикарбазонов пептидил-а-аминоальдегидов в органических растворителях с использованием в качестве катализатора субтилизина 72, сорбированного на макропористом носителе. Получен ряд пептидов, имеющих на С-конце как гидрофобные, так и гидрофильные аналоги природных аминокислот.

3. Исследовано ингибирование гидролиза хромогенных субстратов субтилизина и а-химотрипсина синтезированными модифицированными пептидами. На примере 2-А1а-А1а-РИеа1 экспериментально показано, что пептидил-а-аминоальдегиды являются обратимыми конкурентными и более сильными ингибиторами, чем пептидил-р-аминоспирты соответствующей структуры.

4. Ингибирующие свойства пептидил-а-аминоальдегидов исследованы на препаратах ферментов системы гемостаза. Установлено, что из синтезированных нами соединений наиболее селективным ингибитором тромбина является г-А1а-А1а-Агда1, а плазмина — Рог-А1а-РЬе-1уза1. Показано, что ингибирующий эффект 7-А1а-А1а-Агда1 и Рог-А1а-РЬе-1уза1 не уменьшается в плазме крови по сравнению с действием этих веществ на индивидуальные ферменты.

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167. Автор выражает глубокую благодарность Е. А. Тимохиной и другим сотрудникам отдела аминокислотного анализа за активное участие и помощь при исследовании структуры полученных в ходе работы соединений.