Стратегия биокаталитического синтеза модифицированных пептидов-ингибиторов протеиназ тема автореферата и диссертации по химии, 02.00.10 ВАК РФ

СПИСОК СОКРАЩЕНИЙ.

ВВЕДЕНИЕ.

I. ЛИТЕРАТУРНЫЙ ОБЗОР.

1.1. Ингибиторы тромбина и плазмина.

1.1.1. Тромбин и плазмин - ключевые ферменты системы гемостаза.

1.1.2. Природные ингибиторы ферментов системы гемостаза.

1.1.3. Бифункциональные синтетические ингибиторы тромбина.

1.1.4. Сайт-направленные синтетические ингибиторы тромбина.

1.1.5. Ингибиторы плазмина.

1.2. Стратегии синтеза пептидил-а-аминоальдегидов.

1.2.1. Химические способы получения а-аминоальдегидов.

1.2.1.1. Восстановительные методы получения а-аминоальдегидов.

1.2.1.2. Окислительные методы получения а-аминоальдегидов.

1.2.1.3. Ферментативные методы синтеза а-аминоальдегидов дегидрированием р-аминоспиртов.

1.2.2. Методы синтеза пептидил-а-аминоальдегидов.

1.2.2.1. Конденсация производных а-аминоальдегидов с эфирами Ы-защищенных аминокислот и эфиров.

1.2.2.2. Получение пептидил-а-аминоальдегидов через лактам аргинина.

1.2.2.3. Твердофазный синтез пептидил-а-аминоальдегидов.

1.2.2.4. Получение пептидил-а-аминоальдегидов через через модифицированные пептиды или производные пептидов.

II. ОБСУЖДЕНИЕ РЕЗУЛЬТАТОВ.

11.1. Ферментативный синтез модифицированных пептидов.

11.1. Выбор условий проведения ферментативного синтеза. 54 II. 1.1. Ферментативный синтез пептидил-/3-аминоспиртов.

11.1.1.1. Синтез трипептидил-/3-аминоспиртов.

11.1.1.2. Синтез дипептидил-0-аминоспиртов.

11.1.1.3. Препаративный синтез трипептидил-/3-аминоспиртов.

11.1.1.4. Гидролиз пептидил-р-аминоспиртов, катализируемый субтилизином 72.

11.1.1.5. Окисление пептидил-р-аминоспиртов в соответствующие пептидил-а-аминоальдегиды.

11.1.2. Синтез пептидил-а-аминоальдегидов через защищенные а-аминоальдегиды.

II. 1.2.1. Синтез a-аминоальдегидов с защищенной альдегидной функцией.

11.1.2.2. Ферментативный синтез семикарбазонов пептидил-а-аминоальдегидов.

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.