Изучение ингибирования тромбина аптамерными олигонуклеотидами
Диссертация
Впервые получены кинетические характеристики ингибирования тромбина различными аптамерами, содержащими фармакофор и дополнительные структурные элементы. Тип ингибирования определяется как сайтом связывания аптамера, так и дополнительными элементами вторичной структуры ингибиторов. Благодарю за помощь в проведении экспериментов на плазме крови д.б.н. Дрозд Наталью Николаевну (ФГБУ Гематологический… Читать ещё >
Содержание
- Список сокращений
- Глава I. Обзор литературы
- 1. 1. Образование и функции тромбина в крови
- Каскад свертывания крови
- Методы изучения каскада свертывания крови in vitro
- Коагуляция
- Тест генерации тромбина
- 1. 2. Ферментативная активность тромбина
- Структура а-тромбина
- Низкомолекулярные субстраты тромбина
- Гидролиз фибриногена тромбином
- 1. 3. Ингибиторы ферментативной активности тромбина
- Классификация ингибиторов
- Ингибиторьгпептидомиметики
- Белковые ингибиторы тромбина
- Антитромбин III
- Кофактор II гепарина
- Тромбомодулин
- Гирудины
- Ботроярацин
- Гемадин
- Пептидные ингибиторы тромбина
- Гиругены
- EGF-пентид
- Бивалентные пептидные ингибиторы тромбина
- Гирулоги
- Модификация гирулогов
- Гирунормы
- Другие ингибиторы активного сайта, соединенные с гиругеном
- Вариегин
- Ингибиторы по экзосайту II тромбина
- Гепарин. у'-пептид
- Синтетический ингибитор к экзосайту II
- 1. 4. Аптамерные олигонуклеотиды — новая парадигма ингибиторов тромбина
- 15-ТВА — минимальный G-квадруплекс-фармакофор
- Дуплексные элементы структуры в комбинации с
- G-квадруплексным фармакофором
- Соединение нескольких G-квадруплексных фармакофоров
- G-квадруплекс содержащий ДНК-аптамер к экзосайту II тромбина
- Бифункциональные ДНК-аптамеры к тромбину
- РНК-аптамеры к тромбину
- Глава II. Экспериментальная часть
- 2. 1. Материалы
- 2. 2. Методы исследования
- Разделение фибринопептидов
- Идентификация фибринопептидов
- Получение и очистка Е-домена фибриногена
- Поверхностный плазмонный резонанс: связывание тромбина и Е-домена фибриногена
- Определение радиусов гирации фибриногена и ассоциатов фибрина
- АСМ ассоциатов фибрина
- ПЭМ ассоциатов фибрина
- Определение мутности раствора турбидиметрическим методом
- Изучение ингибиторов тромбина турбидиметрическим методом
- Преформирование аптамеров
- Проведение экспериментов с конкурирующими лигандами
- Изучение ингибирования аптамерами тромбинов животных
- Изучение влияния гиругена и аптамеров на гидролиз низкомолекулярного субстрата разными формами тромбина
- Получение плазмы крови животных
- Проведение коагуляционных тестов
- Нормирование результатов коагуляционных тестов для разных препаратов тромбинов
- Эксперименты in vivo
- Построение и моделирование кривых
- Глава III. Результаты и их обсуждение
- 3. 1. Теоретическое моделирование гидролиза фибриногена тромбином
- Схема реакции
- Выбор приближения для описания кинетики гидролиза фибриногена
- Описание кинетики гидролиза фибриногена в квазиравновесном приближении
- Моделирование образования протофибрилл и последующего отщепления фибринопептида В
- 3. 2. Описание экспериментальных данных разработанной моделью.75 Определение констант ассоциации и диссоциации комплекса тромбин-фибриноген
- Моделирование отщепления фибринопептидов и образования промежуточных форм фибрина
- Определение степени ассоциации фибрина по динамическому светорассеянию
- 3. 3. Моделирование турбидиметрической кривой
- Светорассеяние
- Геометрия фибрина и его ассоциатов
- Определение связи между оптической плотностью раствора и геометрией ассоциатов фибрина
- 3. 4. Определение связи между кинетикой гидролиза фибриногена и формой турбидиметрической кривой
- Исследование ассоциатов фибрина
- Параметризация турбидиметрической кривой
- Определение констант и типа ингибирования
- 3. 5. Изучение турбидиметрическим методом ингибиторов тромбина, охарактеризованных другими методами
- Ингибиторы активного сайта тромбина
- Ингибиторы экзосайта I тромбина
- Ингибиторы активного сайта и экзосайта I тромбина
- Ингибиторы экзосайта II тромбина
- Ингибиторы активного сайта и экзосайта II тромбина
- Ингибиторы ассоциации фибрина
- Сравнение результатов с данными, опубликованными ранее
- 3. 6. Изучение турбидиметрическим методом аптамерных олигонуклеотидов к тромбину
- Аптамеры с известным сайтом связывания
- Аптамеры с G-квадруплексом и дополнительными элементами вторичной структуры
- Моделирование комплексов 31-ТВА и RA-36 с тромбином
- Подбор условий преформирования G-квадруплекс содержащих аптамеров
- Изучение влияния дополнительных структурных элементов на ингибируюшую активность G-квадруплекс содержащих аптамеров
- Определение констант связывания ДНК-аптамеров с протромбином
- Изучение видоспецифичности G-квадруплекс содержащих аптамеров турбидиметрическим методом
- Выравнивание первичных структур тромбинов человека и животных
- 3. 7. Изучение ДНК-аптамеров к тромбину в биологических жидкостях in vitro и in vivo
- Изучение видоспецифичности G-квадруплекс содержащих аптамеров в коагуляционных тестах
- Изучение ингибирующей активности RA-36 in vivo
- Изучение действия антидота к RA
- 3. 8. Изучение влияния ДНК-аптамеров на гидролиз тромбином низкомолекулярных субстратов
- Конкуренция ДНК-аптамеров с гиругеном в ингибировании тромбина
- Исследование влияния ДНК-аптамеров и гиру гена на гидролиз низкомолекулярного субстрата тромбина
- Конформация тромбина в комплексах с ингибиторами
- Выводы
- Благодарности
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