RU2506274C2 - Способы скрининга с применением g-белок сопряженных рецепторов и родственных композиций - Google Patents

Способы скрининга с применением g-белок сопряженных рецепторов и родственных композиций Download PDF

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RU2506274C2
RU2506274C2 RU2010107292/10A RU2010107292A RU2506274C2 RU 2506274 C2 RU2506274 C2 RU 2506274C2 RU 2010107292/10 A RU2010107292/10 A RU 2010107292/10A RU 2010107292 A RU2010107292 A RU 2010107292A RU 2506274 C2 RU2506274 C2 RU 2506274C2
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Томас Дж. ГАРДЕЛЛА
Джон Т. ПОТТС
Масару ШИМИЦУ
Фумихико ИЧИКАВА
Харальд ЮППНЕР
Макото ОКАЗАКИ
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Дзе Дженерал Хоспитал Корпорейшн
Чугай Фармасьютикл Ко., Лтд.
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Abstract

Изобретение относится к области биотехнологии, конкретно к агонистам рецептора РТН, и может быть использовано в медицине. Конструируют полипептид формулы PTH(1-X)/PTHrP(Y-36), где X обозначает целое число между 11 и 18 и Y=X+1, где PTH(1-X) представляет аминокислоты с 1 по X последовательности PTH человека (SEQ ID NO:5) и PTHrP(Y-36) представляет аминокислоты с Y по 36 последовательности PTHrP человека (SEQ ID NO:6). При этом полипептид содержит одну или более из следующих мутаций в последовательности PTH(1-X): Ala в положении 1, Ala или Aib в положении 3, Gln в положении 10, Arg или гомоаргинин в положении 11, Ala в положении 12 и Trp в положении 14. Полученный полипептид используют для репарации перелома, лечения гипопаратиреоидизма, гиперфосфатемии, опухолевого кальциноза, остеопороза, остеомаляции, артрита, тромбоцитопении, а также для повышения мобилизации стволовых клеток у субъекта. Изобретение позволяет получить полипептид, обладающий пролонгированной активностью в отношении рецептора PTH. 7 н. и 11 з.п. ф-лы, 37 ил., 8 табл., 11 пр.

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Claims (18)

1. Полипептид, характеризующийся формулой PTH(1-X)/PTHrP(Y-36) и обладающий пролонгированной активностью в отношении рецептора РТН, где X обозначает целое число между 11 и 18, и Y=X+1, где указанный PTH(1-X) представляет аминокислоты с 1 по X последовательности PTH человека (SEQ ID NO:5) и указанный PTHrP(Y-36) представляет аминокислоты с Y по 36 последовательности PTHrP человека (SEQ ID NO:6), причем указанный полипептид содержит одну или более из следующих мутаций в указанной последовательности PTH(1-X): Ala в положении 1, Ala или Aib в положении 3, Gin в положении 10, Arg или гомоаргинин в положении 11, Ala в положении 12, и Trp в положении 14.
2. Полипептид по п.1, который содержит Ala в положении 1 и 12, Aib в положении 3, Gln в положении 10, гомоаргинин в положении 11, и Тгр в положении 14.
3. Полипептид по п.1, который содержит Ala в положении 1, 3 и 12, Gln в положении 10, Arg в положении 11, и Trp в положении 14.
4. Полипептид по п.1, который выбран из группы, состоящей из Мс-PTH(1-14)/PTHrP(15-36) (#1161; SEQ ID NO:15); Мс-PTH(1-18)/PTHrP(19-36) (#1163; SEQ ID NO:16); Mc-PTH(1-17)/PTHrP(18-36) (#1162; SEQ ID NO:139); и Mc-PTH(1-11)/PTHrP(l2-36) (#1160; SEQ ID NO:14).
5. Полипептид по п.4, который представляет собой Mc-PTH(1-14)/PTHrP(15-36) (#1161; SEQ ID NO:15).
6. Полипептид по п.4, который представляет собой Мс-PTH(1-18)/PTHrP(19-36) (#1163; SEQ ID NO:16).
7. Полипептид по п.4, который представляет собой Мс-PTH(1-17)/PTHrP(18-36) (#1162; SEQ ID NO:139).
8. Полипептид по п.4, который представляет собой Мс-PTH(1-11)/PTHrP(12-36) (#1160; SEQ ID NO:14).
9. Фармацевтическая композиция, обладающая пролонгированной активностью в отношении рецептора PTH, включающая:
(а) полипептид по любому из пп.1-8; и
(б) фармацевтически приемлемый носитель.
10. Способ лечения субъекта, нуждающегося в репарации перелома, или имеющего заболевание, выбранное из группы, включающей гипопаратиреоидизм, гиперфосфатемию, опухолевый кальциноз, остеопороз и остеомаляцию, включающий введение полипептида по любому из пп.1-8 или фармацевтической композиции по п.9 субъекту в количестве, достаточном для репарации перелома или для лечения указанного заболевания.
11. Способ по п.10, в котором указанным заболеванием является гипопаратиреоидизм.
12. Способ по п.10, в котором указанным заболеванием является гиперфосфатемия или опухолевый кальциноз.
13. Способ по п.10, в котором указанным заболеванием является остеопороз и остеомаляция.
14. Способ лечения субъекта, страдающего артритом, включающий введение полипептида по любому из пп.1-8 или фармацевтической композиции по п.9 субъекту в количестве, достаточном для лечения артрита.
15. Способ лечения субъекта, страдающего тромбоцитопенией, включающий введение полипептида по любому из пп.1-8 или фармацевтической композиции по п.9 субъекту в количестве, достаточном для лечения тромбоцитопении.
16. Способ повышения мобилизации стволовых клеток у субъекта, включающий введение полипептида по любому из пп.1-8 или фармацевтической композиции по п.9 указанному субъекту.
17. Способ по любому из пп.10-16, отличающийся тем, что путь введения выбирают из группы, состоящей из подкожного, внутривенного, интраназального, чрезлегочного, трансдермального и перорального пути введения.
18. Нуклеиновая кислота, кодирующая полипептид по любому из пп.1-8.
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FR3092115B1 (fr) * 2019-01-30 2021-11-12 Cisbio Bioassays analogues de GTP fluorescents et utilisation
KR102264116B1 (ko) * 2019-06-19 2021-06-14 한국과학기술연구원 세포 소포체 내 g-단백질 연결 수용체(gpcr)의 실시간 활성 상태 분석 방법 및 컴퓨터 프로그램
CN112111003B (zh) * 2019-06-20 2022-02-11 中国农业大学 含有me序列的一类新型抑制血小板聚集和抗血栓形成寡肽

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