WO2017116205A1 - 글루카곤, glp-1 및 gip 수용체 모두에 활성을 갖는 삼중 활성체의 지속형 결합체 - Google Patents
글루카곤, glp-1 및 gip 수용체 모두에 활성을 갖는 삼중 활성체의 지속형 결합체 Download PDFInfo
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- WO2017116205A1 WO2017116205A1 PCT/KR2016/015555 KR2016015555W WO2017116205A1 WO 2017116205 A1 WO2017116205 A1 WO 2017116205A1 KR 2016015555 W KR2016015555 W KR 2016015555W WO 2017116205 A1 WO2017116205 A1 WO 2017116205A1
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- WIPO (PCT)
- Prior art keywords
- cysteine
- glutamine
- alanine
- lysine
- glutamic acid
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Abstract
Description
서열번호 | 서열 | 정보 |
1 | H X Q G T F T S D V S S Y L D G Q A A K E F I A W L V K G C | |
2 | H X Q G T F T S D V S S Y L D G Q A Q K E F I A W L V K G C | |
3 | H X Q G T F T S D V S S Y L L G Q A A K Q F I A W L V K G G G P S S G A P P P S C | |
4 | H X Q G T F T S D V S S Y L L G Q Q Q K E F I A W L V K G C | |
5 | H X Q G T F T S D V S S Y L L G Q Q Q K E F I A W L V K G G G P S S G A P P P S C | |
6 | H X Q G T F T S D V S S Y L D G Q A A K E F V A W L L K G C | |
7 | H X Q G T F T S D V S K Y L D G Q A A K E F V A W L L K G C | |
8 | H X Q G T F T S D V S K Y L D G Q A A Q E F V A W L L K G C | |
9 | H X Q G T F T S D V S K Y L D G Q A A Q E F V A W L L A G C | |
10 | H X Q G T F T S D V S K Y L D G Q A A Q E F V A W L L A G G G P S S G A P P P S C | |
11 | CA G E G T F T S D L S K Y L D S R R Q Q L F V Q W L K A G G P S S G A P P P S H G | |
12 | CA G E G T F I S D L S K Y M D E Q A V Q L F V E W L M A G G P S S G A P P P S H G | |
13 | CA G E G T F I S D Y S I Q L D E I A V Q D F V E W L L A Q K P S S G A P P P S H G | |
14 | CA G Q G T F T S D Y S I Q L D E I A V R D F V E W L K N G G P S S G A P P P S H G | |
15 | CA G Q G T F T S D L S K Q M D E E A V R L F I E W L K N G G P S S G A P P P S H G | |
16 | CA G Q G T F T S D L S K Q M D S E A Q Q L F I E W L K N G G P S S G A P P P S H G | |
17 | CA G Q G T F T S D L S K Q M D E E R A R E F I E W L L A Q K P S S G A P P P S H G | |
18 | CA G Q G T F T S D L S K Q M D S E R A R E F I E W L K N T G P S S G A P P P S H G | |
19 | CA G Q G T F T S D L S I Q Y D S E H Q R D F I E W L K D T G P S S G A P P P S H G | |
20 | CA G Q G T F T S D L S I Q Y E E E A Q Q D F V E W L K D T G P S S G A P P P S H G | |
21 | Y X Q G T F T S D Y S K Y L D E C R A K E F V Q W L L D H H P S S G Q P P P S | 고리 형성 |
22 | Y X Q G T F T S D Y S K C L D E K R A K E F V Q W L L D H H P S S G Q P P P S | 고리 형성 |
23 | Y X Q G T F T S D Y S K Y L D E C R A K E F V Q W L L A Q K G K K N D W K H N I T | 고리 형성 |
24 | Y X Q G T F T S D Y S K Y L D E C R A K E F V Q W L K N G G P S S G A P P P S | 고리 형성 |
25 | H X Q G T F T S D C S K Y L D E R A A Q D F V Q W L L D G G P S S G A P P P S | |
26 | H X Q G T F T S D C S K Y L D S R A A Q D F V Q W L L D G G P S S G A P P P S | |
27 | H X Q G T F T S D Y S K Y L D E R A C Q D F V Q W L L D Q G G P S S G A P P P S | |
28 | H X Q G T F T S D Y S K Y L D E K R A Q E F V C W L L A Q K G K K N D W K H N I T | |
29 | H X Q G T F T S D Y S K Y L D E K A A K E F V Q W L L N T C | 고리 형성 |
30 | H X Q G T F T S D Y S K Y L D E K A Q K E F V Q W L L D T C | 고리 형성 |
31 | H X Q G T F T S D Y S K Y L D E K A C K E F V Q W L L A Q | 고리 형성 |
32 | H X Q G T F T S D Y S K Y L D E K A C K D F V Q W L L D G G P S S G A P P P S | 고리 형성 |
33 | H X Q G T F T S D Y S I A M D E I H Q K D F V N W L L A Q K C | 고리 형성 |
34 | H X Q G T F T S D Y S K Y L D E K R Q K E F V N W L L A Q K C | 고리 형성 |
35 | H X Q G T F T S D Y S I A M D E I H Q K D F V N W L L N T K C | 고리 형성 |
36 | H X Q G T F T S D Y S K Y L C E K R Q K E F V Q W L L N G G P S S G A P P P S G | 고리 형성 |
37 | H X Q G T F T S D Y S K Y L D E C R Q K E F V Q W L L N G G P S S G A P P P S G | 고리 형성 |
38 | CA X Q G T F T S D K S S Y L D E R A A Q D F V Q W L L D G G P S S G A P P P S S | |
39 | H X Q G T F T S D Y S K Y L D G Q H A Q C F V A W L L A G G G P S S G A P P P S | |
40 | H X Q G T F T S D K S K Y L D E R A C Q D F V Q W L L D G G P S S G A P P P S | |
41 | H X Q G T F T S D K S K Y L D E C A A Q D F V Q W L L D G G P S S G A P P P S | |
42 | Y X Q G T F T S D Y S K Y L D E K R A K E F V Q W L L D H H P S S G Q P P P S C | 고리 형성 |
43 | Y X Q G T F T S D Y S K Y L D E K R A K E F V Q W L L D H H C S S G Q P P P S | 고리 형성 |
44 | H G Q G T F T S D C S K Q L D G Q A A Q E F V A W L L A G G P S S G A P P P S | |
45 | H G Q G T F T S D C S K Y M D G Q A A Q D F V A W L L A G G P S S G A P P P S | |
46 | H G Q G T F T S D C S K Y L D E Q H A Q E F V A W L L A G G P S S G A P P P S | |
47 | H G Q G T F T S D C S K Y L D G Q R A Q E F V A W L L A G G P S S G A P P P S | |
48 | H G Q G T F T S D C S K Y L D G Q R A Q D F V N W L L A G G P S S G A P P P S | |
49 | CA X Q G T F T S D Y S I C M D E I H Q K D F V N W L L N T K | 고리 형성 |
50 | H X Q G T F T S D Y S K Y L D E K R A K E F V Q W L L D H H P S S G Q P P P S C | 고리 형성 |
51 | H X Q G T F T S D Y S K Y L D E K R Q K E F V Q W L L N T C | 고리 형성 |
52 | H X Q G T F T S D Y S K Y L D E K R Q K E F V Q W L L D T C | 고리 형성 |
53 | H X E G T F T S D Y S I A M D E I H Q K D F V N W L L A Q C | 고리 형성 |
54 | H X E G T F T S D Y S I A M D E I H Q K D F V D W L L A E C | 고리 형성 |
55 | H X Q G T F T S D Y S I A M D E I H Q K D F V N W L L A Q C | 고리 형성 |
56 | H X Q G T F T S D Y S K Y L D E K R Q K E F V N W L L A Q C | 고리 형성 |
57 | H X Q G T F T S D Y S I A M D E I H Q K D F V N W L L N T C | 고리 형성 |
58 | H X Q G T F T S D Y S K Y L D E K R Q K E F V Q W L L N T K C | 고리 형성 |
59 | CA X Q G T F T S D Y S I C M D E K H Q K D F V N W L L N T K | 고리 형성 |
60 | CA X Q G T F T S D Y S I A M D E K H C K D F V N W L L N T K | 고리 형성 |
61 | CA X Q G T F T S D Y S I A M D E I A C K D F V N W L L N T K | 고리 형성 |
62 | CA X Q G T F T S D K S K Y L D E R A A Q D F V Q W L L D G G P S S G A P P P S | - |
63 | CA X Q G T F T S D C S K Y L D E R A A Q D F V Q W L L D G G P S S G A P P P S | - |
64 | Y X Q G T F T S D Y S K Y L D E C A A K E F V Q W L L D H H P S S G Q P P P S | 고리 형성 |
65 | H X Q G T F T S D Y S K C L D E K R A K E F V Q W L L D H H P S S G Q P P P S | 고리 형성 |
66 | Y X Q G T F T S D Y S K Y L D E C R A K D F V Q W L L D H H P S S G Q P P P S | 고리 형성 |
67 | Y X Q G T F T S D Y S K Y L D E C A A K D F V Q W L L D H H P S S G Q P P P S | 고리 형성 |
68 | Y X Q G T F T S D Y S K C L D E K A A K E F V Q W L L D H H P S S G Q P P P S | 고리 형성 |
69 | Y X Q G T F T S D Y S K C L D E R A A K E F V Q W L L D H H P S S G Q P P P S | 고리 형성 |
70 | Y X Q G T F T S D Y S K C L D E K R A K D F V Q W L L D H H P S S G Q P P P S | 고리 형성 |
71 | Y X Q G T F T S D Y S K Y L D E R A C K D F V Q W L L D H H P S S G Q P P P S | 고리 형성 |
72 | Y X Q G T F T S D C S K Y L D E R A A K D F V Q W L L D H H P S S G Q P P P S | 고리 형성 |
73 | CA X Q G T F T S D Y S K Y L D E C R A K E F V Q W L L D H H P S S G Q P P P S | 고리 형성 |
74 | CA X Q G T F T S D Y S K C L D E K R A K E F V Q W L L D H H P S S G Q P P P S | 고리 형성 |
75 | Y X Q G T F T S D Y S K Y L D E K A A K E F V Q W L L D H H P S S G Q P P P S C | 고리 형성 |
76 | Y X Q G T F T S D Y S K Y L D E K R A K D F V Q W L L D H H P S S G Q P P P S C | 고리 형성 |
77 | Y X Q G T F T S D Y S K Y L D E K A A K D F V Q W L L D H H P S S G Q P P P S C | 고리 형성 |
78 | H X Q G T F T S D Y S K Y L D E K R Q K E F V Q W L L D T K C | 고리 형성 |
79 | H X E G T F T S D Y S I A M D E I H Q K D F V N W L L A Q K C | 고리 형성 |
80 | H X E G T F T S D Y S I A M D E I H Q K D F V D W L L A E K C | 고리 형성 |
81 | CA X Q G T F T S D Y S K Y L D E K R Q K E F V Q W L L N T C | 고리 형성 |
82 | CA X Q G T F T S D Y S K Y L D E K R Q K E F V Q W L L D T C | 고리 형성 |
83 | CA X E G T F T S D Y S I A M D E I H Q K D F V N W L L A Q C | 고리 형성 |
84 | CA X E G T F T S D Y S I A M D E I H Q K D F V D W L L A E C | 고리 형성 |
85 | CA X Q G T F T S D Y S I A M D E I H Q K D F V N W L L A Q C | 고리 형성 |
86 | CA X Q G T F T S D Y S K Y L D E K R Q K E F V N W L L A Q C | 고리 형성 |
87 | CA X Q G T F T S D Y S I A M D E I H Q K D F V N W L L N T C | 고리 형성 |
88 | CA X Q G T F T S D Y S K Y L D E K R Q K E F V Q W L L N T K C | 고리 형성 |
89 | CA X Q G T F T S D Y S K Y L D E K R Q K E F V Q W L L D T K C | 고리 형성 |
90 | CA X E G T F T S D Y S I A M D E I H Q K D F V N W L L A Q K C | 고리 형성 |
91 | CA X E G T F T S D Y S I A M D E I H Q K D F V D W L L A E K C | 고리 형성 |
92 | CA X Q G T F T S D Y S I A M D E I H Q K D F V N W L L A Q K C | 고리 형성 |
93 | CA X Q G T F T S D Y S K Y L D E K R Q K E F V N W L L A Q K C | 고리 형성 |
94 | CA X Q G T F T S D Y S I A M D E I H Q K D F V N W L L N T K C | 고리 형성 |
95 | Y X Q G T F T S D Y S K Y L D E K R A K E F V Q W L L C H H P S S G Q P P P S | 고리 형성 |
96 | Y X Q G T F T S D Y S K Y L D E K R A K E F V Q W L L D H C P S S G Q P P P S | 고리 형성 |
97 | Y X Q G T F T S D Y S K Y L D E K R A K E F V Q W L L D C H P S S G Q P P P S | 고리 형성 |
98 | Y X Q G T F T S D Y S K A L D E K A A K E F V N W L L D H H P S S G Q P P P S C | 고리 형성 |
99 | Y X Q G T F T S D Y S K A L D E K A A K D F V N W L L D H H P S S G Q P P P S C | 고리 형성 |
100 | Y X Q G T F T S D Y S K A L D E K A A K E F V Q W L L D Q H P S S G Q P P P S C | 고리 형성 |
101 | Y X Q G T F T S D Y S K A L D E K A A K E F V N W L L D Q H P S S G Q P P P S C | 고리 형성 |
102 | Y X Q G T F T S D Y S K A L D E K A A K D F V N W L L D Q H P S S G Q P P P S C | 고리 형성 |
천연형 펩타이드 대비in vitro 활성 (%) | |||
서열번호 | vs GLP-1 | vs Glucagon | vs GIP |
1 | 3.2 | <0.1 | <0.1 |
2 | 5.9 | <0.1 | <0.1 |
3 | 1.8 | <0.1 | <0.1 |
4 | 8.5 | <0.1 | <0.1 |
5 | 42.1 | <0.1 | <0.1 |
6 | 17.0 | <0.1 | <0.1 |
7 | 13.7 | <0.1 | <0.1 |
8 | 14.2 | 0.10 | <0.1 |
9 | 32.1 | 0.13 | <0.1 |
10 | 46.0 | <0.1 | <0.1 |
11 | 1.4 | <0.1 | <0.1 |
12 | 0.4 | <0.1 | <0.1 |
13 | < 0.1 | < 0.1 | < 0.1 |
14 | 28.0 | < 0.1 | < 0.1 |
15 | 79.2 | <0.1 | <0.1 |
16 | 2.1 | < 0.1 | < 0.1 |
17 | 0.2 | < 0.1 | < 0.1 |
18 | <0.1 | <0.1 | <0.1 |
19 | <0.1 | <0.1 | <0.1 |
20 | <0.1 | <0.1 | <0.1 |
21 | 17.8 | 267 | 22.7 |
22 | 20.1 | 140 | 59.7 |
23 | 4.01 | 9.3 | <0.1 |
24 | 41.2 | 9.3 | < 0.1 |
25 | 82.6 | 0.1 | <0.1 |
26 | 64.5 | 0.2 | <0.1 |
27 | 83.1 | 0.8 | 0.9 |
28 | 17.2 | 1.6 | <0.1 |
29 | 38.5 | 6.0 | <0.1 |
30 | 142 | 0.7 | 0.8 |
31 | 135 | 2.2 | 2.4 |
32 | 151 | 1.7 | 8.8 |
33 | 24.5 | <0.1 | 10.4 |
34 | 19.1 | 0.92 | 0.6 |
35 | 7.5 | <0.1 | 1.3 |
36 | 37.4 | 0.39 | 0.2 |
37 | 236 | 6.21 | 2.2 |
38 | 2.3 | - | - |
39 | 13.9 | 0.53 | <0.1 |
40 | 75.2 | <0.1 | <0.1 |
41 | 34.3 | <0.1 | <0.1 |
42 | 33.9 | 205.8 | 7.8 |
43 | 12.6 | 88.4 | 3.70 |
44 | 1.3 | <0.1 | <0.1 |
45 | 6.6 | < 0.1 | < 0.1 |
46 | 1.4 | < 0.1 | < 0.1 |
47 | 2.4 | < 0.1 | < 0.1 |
48 | 1.5 | < 0.1 | < 0.1 |
49 | 29.8 | <0.1 | 3.3 |
50 | 67.4 | 50.5 | 2.7 |
51 | 14.4 | 2.0 | 0.1 |
52 | 44.1 | 7.5 | 0.3 |
53 | 161 | 8.4 | 1.3 |
54 | 30.6 | 1.4 | 0.1 |
55 | 27.1 | 0.7 | 2.4 |
56 | 57.9 | 4.9 | 0.8 |
57 | 11.7 | <0.1 | 0.3 |
58 | 39.1 | 2.6 | 0.2 |
59 | 40.3 | <0.1 | 4.0 |
60 | 106.2 | <0.1 | 8.2 |
61 | 59.8 | <0.1 | 2.8 |
62 | 5.2 | <0.1 | <0.1 |
63 | 15.3 | <0.1 | <0.1 |
64 | 64.6 | 60.1 | 92.9 |
65 | 95.4 | 25.2 | 11.6 |
66 | 15.8 | 172 | 17.2 |
67 | 28.5 | 46.2 | 39.8 |
68 | 27.9 | 8.8 | 107 |
69 | 24.3 | 9.6 | 62.8 |
70 | 15.1 | 71.3 | 64.4 |
71 | 90.1 | 12.7 | 94.7 |
72 | 11.5 | 1.0 | 1.6 |
73 | 22.6 | 5.4 | 3.0 |
74 | 12.9 | 0.9 | 1.0 |
75 | 35.1 | 8.5 | 18.0 |
76 | 10.3 | 47.6 | 11.7 |
77 | 38.7 | 12.2 | 35.5 |
78 | 51.0 | 14.0 | 0.12 |
79 | 41.5 | 4.9 | 1.4 |
80 | 8.1 | 0.0 | 0.1 |
81 | 7.8 | 0.3 | <0.1 |
82 | 9.5 | 1.1 | <0.1 |
83 | 47.3 | 1.3 | 0.4 |
84 | 4.2 | <0.1 | <0.1 |
85 | 4.3 | <0.1 | 0.3 |
86 | 28.4 | 0.4 | 0.2 |
87 | 0.9 | <0.1 | <0.1 |
88 | 9.6 | 0.3 | <0.1 |
89 | 7.1 | 0.7 | <0.1 |
90 | 7.4 | <0.1 | <0.1 |
91 | 31.9 | 16.8 | 0.3 |
92 | 0.8 | <0.1 | 0.4 |
93 | 5.7 | 0.3 | 0.7 |
94 | 0.5 | <0.1 | <0.1 |
95 | 2.1 | 0.4 | <0.1 |
96 | 34.4 | 194.8 | 5.2 |
97 | 10.5 | 62.8 | 2.6 |
98 | 28.1 | 8.2 | 47.1 |
99 | 20.9 | 14.9 | 57.7 |
100 | 42.2 | 12.7 | 118.5 |
101 | 23.2 | 13.9 | 40.1 |
102 | 23.3 | 29.5 | 58.0 |
지속형 결합체 | 천연형 펩타이드 대비 in vitro 활성 (%) | ||
vs GLP-1 | vs Glucagon | vs GIP | |
21 | 0.1 | 1.6 | 0.2 |
22 | 0.1 | 0.9 | 0.5 |
42 | 3.1 | 23.1 | 1.2 |
43 | 2.1 | 13.5 | 0.6 |
50 | 15.4 | 6.9 | 0.7 |
77 | 6.7 | 1.7 | 6.6 |
96 | 0.3 | 4.0 | 0.3 |
Claims (24)
- 하기 화학식 1로 표시되는, 결합체:[화학식 1]X - La - F여기서,X는, 글루카곤 수용체, GLP-1 (Glucagon-like peptide-1) 수용체, 및 GIP (Glucose-dependent insuliontropic polypeptide) 수용체에 대해 활성을 갖는, 펩타이드이고;L은, 링커이며;a는, 0 또는 자연수이며, 다만 a가 2 이상일 때, 각각의 L은 서로 독립적이고;F는, X의 반감기를 증가시킬 수 있는 물질임.
- 제1항에 있어서,상기 X는 천연형 글루카곤 서열에서 적어도 하나 이상의 아미노산에 치환(substitution), 추가(addition), 제거(deletion), 수식(modification) 및 이들의 조합으로 이루어지는 군에서 선택된 변형이 일어난, 천연형 글루카곤의 아날로그인, 결합체.
- 제2항에 있어서,추가되는 아미노산 서열은 천연형 GLP-1, 천연형 GIP, 또는 천연형 엑센딘-4 아미노산 서열에서 유래되는, 결합체.
- 제1항에 있어서, 상기 X는 하기 일반식 1로 표시되는 아미노산 서열을 포함하는 펩타이드인, 결합체:Xaa1-Xaa2-Xaa3-Gly-Thr-Phe-Xaa7-Ser-Asp-Xaa10-Ser-Xaa12-Xaa13-Xaa14-Xaa15-Xaa16-Xaa17-Xaa18-Xaa19-Xaa20-Xaa21-Phe-Xaa23-Xaa24-Trp-Leu-Xaa27-Xaa28-Xaa29-Xaa30-R1 (일반식 1, 서열번호 103)상기 일반식 1에서,Xaa1은 히스티딘 (His, H), 4-이미다조아세틸 (CA), 또는 티로신 (Tyr, Y)이고,Xaa2는 글리신 (Gly, G), 알파-메틸-글루탐산, 또는 Aib (aminoisobutyric acid)이며,Xaa3은 글루탐산 (Glu, E) 또는 글루타민 (Gln, Q)이고,Xaa7은 트레오닌 (Thr, T) 또는 이소류신 (Ile, I)이며,Xaa10은 류신 (Leu, L), 티로신 (Tyr, Y), 리신 (Lys, K), 시스테인 (Cys, C), 또는 발린 (Val, V)이고,Xaa12는 리신 (Lys, K), 세린 (Ser, S), 또는 이소류신 (Ile, I)이며,Xaa13은 글루타민 (Gln, Q), 티로신 (Tyr, Y), 알라닌 (Ala, A), 또는 시스테인 (Cys, C)이고,Xaa14는 류신 (Leu, L), 메티오닌 (Met, M), 또는 티로신 (Tyr, Y)이며,Xaa15는 시스테인 (Cys, C), 아스파르트산 (Asp, D), 글루탐산 (Glu, E), 또는 류신 (Leu, L)이며,Xaa16은 글리신 (Gly, G), 글루탐산 (Glu, E), 또는 세린 (Ser, S)이고,Xaa17은 글루타민 (Gln, Q), 아르기닌 (Arg, R), 이소류신 (Ile, I), 글루탐산 (Glu, E), 시스테인 (Cys, C), 또는 리신 (Lys, K)이며,Xaa18은 알라닌 (Ala, A), 글루타민 (Gln, Q), 아르기닌 (Arg, R), 또는 히스티딘 (His, H)이고,Xaa19는 알라닌 (Ala, A), 글루타민 (Gln, Q), 시스테인 (Cys, C), 또는 발린 (Val, V)이며,Xaa20은 리신 (Lys, K), 글루타민 (Gln, Q), 또는 아르기닌 (Arg, R)이고,Xaa21은 글루탐산 (Glu, E), 글루타민 (Gln, Q), 류신 (Leu, L), 시스테인 (Cys, C), 또는 아스파르트산 (Asp, D)이며,Xaa23은 이소류신 (Ile, I) 또는 발린 (Val, V)이고,Xaa24는 알라닌 (Ala, A), 글루타민 (Gln, Q), 시스테인 (Cys, C), 아스파라긴 (Asn, N), 아스파르트산 (Asp, D), 또는 글루탐산 (Glu, E)이며,Xaa27은 발린 (Val, V), 류신 (Leu, L), 리신 (Lys, K), 또는 메티오닌 (Met, M)이고,Xaa28은 시스테인 (Cys, C), 리신 (Lys, K), 알라닌 (Ala, A), 아스파라긴 (Asn, N), 또는 아스파르트산 (Asp, D)이며,Xaa29는 시스테인 (Cys, C), 글리신 (Gly, G), 글루타민 (Gln, Q), 트레오닌 (Thr, T), 글루탐산 (Glu, E), 또는 히스티딘 (His, H)이고,Xaa30은 시스테인 (Cys, C), 글리신 (Gly, G), 리신 (Lys, K), 또는 히스티딘 (His, H)이거나, 부존재하며,R1은 시스테인 (Cys, C), GKKNDWKHNIT (서열번호 106), m-SSGAPPPS-n (서열번호 107), 또는 m-SSGQPPPS-n (서열번호 108)이거나, 부존재하며,여기서,m은 -Cys-, -Pro-, 또는 -Gly-Pro-이고,n은 -Cys-, -Gly-, -Ser-, 또는 -His-Gly-이거나, 부존재함.
- 제4항에 있어서,Xaa14는 류신 또는 메티오닌이며,Xaa15는 시스테인, 아스파르트산, 또는 류신인, 결합체.
- 제4항에 있어서,상기 일반식 1에서,Xaa2는 글리신, 알파-메틸-글루탐산, 또는 Aib이고,Xaa7은 트레오닌이며,Xaa10은 티로신, 시스테인, 또는 발린이고,Xaa12는 리신 또는 이소류신이며,Xaa13은 티로신, 알라닌, 글루타민, 또는 시스테인이고,Xaa14는 류신, 시스테인, 또는 메티오닌이며;Xaa15는 시스테인, 류신, 글루탐산, 또는 아스파르트산이고,Xaa17은 글루타민, 아르기닌, 이소류신, 시스테인, 글루탐산, 또는 리신이며,Xaa18은 알라닌, 글루타민, 아르기닌, 또는 히스티딘이고,Xaa19는 알라닌, 글루타민, 발린, 또는 시스테인이며,Xaa20은 리신, 아르기닌, 또는 글루타민이고,Xaa21은 글루탐산, 글루타민, 류신, 시스테인, 또는 아스파르트산이며,Xaa23은 이소류신 또는 발린이고,Xaa24는 시스테인, 알라닌, 글루타민, 아스파라긴, 글루탐산, 또는 아스파르트산이며,Xaa27은 류신 또는 리신인, 결합체.
- 제4항에 있어서, 상기 X는 하기 일반식 2로 표시되는 아미노산 서열을 포함하는 펩타이드인, 결합체:Xaa1-Xaa2-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Xaa10-Ser-Lys-Xaa13-Xaa14-Xaa15-Xaa16-Xaa17-Xaa18-Xaa19-Xaa20-Xaa21-Phe-Xaa23-Xaa24-Trp-Leu-Leu-Xaa28-Xaa29-Xaa30-Xaa31- Ser-Ser-Gly-Gln-Pro-Pro-Pro-Ser-Xaa40 (일반식 2, 서열번호 104)상기 식에서,Xaa1은 4-이미다조아세틸, 히스티딘, 또는 티로신이고,Xaa2는 글리신, 알파-메틸-글루탐산, 또는 Aib이며,Xaa10은 티로신, 또는 시스테인이고,Xaa13은 알라닌, 글루타민, 티로신, 또는 시스테인이며,Xaa14는 류신, 메티오닌, 또는 티로신이고,Xaa15는 아스파르트산, 글루탐산, 또는 류신이며,Xaa16은 글리신, 글루탐산, 또는 세린이고,Xaa17은 글루타민, 아르기닌, 이소류신, 글루탐산, 시스테인, 또는 리신이며,Xaa18은 알라닌, 글루타민, 아르기닌, 또는 히스티딘이고,Xaa19는 알라닌, 글루타민, 시스테인, 또는 발린이며,Xaa20은 리신, 글루타민, 또는 아르기닌이고,Xaa21은 시스테인, 글루탐산, 글루타민, 류신, 또는 아스파르트산이며,Xaa23은 이소류신 또는 발린이고,Xaa24는 시스테인, 알라닌, 글루타민, 아스파라긴, 또는 글루탐산이며,Xaa28은 리신, 시스테인, 아스파라긴, 또는 아스파르트산이고,Xaa29는 글리신, 글루타민, 시스테인, 또는 히스티딘이며,Xaa30은 시스테인, 글리신, 리신, 또는 히스티딘이고,Xaa31은 프롤린 또는 시스테인이며;Xaa40은 시스테인이거나, 부존재함.
- 제4항에 있어서,상기 일반식 1에서,Xaa2는 글리신, 알파-메틸-글루탐산, 또는 Aib이고,Xaa7은 트레오닌이며,Xaa10은 티로신, 시스테인, 또는 발린이고,Xaa12는 리신 또는 이소류신이며,Xaa13은 티로신, 알라닌, 또는 시스테인이고,Xaa14는 류신 또는 메티오닌이며,Xaa15는 시스테인 또는 아스파르트산이고,Xaa17은 글루타민, 아르기닌, 이소류신, 시스테인, 또는 리신이며,Xaa18은 알라닌, 아르기닌, 또는 히스티딘이고,Xaa19는 알라닌, 글루타민, 또는 시스테인이며,Xaa20은 리신 또는 글루타민이고,Xaa21은 글루탐산, 시스테인, 또는 아스파르트산이며,Xaa23은 발린이고,Xaa24는 알라닌, 글루타민, 시스테인, 아스파라긴, 또는 아스파르트산이며,Xaa27은 류신 또는 리신인, 결합체.
- 제7항에 있어서,상기 일반식 2에서,Xaa13은 알라닌, 티로신, 또는 시스테인이고,Xaa15는 아스파르트산 또는 글루탐산이며,Xaa17은 글루타민, 아르기닌, 시스테인, 또는 리신이고,Xaa18은 알라닌, 아르기닌, 또는 히스티딘이며,Xaa21은 시스테인, 글루탐산, 글루타민, 또는 아스파르트산이고,Xaa23은 이소류신 또는 발린이며,Xaa24는 시스테인, 글루타민, 또는 아스파라긴이고,Xaa28은 시스테인, 아스파라긴, 또는 아스파르트산이며,Xaa29는 글루타민, 시스테인, 또는 히스티딘이고,Xaa30은 시스테인, 리신, 또는 히스티딘인, 결합체.
- 제4항에 있어서,상기 일반식 1에서,Xaa2는 알파-메틸-글루탐산 또는 Aib이고,Xaa7은 트레오닌이며,Xaa10은 티로신 또는 시스테인이고,Xaa12는 리신 또는 이소류신이며,Xaa13은 티로신, 알라닌, 또는 시스테인이고,Xaa14는 류신 또는 메티오닌이며,Xaa15는 시스테인 또는 아스파르트산이고,Xaa16은 글루탐산이며,Xaa17은 아르기닌, 이소류신, 시스테인, 또는 리신이고,Xaa18은 알라닌, 아르기닌, 또는 히스티딘이며,Xaa19는 알라닌, 글루타민, 또는 시스테인이고,Xaa20은 리신 또는 글루타민이며,Xaa21은 글루탐산 또는 아스파르트산이고,Xaa23은 발린이며,Xaa24는 글루타민, 아스파라긴, 또는 아스파르트산이고,Xaa27은 류신이며,Xaa28은 시스테인, 알라닌, 아스파라긴, 또는 아스파르트산인, 결합체.
- 제4항에 있어서,상기 일반식 1에서,Xaa1은 히스티딘 또는 4-이미다조아세틸이고,Xaa2는 알파-메틸-글루탐산 또는 Aib이며,Xaa3은 글루타민이고,Xaa7은 트레오닌이며,Xaa10은 티로신이고,Xaa12는 이소류신이며,Xaa13은 알라닌 또는 시스테인이고,Xaa14는 메티오닌이며,Xaa15는 아스파르트산이고,Xaa16은 글루탐산이며,Xaa17은 이소류신 또는 리신이고,Xaa18은 알라닌 또는 히스티딘이며,Xaa19는 글루타민 또는 시스테인이고,Xaa20은 리신이며,Xaa21은 아스파르트산이고,Xaa23은 발린이며,Xaa24는 아스파라긴이고,Xaa27은 류신이며,Xaa28은 알라닌 또는 아스파라긴이고,Xaa29는 글루타민 또는 트레오닌이며,Xaa30은 시스테인 또는 리신이거나, 부존재하는, 결합체.
- 제4항에 있어서,상기 X는 하기 일반식 3의 아미노산 서열을 포함하는 펩타이드인, 결합체:Xaa1-Xaa2-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-Xaa13-Leu-Asp-Glu-Xaa17-Xaa18-Xaa19-Lys-Xaa21-Phe-Val-Xaa24-Trp-Leu-Leu-Xaa28-Xaa29-Xaa30-Xaa31-Ser-Ser-Gly-Gln-Pro-Pro-Pro-Ser-Xaa40 (일반식 3, 서열번호 105),상기 일반식 3에서,Xaa1은 히스티딘 또는 티로신이고,Xaa2는 알파-메틸-글루탐산 또는 Aib이며,Xaa13은 알라닌, 티로신 또는 시스테인이고,Xaa17은 아르기닌, 시스테인, 또는 리신이며,Xaa18은 알라닌 또는 아르기닌이고,Xaa19는 알라닌 또는 시스테인이며,Xaa21은 글루탐산 또는 아스파르트산이고,Xaa24는 글루타민 또는 아스파라긴이며,Xaa28은 시스테인 또는 아스파르트산이고,Xaa29는 시스테인, 히스티딘, 또는 글루타민이며,Xaa30은 시스테인 또는 히스티딘이고,Xaa31은 프롤린 또는 시스테인이며,Xaa40은 시스테인 또는 부존재함.
- 제4항에 있어서, 상기 R1은 시스테인, GKKNDWKHNIT (서열번호 106), CSSGQPPPS (서열번호 109), GPSSGAPPPS (서열번호 110), GPSSGAPPPSC (서열번호 111), PSSGAPPPS (서열번호 112), PSSGAPPPSG (서열번호 113), PSSGAPPPSHG (서열번호 114), PSSGAPPPSS (서열번호 115), PSSGQPPPS (서열번호 116), 또는 PSSGQPPPSC (서열번호 117)이거나, 부존재하는, 결합체.
- 제4항 내지 제13항 중 어느 한 항에 있어서,상기 일반식에서 N-말단으로부터 16번 아미노산과 20번 아미노산은 서로 고리를 형성하는, 결합체.
- 제1항에 있어서,상기 X는 서열번호: 1 내지 102로 이루어진 군으로부터 선택된 아미노산 서열을 포함하는 펩타이드인, 결합체.
- 제1항 내지 제13항 중 어느 한 항에 있어서,상기 F는 고분자 중합체, 지방산, 콜레스테롤, 알부민 및 이의 단편, 알부민 결합물질, 특정 아미노산 서열의 반복단위의 중합체, 항체, 항체 단편, FcRn 결합물질, 생체 내 결합조직, 뉴클레오타이드, 파이브로넥틴, 트랜스페린(Transferrin), 사카라이드(saccharide), 헤파린, 및 엘라스틴으로 이루어진 군에서 선택되는, 결합체.
- 제16항에 있어서,상기 고분자 중합체는 폴리에틸렌 글리콜, 폴리프로필렌 글리콜, 에틸렌 글리콜-프로필렌 글리콜 공중합체, 폴리옥시에틸화폴리올, 폴리비닐알콜, 폴리사카라이드, 덱스트란, 폴리비닐에틸에테르, 생분해성 고분자, 지질 중합체, 키틴, 히아루론산, 올리고뉴클레오타이드 및 이들의 조합으로 이루어진 군으로부터 선택되는, 결합체.
- 제1항 내지 제13항 중 어느 한 항에 있어서,상기 F는 면역글로불린 Fc 영역인, 결합체.
- 제18항에 있어서,상기 F는 IgG Fc 영역인, 결합체.
- 제1항 내지 제13항 중 어느 한 항에 있어서,상기 L은 펩타이드, 지방산, 사카라이드 (saccharide), 고분자 중합체, 저분자 화합물, 뉴클레오타이드 및 이들의 조합으로 이루어진 군으로부터 선택되는, 결합체.
- 제20항에 있어서, 상기 고분자 중합체는폴리에틸렌 글리콜, 폴리프로필렌 글리콜, 에틸렌 글리콜-프로필렌 글리콜 공중합체, 폴리옥시에틸화폴리올, 폴리비닐알콜, 폴리사카라이드, 덱스트란, 폴리비닐에틸에테르, 생분해성 고분자, 지질 중합체, 키틴, 히아루론산, 올리고뉴클레오타이드 및 이들의 조합으로 이루어진 군으로부터 선택되는, 결합체.
- 제1항 내지 제13항 중 어느 한 항에 있어서,상기 L은 폴리에틸렌 글리콜인, 결합체.
- 제1항 내지 제13항 중 어느 한 항의 결합체를 포함하는, 대사 증후군의 예방 또는 치료용 약학적 조성물.
- 제23항에 있어서, 상기 대사 증후군은 내당증 장애, 고콜레스테롤혈증, 이상지혈증, 비만, 당뇨, 고혈압, 이상지혈증에 의한 동맥경화, 죽상동맥경화증, 동맥경화증, 또는 관상동맥 심질환(관동맥성 심장병)을 포함하는, 조성물.
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MA42891A MA42891B2 (fr) | 2015-12-31 | 2016-12-30 | Conjugué persistant d'un triple activateur activant le récepteur du glucagon, du glp-1 et du gip |
AU2016382394A AU2016382394B2 (en) | 2015-12-31 | 2016-12-30 | Long-acting conjugate of triple glucagon/GLP-1/GIP receptor agonist |
MX2018008128A MX2018008128A (es) | 2015-12-31 | 2016-12-30 | Conjugado persistente de triple activador que activa el receptor de glucagon, glp-1 y gip. |
JP2018534662A JP6712322B2 (ja) | 2015-12-31 | 2016-12-30 | グルカゴン、glp−1及びgip受容体のすべてに活性を有する三重活性体の持続型結合体 |
CR20180381A CR20180381A (es) | 2015-12-31 | 2016-12-30 | Conjugado persistente de triple activador que activa el receptor de glucagón, glp-1 u gip |
MYPI2018001199A MY199261A (en) | 2015-12-31 | 2016-12-30 | Long-acting conjugate of triple glucagon/glp-1/gip receptor agonist |
EA201891359A EA038524B1 (ru) | 2015-12-31 | 2016-12-30 | Длительно действующий конъюгат тройного агониста рецепторов глюкагона/glp 1/gip |
EP16882157.7A EP3398962A4 (en) | 2015-12-31 | 2016-12-30 | PERSISTENT CONJUGATE OF A TRIPLE ACTIVATOR ACTIVATING THE GLUCAGON, GLP-1 AND GIP RECEPTOR |
CN202211656375.4A CN115920077A (zh) | 2015-12-31 | 2016-12-30 | 胰高血糖素/glp-1/gip受体三重激动剂的长效缀合物 |
CN202211287482.4A CN116059389A (zh) | 2015-12-31 | 2016-12-30 | 胰高血糖素/glp-1/gip受体三重激动剂的长效缀合物 |
TNP/2018/000231A TN2018000231A1 (en) | 2015-12-31 | 2016-12-30 | Long-acting conjugate of triple glucagon/glp-1/gip receptor agonist |
CA3010265A CA3010265A1 (en) | 2015-12-31 | 2016-12-30 | Long-acting conjugate of triple glucagon/glp-1/gip receptor agonist |
BR112018013525-9A BR112018013525A2 (pt) | 2015-12-31 | 2016-12-30 | conjugado de longa atuação de agonista de receptor de glucagon/glp-1/gip triplo e composição farmacêutica |
CN201680082339.8A CN109071624B (zh) | 2015-12-31 | 2016-12-30 | 胰高血糖素/glp-1/gip受体三重激动剂的长效缀合物 |
IL260310A IL260310B2 (en) | 2015-12-31 | 2016-12-30 | Long-term coupling of a triple agonist to glucagon/GLP–1/GIP receptors |
SA518391891A SA518391891B1 (ar) | 2015-12-31 | 2018-06-25 | 1 مقترن طويل الأمد من ناهض ثلاثي لمستقبل جلوكاجون/الببتيد الشبيه بالجلوكاجون/عديد الببتيد المحفز للإنسولين المعتمد على الجلوكوز |
PH12018501411A PH12018501411A1 (en) | 2015-12-31 | 2018-06-29 | Long-acting conjugate of triple glucagon/glp-1/gip receptor agonist |
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CONC2018/0006986A CO2018006986A2 (es) | 2015-12-31 | 2018-07-04 | Conjugado de acción prolongada del agonista triple receptor del glucagón /glp-1/gip |
ZA2018/04998A ZA201804998B (en) | 2015-12-31 | 2018-07-25 | Long-acting conjugate of triple glucagon/glp-1/gip receptor agonist |
HK19100534.2A HK1258177A1 (zh) | 2015-12-31 | 2019-01-14 | 激活胰高血糖素、glp-1和gip受體的三重激活劑的持久綴合物 |
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AU2019203891A AU2019203891B2 (en) | 2015-12-31 | 2019-06-04 | Long-acting conjugate of triple glucagon/GLP-1/GIP receptor agonist |
US17/187,098 US20210188937A1 (en) | 2015-12-31 | 2021-02-26 | Long-acting conjugate of triple glucagon/glp-1/gip receptor agonist |
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