KR102493143B1 - Glycosylated exenatide analogs and uses thereof - Google Patents
Glycosylated exenatide analogs and uses thereof Download PDFInfo
- Publication number
- KR102493143B1 KR102493143B1 KR1020200101087A KR20200101087A KR102493143B1 KR 102493143 B1 KR102493143 B1 KR 102493143B1 KR 1020200101087 A KR1020200101087 A KR 1020200101087A KR 20200101087 A KR20200101087 A KR 20200101087A KR 102493143 B1 KR102493143 B1 KR 102493143B1
- Authority
- KR
- South Korea
- Prior art keywords
- acid
- exenatide
- glycosylated
- sugar
- agm
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- HTQBXNHDCUEHJF-XWLPCZSASA-N Exenatide Chemical class C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)NCC(=O)NCC(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CO)C(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCSC)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 HTQBXNHDCUEHJF-XWLPCZSASA-N 0.000 title claims abstract description 85
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- 238000000034 method Methods 0.000 claims description 12
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- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 4
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Abstract
본 발명은 특정 잔기에 당쇄화된 엑세나타이드 유사체 및 이의 용도에 관한것으로, 본 발명은 종래의 엑세나타이드 및 이의 유사체에 비해 향상된 체내 안정성을 보이는 신규 당뇨 치료 물질을 제공한다.The present invention relates to an analog of exenatide glycosylated at a specific residue and a use thereof, and the present invention provides a novel substance for treating diabetes that exhibits improved stability in the body compared to conventional exenatide and analogs thereof.
Description
본 발명은 당쇄화 엑세나타이드 유사체 및 이의 용도에 관한 것이다.The present invention relates to glycosylated exenatide analogs and uses thereof.
생체 내에서 발현되는 단백질에 당이 붙는 과정인 당쇄화 (glycosylation)는 세포 내 소기관인 골지체에서 일어나는 반응으로, 당쇄화로 인해 형성된 당단백질은 세포간 결합, 조직의 발달, 면역 반응, 호르몬 작용 등의 다양한 생체현상에 관여하는 것으로 알려져 있다. 1880년도에 당의 구조 연구가 시작되어 현재까지 당 및 당쇄화 연구는 활발히 진행되고 있으며, 최근 당쇄화 기술을 활용한 약물개발 연구가 진행되고 있는 실정이다.Glycosylation, the process by which sugars are attached to proteins expressed in vivo, is a reaction that occurs in the Golgi apparatus, an organelle within cells. It is known to be involved in various biological phenomena. Research on the structure of sugar began in 1880, and research on sugar and glycosylation has been actively conducted until now, and research on drug development using glycosylation technology is currently being conducted.
엑세나타이드 (Exenatide)는 미국 남서부에 서식하는 왕도마뱀 (Heloderma suspectum)의 침샘으로부터 분리된 GLP-1 (Glucagon-like Peptide-1)의 기능적 유사체 (analog)로서 제2형 당뇨병 펩타이드 치료제로 사용되고 있다. 최근 엑세나타이드를 비롯한 GLP-1 유사체의 체내 안정성이 개선된 지속적 작용성의 유사체 개발이 활발히 이루어지고 있다. Exenatide is a functional analog of GLP-1 (Glucagon-like Peptide-1) isolated from the salivary glands of Heloderma suspectum , which lives in the southwestern United States, and is used as a peptide treatment for type 2 diabetes. . Recently, the development of long-acting analogues with improved in vivo stability of GLP-1 analogues, including exenatide, has been actively pursued.
학술명 'Exendin-4'인 엑세나타이드는 39개 아미노산으로 구성된 생리활성 펩타이드로서 사람 생체 내에 존재하나 GLP-1과 53% 아미노산이 유사하며 DPP-4(Dipetidyl peptidase-4)와 같은 분해효소에 안정하여 GLP-1에 비해 체내 반감기가 비교적 길다.Exenatide, scientific name 'Exendin-4', is a physiologically active peptide composed of 39 amino acids, which exists in the human body, but has 53% amino acid similarity to GLP-1. It is stable and has a relatively long half-life in the body compared to GLP-1.
엑세나타이드는 하루 두 번, 아침과 저녁 식사 이전에 투여한다. 엑세나타이드는 신장으로 배설되므로 심각한 신장 기능의 손상이나 말기 신질환을 가진 환자에게 사용은 추천되지 않는다. Exenatide is administered twice daily, before breakfast and dinner. Because exenatide is excreted by the kidneys, its use is not recommended in patients with severe renal impairment or end-stage renal disease.
엑세나타이드의 배설은 간기능에 의존적이지 않으므로 간으로 대사되는 약물과 상호작용을 가지지 않는다. 반면 엑세나타이드는 위장관 운동성 (gastric motility)에 영향을 주기 때문에 흡수와 관련하여 다른 약물과 상호작용을 일으킬 수 있다.Exenatide excretion is not dependent on hepatic function and therefore does not interact with drugs metabolized by the liver. On the other hand, because exenatide affects gastric motility, it may interact with other drugs in relation to absorption.
또한, 엑세나타이드 펩타이드의 합성 과정에서 과량의 시약과 재료의 비용이 많이 드는 단점이 있다. 또한 반응 단계수가 많고 각 단계별로 중간체를 유리해야하고 또한 이성질체가 생길 가능성이 있어 정제하기도 쉽지 않다.In addition, there is a disadvantage in that an excessive amount of reagents and materials are expensive in the process of synthesizing the exenatide peptide. In addition, since the number of reaction steps is large, intermediates must be released at each step, and isomers are likely to occur, it is not easy to purify.
GLP-1 유사체를 이용한 신규 당뇨병 신규 치료제는 활발히 연구되고 있으나, 대부분의 경우 약효 지속 효과 개선을 위한 제형 개발에 중점을 두고 있으며, 효능 및 안정성을 개선한 획기적인 엑세나타이드 유사체 및 모사체의 개발은 거의 없다.New diabetes treatments using GLP-1 analogues are being actively researched, but in most cases, the focus is on formulation development to improve the sustained effect of the drug, and the development of innovative analogues and mimetics of exenatide with improved efficacy and safety is Few.
한편, 엑세나티이드는 체내 면역반응으로 인한 약물 효능 저하 등의 부작용이 보고되고 있는 실정이다. 따라서, 체내에서 일어나는 당쇄화 과정을 이용한 펩타이드 약물의 개발은 증진된 체내 안정성 및 개선된 면역원성 (immunogenicity)을 나타낼 것으로 기대된다.On the other hand, exenatide has been reported to have side effects such as a decrease in drug efficacy due to an immune response in the body. Therefore, the development of a peptide drug using the glycosylation process occurring in the body is expected to exhibit improved stability in the body and improved immunogenicity.
본 발명에서는 당쇄화 기술을 접목한 엑세나타이드 유사체를 개발하여, 약물의 효능 및 체내 안정성이 증진된 신규 당뇨 치료 후보물질의 개발을 하고자 한다.In the present invention, by developing an exenatide analogue grafted with glycosylation technology, it is intended to develop a novel diabetes treatment candidate with improved drug efficacy and stability in the body.
본 발명의 목적은 당쇄화 엑세나타이드 유사체를 제공하는 것이다.It is an object of the present invention to provide glycosylated exenatide analogs.
본 발명의 다른 목적은 당쇄화 엑세나타이드 유사체를 포함하는 당뇨 개선, 예방 또는 치료용 약제학적 조성물을 제공하는 것이다.Another object of the present invention is to provide a pharmaceutical composition for improving, preventing or treating diabetes containing a glycosylated exenatide analogue.
본 발명의 또 다른 목적은 당쇄화 엑세나타이드 유사체를 포함하는 비만 개선, 예방 또는 치료용 약제학적 조성물을 제공하는 것이다.Another object of the present invention is to provide a pharmaceutical composition for improving, preventing or treating obesity containing a glycosylated exenatide analogue.
본 발명의 또 다른 목적은 당쇄화 엑세나타이드 유사체를 포함하는 당뇨 개선 또는 완화용 식품 조성물을 제공하는 것이다.Another object of the present invention is to provide a food composition for improving or alleviating diabetes comprising a glycosylated exenatide analogue.
본 발명의 또 다른 목적은 당쇄화 엑세나타이드 유사체를 포함하는 비만 개선 또는 완화용 식품 조성물을 제공하는 것이다.Another object of the present invention is to provide a food composition for improving or alleviating obesity containing a glycosylated exenatide analogue.
본 발명의 또 다른 목적은 당쇄화 엑세나타이드 유사체를 포함하는 식욕 억제용 식품 조성물을 제공하는 것이다.Another object of the present invention is to provide a food composition for suppressing appetite comprising a glycosylated exenatide analogue.
본 발명의 또 다른 목적은 당쇄화 엑세나타이드 유사체를 당뇨의 개선, 예방 또는 치료 유효량으로 이를 필요로 하는 대상에 투여하여 당뇨의 개선, 예방 또는 치료하는 방법을 제공하는 것이다.Another object of the present invention is to provide a method for improving, preventing or treating diabetes by administering an effective amount of a glycosylated exenatide analogue to ameliorating, preventing or treating diabetes to a subject in need thereof.
본 발명의 또 다른 목적은 당쇄화 엑세나타이드 유사체를 비만의 개선, 예방 또는 치료 유효량으로 이를 필요로 하는 대상에 투여하여 비만의 개선, 예방 또는 치료하는 방법을 제공하는 것이다.Another object of the present invention is to provide a method for improving, preventing or treating obesity by administering an effective amount of a glycosylated exenatide analogue to ameliorating, preventing or treating obesity to a subject in need thereof.
본 발명의 또 다른 목적은 당쇄화 엑세나타이드 유사체의 당뇨 개선, 예방 또는 치료 용도를 제공하는 것이다.Another object of the present invention is to provide a use of glycosylated exenatide analogues for the improvement, prevention or treatment of diabetes.
본 발명의 또 다른 목적은 당쇄화 엑세나타이드 유사체의 비만 개선, 예방 또는 치료 용도를 제공하는 것이다.Another object of the present invention is to provide a use of glycosylated exenatide analogues for the improvement, prevention or treatment of obesity.
본 발명의 또 다른 목적은 당쇄화 엑세나타이드 유사체의 식욕 억제 용도를 제공하는 것이다.Another object of the present invention is to provide an appetite suppressant use of a glycosylated exenatide analogue.
본 발명은 당쇄화 엑세나타이드 (exenatide) 유사체 및 이의 용도에 관한 것이다. The present invention relates to glycosylated exenatide analogues and uses thereof.
이하 본 발명을 더욱 자세히 설명하고자 한다.Hereinafter, the present invention will be described in more detail.
본 발명의 일 예는 당쇄화 엑세나타이드 유사체에 관한 것이다.One example of the present invention relates to glycosylated exenatide analogues.
본 발명에 있어서 엑세나타이드는 GLP-1 수용체 항진제로, 디펩티딜 펩티데이즈-IV(DPP-IV)에 의해 빠르게 분해되는 GLP-1을 모방한 유사체 (GLP-1 metrics)로서, DPP-IV에 의해 빠르게 분해되지 않으면서 당-의존적 인슐린 분비를 촉진하고 글루카곤 분비, 위 배출 및 식욕을 억제하며, 베타세포 보호효과를 보이는 GLP-1의 효과를 나타내는 약물이다.In the present invention, exenatide is a GLP-1 receptor agonist, an analog mimicking GLP-1 rapidly degraded by dipeptidyl peptidase-IV (DPP-IV) (GLP-1 metrics), It is a drug that promotes glucose-dependent insulin secretion, suppresses glucagon secretion, gastric emptying and appetite, and exhibits the effects of GLP-1, which shows beta cell protection.
본 발명에 있어서 엑세나타이드는 서열번호 1의 아미노산 서열을 포함하는 엑세나타이드 또는 서열번호 1의 아미노산 서열과 서열 상동성 최소 80% 이상, 90% 이상, 95% 이상을 나타내는 엑세나타이드 유사체를 포함한다.In the present invention, exenatide is an exenatide comprising the amino acid sequence of SEQ ID NO: 1 or an exenatide analog showing at least 80% or more, 90% or more, or 95% or more of sequence homology with the amino acid sequence of SEQ ID NO: 1 include
본 발명의 일 예에 있어서, 엑세나타이드는 서열번호 1의 아미노산 서열을 포함하는 것일 수 있으며, 예를 들어, 서열번호 1의 아미노산 서열로 이루어진 것일 수 있다.In one example of the present invention, exenatide may include the amino acid sequence of SEQ ID NO: 1, for example, it may consist of the amino acid sequence of SEQ ID NO: 1.
본 발명에 있어서 엑세나타이드 유사체는 엑세나타이드의 아미노산 서열의 일부 아미노산이 결실되고 지방산이 접합 (conjugation)된 것일 수 있다.In the present invention, the exenatide analogue may be one in which some amino acids in the amino acid sequence of exenatide are deleted and fatty acids are conjugated.
본 발명에 있어서 결실은 엑세나타이드의 아미노산 서열의 1 내지 15개, 1 내지 14개, 1 내지 13개, 1 내지 12개, 1 내지 11개, 1 내지 10, 1 내지 9개, 4 내지 15개, 4 내지 14개, 4 내지 13개, 4 내지 12개, 4 내지 11개, 4 내지 10, 4 내지 9개, 7 내지 15개, 7 내지 14개, 7 내지 13개, 7 내지 12개, 7 내지 11개, 7 내지 10, 예를 들어, 7 내지 9개의 아미노산이 결실된 것일 수 있다.In the present invention, deletions are 1 to 15, 1 to 14, 1 to 13, 1 to 12, 1 to 11, 1 to 10, 1 to 9, 4 to 15 of the amino acid sequence of exenatide. 4 to 14, 4 to 13, 4 to 12, 4 to 11, 4 to 10, 4 to 9, 7 to 15, 7 to 14, 7 to 13, 7 to 12 , 7 to 11, 7 to 10, for example, 7 to 9 amino acids may be deleted.
본 발명에 있어서 결실은 엑세나타이드의 아미노산 서열의 N-말단 또는 C-말단의 아미노산이 결실된 것일 수 있으며, 예를 들어, 엑세나타이드의 아미노산 서열의 C-말단의 아미노산이 결실된 것일 수 있다.In the present invention, the deletion may be the deletion of the N-terminal or C-terminal amino acid of the amino acid sequence of exenatide, for example, the deletion of the C-terminal amino acid of the amino acid sequence of exenatide. there is.
본 발명의 일 구체예에 있어서, 결실은 엑세나타이드의 아미노산 서열의 C-말단의 아미노산이 1 내지 15개, 1 내지 14개, 1 내지 13개, 1 내지 12개, 1 내지 11개, 1 내지 10, 1 내지 9개, 4 내지 15개, 4 내지 14개, 4 내지 13개, 4 내지 12개, 4 내지 11개, 4 내지 10, 4 내지 9개, 7 내지 15개, 7 내지 14개, 7 내지 13개, 7 내지 12개, 7 내지 11개, 7 내지 10, 예를 들어, 7 내지 9개 결실된 것일 수 있다.In one embodiment of the present invention, the deletion is 1 to 15, 1 to 14, 1 to 13, 1 to 12, 1 to 11, 1 C-terminal amino acids in the amino acid sequence of exenatide. to 10, 1 to 9, 4 to 15, 4 to 14, 4 to 13, 4 to 12, 4 to 11, 4 to 10, 4 to 9, 7 to 15, 7 to 14 7 to 13, 7 to 12, 7 to 11, 7 to 10, for example, 7 to 9 may be deleted.
본 발명의 엑세나타이드 유사체에서의 지방산은 아미노산 서열의 일부 아미노산이 결실된 엑세나타이드의 다양한 위치에 접합된 것일 수 있다.Fatty acids in the exenatide analogs of the present invention may be conjugated to various positions of exenatide in which some amino acids in the amino acid sequence are deleted.
본 발명에 있어서 지방산은 당업계에 공지된 다양한 포화 지방산 및 불포화 지방산을 포함한다.In the present invention, fatty acids include various saturated fatty acids and unsaturated fatty acids known in the art.
본 발명에 있어서 지방산은 C3 내지 C36의 탄소수를 갖는 지방산인 것일 수 있으며, 예를 들어, 프로피온산 (propionic acid), 부티르산 (butyric acid), 발레르산 (valeric acid), 카프로산 (caproic acid), 에난트산 (enanthic acid), 카프릴릭산 (caprylic acid), 펠라르곤산 (pelargonic acid), 카프릭산 (capric acid), 언데실산 (undecylic acid), 라우르산 (lauric acid), 트리데실산 (tridecylic acid), 미리스트산 (myristic acid), 펜타데실산 (pentadecylic acid), 팔미트산 (palmitic acid), 마르가르산 (margaric acid), 스테아르산 (stearic acid), 논아데실산 (nonadecylic acid), 아라키트산 (arachidic acid), 헤네이코실산 (heneicosylic acid), 베헨산 (behenic acid), 트리코실(tricosylic acid), 리그노세르산 (lignoceric acid), 펜타코실산 (pentacosylic acid), 세로트산 (cerotic acid), 헵타코실산 (heptacosylic acid), 몬탄산 (montanic acid), 논아코실산 (nonacosylic acid), 멜리스산 (melissic acid), 헤나트리아콘틸산 (henatriacontylic acid), 라세로산 (lacceroic acid), 사일산 (psyllic acid), 게드산 (geddic acid), 세로플라스트산 (ceroplastic acid) 및 헥사트리아콘틸산 (hexatriacontylic acid)로 이루어진 군에서 선택된 1종 이상인 것일 수 있으나, 이에 한정되는 것은 아니다.In the present invention, the fatty acid may be a fatty acid having a carbon number of C 3 to C 36 , for example, propionic acid, butyric acid, valeric acid, caproic acid , enanthic acid, caprylic acid, pelargonic acid, capric acid, undecylic acid, lauric acid, tridecylic acid (tridecylic acid), myristic acid, pentadecylic acid, palmitic acid, margaric acid, stearic acid, nonadecylic acid ), arachidic acid, heneicosylic acid, behenic acid, tricosylic acid, lignoceric acid, pentacosylic acid, cerotic acid, heptacosylic acid, montanic acid, nonacosylic acid, melissic acid, henatriacontylic acid, raceroic acid ( lacceroic acid), psyllic acid, geddic acid, ceroplastic acid, and hexatriacontylic acid, but may be at least one selected from the group consisting of, but is limited thereto It is not.
본 발명의 일 구현예에 있어서, 지방산은 일부 아미노산이 결실된 엑세나타이드의 아미노산 서열의 C-말단의 Lys 잔기, N-말단 또는 C-말단에 접합된 것일 수 있으며, 예를 들어, C-말단에 접합된 것일 수 있다.In one embodiment of the present invention, the fatty acid may be one conjugated to the C-terminal Lys residue, N-terminus or C-terminus of the amino acid sequence of exenatide in which some amino acids are deleted, for example, C- It may be spliced at the end.
본 발명에 있어서 아미노산 서열의 일부 아미노산이 결실된 엑세나타이드 및 지방산의 접합은 직접 결합 및/또는 간접 결합을 모두 포함한다. In the present invention, bonding between exenatide and fatty acids in which some amino acids in the amino acid sequence are deleted includes both direct and/or indirect bonding.
본 발명에 있어서 직접 결합은 지방산에 있는 카복실기와 같은 작용기와 아미노산이 결실된 엑세나타이드의 작용기 (예를 들어, -NH2)가 반응하여 공유결합을 형성함으로써 결실된 엑세나타이드-지방산 접합을 형성할 수 있다. In the present invention, the direct linkage is formed by reacting a functional group (eg, -NH 2 ) of exenatide with a functional group such as a carboxyl group in a fatty acid and an amino acid deleted exenatide to form a covalent bond, thereby forming a deleted exenatide-fatty acid junction. can form
본 발명에 있어서 간접 결합은 당업계에서 링커로 통상적으로 이용되는 화합물이 중개하여 결실된 엑세나타이드-지방산 접합을 형성할 수 있다.In the present invention, indirect coupling can form a deleted exenatide-fatty acid junction mediated by a compound commonly used as a linker in the art.
본 발명에서 이용되는 링커는 당업계에서 링커로 이용되는 어떠한 화합물도 가능하며, 결실된 엑세나타이드에 있는 작용기 종류에 따라 적합한 링커를 선택할 수 있으며, 예를 들어, 링커는 N-숙시니미딜 요오도아세테이드 (N-succinimidyl iodoacetate), N-히드록시숙시니미딜 브로모아세테이트(N-Hydroxysuccinimidyl Bromoacetate), m-말레이미도벤조일-N-히드록시숙신이미드 에스테르 (m-Maleimidobenzoyl-N-hydroxysuccinimide ester), m-말레이미도벤조일-N-히드록시설포숙신이미드 에스테르 (m-Maleimidobenzoyl-N-hydroxysulfosuccinimide ester), N-말레이미도부티릴옥시숙신아미드 에스테르 (N-Maleimidobutyryloxysuccinamide ester) 및 Lys을 포함하나, 이에 한정되는 것은 아니다.The linker used in the present invention can be any compound used as a linker in the art, and a suitable linker can be selected according to the type of functional group in the deleted exenatide. For example, the linker is N-succinimidyl iodine N-succinimidyl iodoacetate, N-hydroxysuccinimidyl bromoacetate, m-maleimidobenzoyl-N-hydroxysuccinimide ester (m-Maleimidobenzoyl-N-hydroxysuccinimide ester), m-Maleimidobenzoyl-N-hydroxysulfosuccinimide ester, N-maleimidobutyryloxysuccinamide ester and Lys. , but is not limited thereto.
구체적으로, 아미노산이 결실된 엑세나타이드는 그의 C-말단에 링커를 추가적으로 결합되며, 상기 지방산은 상기 C-말단에 결합된 링커에 접합되어 있다. 예를 들어, 아미노산이 결실된 엑세나타이드의 C-말단에 링커로서 Lys이 결합되고 이 Lys에 지방산이 접합될 수 있다. 이 경우, 상기 추가적인 Lys의 -NH2 작용기와 지방산의 카복실기가 반응하여 컨쥬게이트를 형성할 수 있다.Specifically, exenatide in which an amino acid is deleted is additionally coupled to a linker at its C-terminus, and the fatty acid is conjugated to the linker coupled to the C-terminus. For example, Lys may be linked as a linker to the C-terminus of an amino acid-deleted exenatide, and a fatty acid may be conjugated to the Lys. In this case, a conjugate may be formed by reacting the -NH 2 functional group of the additional Lys with the carboxyl group of the fatty acid.
본 발명에 있어서 당쇄화 엑세나타이드 유사체는 엑세나타이드 유사체의 적어도 하나 이상의 아미노산에 당류가 결합된 것일 수 있으며, 당류가 결합된 아미노산은 다른 일 아미노산으로 치환된 후 당류가 결합된 것일 수 있다.In the present invention, the glycosylated exenatide analog may be one in which a saccharide is linked to at least one amino acid of the exenatide analog, and the amino acid to which the saccharide is linked may be substituted with another amino acid and then a saccharide is linked.
본 발명의 일 구체예에 있어서, 상기 당류의 결합은 서열번호 1의 아미노산 서열로 이루어진 엑세나타이드의 17, 24 및 28번째 위치로 이루어진 군에서 선택된 1종 이상의 위치에서 이루어진 것일 수 있으나, 이에 한정되는 것은 아니다.In one embodiment of the present invention, the binding of the saccharide may be at one or more positions selected from the group consisting of the 17th, 24th and 28th positions of exenatide consisting of the amino acid sequence of SEQ ID NO: 1, but is limited thereto it is not going to be
본 발명의 일 구체예에 있어서, 상기 치환은 서열번호 1의 아미노산 서열로 이루어진 엑세나타이드의 17번째 아미노산 Glu이 Cys로 치환, 서열번호 1의 아미노산 서열로 이루어진 엑세나타이드의 24번째 아미노산 Glu이 Cys로 치환, 및 서열번호 1의 아미노산 서열로 이루어진 엑세나타이드의 28번째 아미노산 Asn이 Cys로 치환으로 이루어진 군에서 선택된 1종 이상인 것일 수 있으나, 이에 한정되는 것은 아니다.In one embodiment of the present invention, in the substitution, the 17th amino acid Glu of Exenatide consisting of the amino acid sequence of SEQ ID NO: 1 is substituted with Cys, and the 24th amino acid Glu of Exenatide consisting of the amino acid sequence of SEQ ID NO: 1 is Substitution with Cys, and 28th amino acid Asn of exenatide consisting of the amino acid sequence of SEQ ID NO: 1 may be one or more selected from the group consisting of substitution with Cys, but is not limited thereto.
본 발명에 있어서 당류는 1 내지 11당, 2 내지 11당, 3 내지 11당, 4 내지 11당, 5 내지 11당, 6 내지 11당, 7 내지 11당, 8 내지 11당, 9 내지 11당, 10 내지 11당, 예를 들어, 11당인 것일 수 있으며, 구체적으로는 하기 구조식 1의 브로모아세틸 글리칸 (Bromoacetyl glycan) 및/또는 하기 구조식 2의 11NC-Asn-Fmoc인 것일 수 있으나, 이에 한정되는 것은 아니다.In the present invention, sugars are 1 to 11 sugars, 2 to 11 sugars, 3 to 11 sugars, 4 to 11 sugars, 5 to 11 sugars, 6 to 11 sugars, 7 to 11 sugars, 8 to 11 sugars, 9 to 11 sugars . It is not limited.
[구조식 1][Structural Formula 1]
[구조식 2] [Structural Formula 2]
본 명세서에서 용어 "AGM-212"는 서열번호 1로 이루어진 엑세나타이드의 서열의 1번부터 32번까지의 서열로 이루어지며, 상기 서열 C-말단에 카프릭 산 (capric acid)이 측쇄에 결합된 라이신 (lysine)을 접합한 것으로, Ex4(1-32)K-cap의 서열로 명시한다.In the present specification, the term "AGM-212" consists of sequences 1 to 32 of the sequence of exenatide consisting of SEQ ID NO: 1, and capric acid is bound to the side chain at the C-terminus of the sequence. lysine was conjugated, and it is specified as the sequence of Ex4(1-32)K-cap.
본 명세서에서 용어 "AGM-212(E17C-11 sugar)"는 Ex4(1-32)-cap의 서열에서, 17번의 글루탐산 (Glutamic acid, Glu, E)이 Cys로 치환되고, 치환된 아미노산에 11 당의 구조를 갖는 당이 결합된 서열이다. In the present specification, the term "AGM-212 (E17C-11 sugar)" means that in the sequence of Ex4 (1-32)-cap, glutamic acid (Glu, E) at 17 times is substituted with Cys, and the substituted amino acid is 11 It is a sequence in which sugars having a sugar structure are linked.
본 명세서에서 용어 "AGM-212(N28C-11 sugar)"는 Ex4(1-32)-cap의 서열에서, 28번의 아스파라진 (Asparagine, Asn, N)이 Cys로 치환되고, 치환된 아미노산에 11 당의 구조를 갖는 당이 결합된 서열이다.In the present specification, the term "AGM-212 (N28C-11 sugar)" means that in the sequence of Ex4 (1-32)-cap, 28 asparagine, Asn, N) is substituted with Cys, and the substituted amino acid is 11 It is a sequence in which sugars having a sugar structure are linked.
본 명세서에서 용어 "AGM-212(N28-11 sugar)"는 Ex4(1-32)-cap의 서열에서, 28번의 아스파라진에 11 당의 구조를 갖는 당이 결합된 서열이다.In the present specification, the term "AGM-212 (N28-11 sugar)" is a sequence in which a sugar having a structure of 11 sugars is linked to asparagine at position 28 in the sequence of Ex4 (1-32)-cap.
본 명세서에서 용어 "AGM-212(E24-11 sugar)"는 Ex4(1-32)-cap의 서열에서, 24번의 글루탐산이 이 Cys로 치환되고, 치환된 아미노산에 11 당의 구조를 갖는 당이 결합된 서열이다.In the present specification, the term "AGM-212 (E24-11 sugar)" means that in the sequence of Ex4 (1-32)-cap, glutamic acid at position 24 is substituted with this Cys, and a sugar having an 11-sugar structure is bonded to the substituted amino acid. is a sequence
본 명세서에서 용어 "AGM-212(E17C-11 sugar & E24C-11 sugar)"는 Ex4(1-32)-cap의 서열에서, 17번의 글루탐산을 Cys로 치환하고 24번의 글루탐산을 치환하여, 각각의 치환된 아미노산에 11 당의 구조를 갖는 당이 결합된 서열이다.In the present specification, the term "AGM-212 (E17C-11 sugar & E24C-11 sugar)" refers to the substitution of glutamic acid at position 17 with Cys and glutamic acid at position 24 in the sequence of Ex4 (1-32)-cap, respectively. It is a sequence in which a sugar having a structure of 11 sugars is linked to a substituted amino acid.
본 명세서에서 용어 "AGM-212(E17C-11 sugar & N28C-11 sugar)"는 Ex4(1-32)-cap의 서열에서, 17번의 글루탐산을 Cys로 치환하고 28번의 아스파라진을 치환하여, 각각의 치환된 아미노산에 11 당의 구조를 갖는 당이 결합된 서열이다.In the present specification, the term "AGM-212 (E17C-11 sugar & N28C-11 sugar)" refers to the substitution of Cys for glutamic acid at position 17 and asparagine at position 28 in the sequence of Ex4(1-32)-cap, respectively. It is a sequence in which a sugar having a structure of 11 sugars is linked to the substituted amino acid of
본 발명의 다른 일 예는 당쇄화 엑세나타이드 유사체를 포함하는 당뇨 개선, 예방 또는 치료용 약제학적 조성물에 관한 것이다.Another embodiment of the present invention relates to a pharmaceutical composition for improving, preventing or treating diabetes comprising a glycosylated exenatide analogue.
본 발명의 또 다른 일 예는 당쇄화 엑세나타이드 유사체를 포함하는 비만 개선, 예방 또는 치료용 약제학적 조성물에 관한 것이다.Another embodiment of the present invention relates to a pharmaceutical composition for improving, preventing or treating obesity containing a glycosylated exenatide analogue.
본 발명의 약제학적 조성물에 있어서 당쇄화 엑세나타이드 유사체에 관한 기재는 상술한 바와 동일하여, 그 기재를 생략한다. The description of the glycosylated exenatide analogue in the pharmaceutical composition of the present invention is the same as described above, so the description thereof is omitted.
본 발명의 약제학적 조성물은 약제학적으로 허용되는 담체를 포함할 수 있다. The pharmaceutical composition of the present invention may include a pharmaceutically acceptable carrier.
본 발명에 있어서 약제학적으로 허용되는 담체는 제제시에 통상적으로 이용되는 것으로서, 락토스, 덱스트로스, 수크로스, 솔비톨, 만니톨, 전분, 아카시아 고무, 인산 칼슘, 알기네이트, 젤라틴, 규산 칼슘, 미세결정성 셀룰로스, 폴리비닐피롤리돈, 셀룰로스, 물, 시럽, 메틸 셀룰로스, 메틸히드록시벤조에이트, 프로필히드록시벤조에이트, 활석, 스테아르산 마그네슘 및 미네랄 오일 등을 포함하나, 이에 한정되는 것은 아니다. In the present invention, pharmaceutically acceptable carriers are commonly used in formulation, and include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, microcrystals. cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, mineral oil, and the like.
본 발명의 약제학적 조성물은 상기 성분들 이외에 윤활제, 습윤제, 감미제, 향미제, 유화제, 현탁제, 보존제 등을 추가로 포함할 수 있다. 적합한 약제학적으로 허용되는 담체 및 제제는 Remington's Pharmaceutical Sciences (19th ed., 1995)에 상세히 기재되어 있다.The pharmaceutical composition of the present invention may further include a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, and the like in addition to the above components. Suitable pharmaceutically acceptable carriers and agents are described in detail in Remington's Pharmaceutical Sciences (19th ed., 1995).
본 발명의 약제학적 조성물은 경구 또는 비경구로 투여할 수 있고, 비경구 투여인 경우에는 정맥내 주입, 피하 주입, 근육 주입, 복강 주입, 경피 투여 등으로 투여할 수 있다.The pharmaceutical composition of the present invention can be administered orally or parenterally, and in the case of parenteral administration, intravenous injection, subcutaneous injection, intramuscular injection, intraperitoneal injection, transdermal administration, etc. can be administered.
본 발명의 약제학적 조성물의 적합한 투여량은 제제화 방법, 투여 방식, 환자의 연령, 체중, 성, 병적 상태, 음식, 투여 시간, 투여 경로, 배설 속도 및 반응 감응성과 같은 요인들에 의해 다양하며, 보통으로 숙련된 의사는 소망하는 치료 또는 예방에 효과적인 투여량을 용이하게 결정 및 처방할 수 있다. The suitable dosage of the pharmaceutical composition of the present invention varies depending on factors such as formulation method, administration method, patient's age, weight, sex, medical condition, food, administration time, route of administration, excretion rate and reaction sensitivity, A ordinarily skilled physician can readily determine and prescribe dosages effective for the desired treatment or prophylaxis.
본 발명의 바람직한 구현예에 따르면, 본 발명의 약제학적 조성물의 1일 투여량은 0.001-10000 ㎎/㎏이다.According to a preferred embodiment of the present invention, the daily dosage of the pharmaceutical composition of the present invention is 0.001-10000 mg/kg.
본 발명의 약제학적 조성물은 당해 발명이 속하는 기술분야에서 통상의 지식을 가진 자가 용이하게 실시할 수 있는 방법에 따라, 약제학적으로 허용되는 담체 및/또는 부형제를 이용하여 제제화 함으로써 단위 용량 형태로 제조되거나 또는 다용량 용기 내에 내입시켜 제조될 수 있다. 이때 제형은 오일 또는 수성 매질중의 용액, 현탁액 또는 유화액 형태이거나 엑스제, 분말제, 과립제, 정제 또는 캅셀제 형태일 수도 있으며, 분산제 또는 안정화제를 추가적으로 포함할 수 있다.The pharmaceutical composition of the present invention is prepared in unit dosage form by formulation using a pharmaceutically acceptable carrier and/or excipient according to a method that can be easily performed by those skilled in the art. or it may be prepared by incorporating into a multi-dose container. In this case, the formulation may be in the form of a solution, suspension or emulsion in an oil or aqueous medium, or may be in the form of an extract, powder, granule, tablet or capsule, and may additionally contain a dispersing agent or stabilizer.
본 명세서에서 용어 '유효성분으로 포함하는'이란 하기의 엑세타나이드 유사체의 효능 또는 활성을 달성하는 데 충분한 양을 포함하는 것을 의미한다. 본 발명의 조성물에 포함된 양적 상한은 당업자가 적절한 범위 내에서 선택하여 실시할 수 있다.In the present specification, the term 'comprising as an active ingredient' means containing an amount sufficient to achieve the efficacy or activity of the following exetanide analog. The upper limit of the amount included in the composition of the present invention can be selected and implemented by those skilled in the art within an appropriate range.
본 발명의 또 다른 일 예는 당쇄화 엑세나타이드 유사체를 포함하는 당뇨 개선 또는 완화용 식품 조성물에 관한 것이다.Another embodiment of the present invention relates to a food composition for improving or alleviating diabetes comprising a glycosylated exenatide analogue.
본 발명의 또 다른 일 예는 당쇄화 엑세나타이드 유사체를 포함하는 비만 개선 또는 완화용 식품 조성물에 관한 것이다.Another embodiment of the present invention relates to a food composition for improving or alleviating obesity, including a glycosylated exenatide analogue.
본 발명의 또 다른 일 예는 당쇄화 엑세나타이드 유사체를 포함하는 식욕 억제용 식품 조성물에 관한 것이다.Another embodiment of the present invention relates to a food composition for suppressing appetite comprising a glycosylated exenatide analogue.
본 발명의 식품 조성물에 있어서 당쇄화 엑세나타이드 유사체에 관한 기재는 상술한 바와 동일하여, 그 기재를 생략한다. The description of the glycosylated exenatide analog in the food composition of the present invention is the same as described above, so the description thereof is omitted.
본 발명의 조성물이 식품 조성물인 경우에는 분말, 과립, 정제, 캡슐 또는 음료 등의 형태로 제조될 수 있다. 예컨대 캔디류의 각종 식품류, 음료, 껌, 차, 비타민 복합제, 또는 건강보조 식품류 등이 있다.When the composition of the present invention is a food composition, it may be prepared in the form of a powder, granule, tablet, capsule or beverage. For example, there are various foods such as candy, beverages, gum, tea, vitamin complexes, or health supplements.
본 발명의 식품 조성물은 유효성분으로서 아칸토사이드 B 뿐만 아니라, 식품 제조 시에 통상적으로 첨가되는 성분을 포함할 수 있으며, 예를 들어, 단백질, 탄수화물, 지방, 영양소, 조미제 및 향미제를 포함한다. The food composition of the present invention may include not only acantoside B as an active ingredient, but also ingredients commonly added during food preparation, such as proteins, carbohydrates, fats, nutrients, seasonings and flavoring agents. do.
상술한 탄수화물의 예는 모노사카라이드, 예를 들어, 포도당, 과당 등; 디사카라이드, 예를 들어 말토스, 슈크로스, 올리고당 등; 및 폴리사카라이드, 예를 들어 덱스트린, 사이클로덱스트린 등과 같은 통상적인 당 및 자일리톨, 소르비톨, 에리트리톨 등의 당알콜이다. 향미제로서 천연 향미제 [타우마틴, 스테비아 추출물 (예를 들어 레바우디오시드 A, 글리시르히진 등]) 및 합성 향미제(사카린, 아스파르탐 등)를 사용할 수 있다. 예컨대, 본 발명의 식품 조성물이 드링크제로 제조되는 경우에는 본 발명의 아칸토사이드 B 화합물 이외에 구연산, 액상과당, 설탕, 포도당, 초산, 사과산, 과즙, 두충 추출액, 대추 추출액, 감초 추출액 등을 추가로 포함시킬 수 있다.Examples of the aforementioned carbohydrates include monosaccharides such as glucose, fructose, and the like; disaccharides such as maltose, sucrose, oligosaccharides and the like; and polysaccharides such as conventional sugars such as dextrins and cyclodextrins and sugar alcohols such as xylitol, sorbitol and erythritol. As flavoring agents, natural flavoring agents [thaumatin, stevia extract (eg, rebaudioside A, glycyrrhizin, etc.]) and synthetic flavoring agents (saccharin, aspartame, etc.) can be used. For example, when the food composition of the present invention is prepared as a drink, in addition to the acantoside B compound of the present invention, citric acid, high fructose corn syrup, sugar, glucose, acetic acid, malic acid, fruit juice, euworm extract, jujube extract, licorice extract, etc. can include
본 발명의 또 다른 목적은 엑세나타이드 유사체를 당뇨의 개선, 예방 또는 치료 유효량으로 이를 필요로 하는 대상에 투여하여 당뇨의 개선, 예방 또는 치료하는 방법을 제공하는 것이다.Another object of the present invention is to provide a method for improving, preventing or treating diabetes by administering an exenatide analogue in an effective amount to ameliorating, preventing or treating diabetes to a subject in need thereof.
본 발명의 또 다른 목적은 엑세나타이드 유사체를 비만의 개선, 예방 또는 치료 유효량으로 이를 필요로 하는 대상에 투여하여 비만의 개선, 예방 또는 치료하는 방법을 제공하는 것이다.Another object of the present invention is to provide a method for improving, preventing or treating obesity by administering an exenatide analog in an effective amount to ameliorating, preventing or treating obesity to a subject in need thereof.
본 발명의 또 다른 목적은 엑세나타이드 유사체의 당뇨 개선, 예방 또는 치료 용도를 제공하는 것이다.Another object of the present invention is to provide a use of exenatide analogues for improving, preventing or treating diabetes.
본 발명의 또 다른 목적은 엑세나타이드 유사체의 비만 개선, 예방 또는 치료 용도를 제공하는 것이다.Another object of the present invention is to provide a use of exenatide analogues for the improvement, prevention or treatment of obesity.
본 발명의 또 다른 목적은 엑세나타이드 유사체의 식욕 억제 용도를 제공하는 것이다.Another object of the present invention is to provide an appetite suppressant use of exenatide analogues.
본 명세서에서 용어 "당뇨"는 포도당-비관용 (intolerance)을 초래하는 인슐린의 상대적 또는 절대적 부족으로 특징되는 만성질환을 의미한다. 용어 당뇨는 모든 종류의 당뇨병을 포함하며, 예를 들어, 제1형 당뇨, 제2형 당뇨 및 유전성 당뇨를 포함한다. 제1형 당뇨는 인슐린 의존성 당뇨병으로서, β-세포의 파괴에 의해 주로 초래된다. 제2형 당뇨는 인슐린 비의존성 당뇨병으로서, 식사 후 불충분한 인슐린 분비에 의해 초래되거나 또는 인슐린 내성에 의해 초래된다.As used herein, the term "diabetes" refers to a chronic disease characterized by a relative or absolute lack of insulin leading to glucose- intolerance. The term diabetes includes all types of diabetes, including, for example, type 1 diabetes, type 2 diabetes and hereditary diabetes. Type 1 diabetes is insulin-dependent diabetes, which is mainly caused by the destruction of β-cells. Type 2 diabetes is non-insulin dependent diabetes, caused either by insufficient secretion of insulin after a meal or by insulin resistance.
본 명세서에서 용어 "비만"은 건강에 이상을 초래할 정도로 지방 조직이 체내에 과잉으로 축적된 상태를 의미한다.As used herein, the term "obesity" refers to a state in which fat tissue is excessively accumulated in the body to the extent of causing health problems.
본 명세서에서 용어 "식욕 억제"는 음식을 섭취하고자 하는 욕구가 억제되는 것을 의미한다.As used herein, the term "appetite suppression" means that the desire to eat food is suppressed.
본 발명은 특정 잔기에 당쇄화된 엑세나타이드 유사체 및 이의 용도에 관한것으로, 본 발명은 종래의 엑세나타이드 및 이의 유사체에 비해 향상된 체내 안정성을 보이는 신규 당뇨 치료 물질을 제공한다.The present invention relates to an analog of exenatide glycosylated at a specific residue and a use thereof, and the present invention provides a novel substance for treating diabetes that exhibits improved stability in the body compared to conventional exenatide and analogs thereof.
도 1은 본 발명의 일 실시예에 따른 당쇄화 AGM-212 유사체(실시예 1,2 및 4)의 인슐린 분비능을 rat islets에서 rat insulin ELISA를 통해 분석한 결과이다.
도 2는 본 발명의 일 실시예에 따른 당쇄화 AGM-212 유사체(실시예 5 및 6)의 인슐린 분비능을 rat islets에서 rat insulin ELISA를 통해 분석한 결과이다.
도 3은 본 발명의 일 실시예에 따른 당쇄화 AGM-212 유사체를 피하 투여하여 2형 당뇨 질병 마우스 동물 모델에서의 당부하 정도를 혈당측정기를 통해 분석한 결과이다.
도 4는 본 발명의 일 실시예에 따른 당쇄화 AGM-212 유사체를 피하 투여하여 야생형 마우스 동물 모델에서의 약동력학 평가 시험을 분석한 결과이다.
도 5는 본 발명의 일 실시예에 따른 당쇄화 AGM-212 유사체의 면역원성 시험 결과이다.1 is a result of analyzing the insulin secretion ability of glycosylated AGM-212 analogs (Examples 1, 2 and 4) according to an embodiment of the present invention in rat islets through rat insulin ELISA.
2 is a result of analyzing the insulin secretion ability of glycosylated AGM-212 analogs (Examples 5 and 6) according to an embodiment of the present invention in rat islets through rat insulin ELISA.
3 is a result of analyzing the level of glucose load in a mouse animal model of type 2 diabetes by subcutaneously administering a glycosylated AGM-212 analog according to an embodiment of the present invention through a blood glucose meter.
4 is a result of an analysis of a pharmacokinetic evaluation test in a wild-type mouse animal model by subcutaneously administering a glycosylated AGM-212 analogue according to an embodiment of the present invention.
5 is an immunogenicity test result of glycosylated AGM-212 analogs according to an embodiment of the present invention.
이하, 본 발명을 하기의 실시예에 의하여 더욱 상세히 설명한다. 그러나 이들 실시예는 본 발명을 예시하기 위한 것일 뿐이며, 본 발명의 범위가 이들 실시예에 의하여 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail by the following examples. However, these examples are only for illustrating the present invention, and the scope of the present invention is not limited by these examples.
실시예 1. AGM-212(E17C-11 sugar)의 제조Example 1. Preparation of AGM-212 (E17C-11 sugar)
1-1. 화학식 11-1. Formula 1
AGM-212의 구성 서열인 Ex4(1-32)K-cap을 제조하기 위해, 트리틸 레진(trityl resin)에 Fmoc-Lys(dde)-OH 및 DMF를 첨가하여 Fmoc-Lys(dde) 트리틸 레진을 제조하였다. Fmoc-Lys(dde) 트리틸 레진에 20% 피페리딘(piperidine)이 포함된 DMF 및 Fmoc-Ser(tBu)-OH 및 HOBt(hydroxyl-benzo triazole)를 첨가하여 Fmoc-Ser(tBu)-Lys(dde) 트리틸 레진을 제조하였다. Fmoc-Ser(tBu)-Lys(dde) 트리틸 레진에 상기 제작 방법을 동일하게 하여 순차적으로 Fmoc-Pro-OH, Fmoc-Gly-OH, Fmoc-Gly-OH, Fmoc-Asn(trt)-OH, Fmoc-Lys(boc)-OH, Fmoc-Leu-OH, Fmoc-Trp(Boc)-OH, Fmoc-Glu(tBu)-OH, Fmoc-Ile-OH, Fmoc-Phe-OH, Fmoc-Leu-OH, Fmoc-Arg(pbf)-OH, Fmoc-Val-OH, Fmoc-Ala-OH, Fmoc-Glu(tBu)-OH, Fmoc-Glu(tBu)-OH, Fmoc-Glu(tBu)-OH, Fmoc-Met-OH, Fmoc-Gln(trt)-OH, Fmoc-Lys(boc)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Le)-OH, Fmoc-Asp(tBu)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Phe-OH, Fmoc-Thr(tBu)-OH, Fmoc-Gly-OH, Fmoc-GlutBu()-OH, Fmoc-Gly-OH, Fmoc-His(trt)-OH을 첨가하여 아래의 화학식 1을 제조하였다.To prepare Ex4(1-32)K-cap, a constituent sequence of AGM-212, Fmoc-Lys(dde)-OH and DMF were added to trityl resin to obtain Fmoc-Lys(dde) trityl. Resin was prepared. Fmoc-Lys(dde) Trityl resin was added with DMF containing 20% piperidine and Fmoc-Ser(tBu)-OH and HOBt(hydroxyl-benzo triazole) to Fmoc-Ser(tBu)-Lys (dde) Trityl resin was prepared. Fmoc-Pro-OH, Fmoc-Gly-OH, Fmoc-Gly-OH, Fmoc-Asn(trt)-OH in the same manner as above for Fmoc-Ser(tBu)-Lys(dde) trityl resin , Fmoc-Lys(boc)-OH, Fmoc-Leu-OH, Fmoc-Trp(Boc)-OH, Fmoc-Glu(tBu)-OH, Fmoc-Ile-OH, Fmoc-Phe-OH, Fmoc-Leu- OH, Fmoc-Arg(pbf)-OH, Fmoc-Val-OH, Fmoc-Ala-OH, Fmoc-Glu(tBu)-OH, Fmoc-Glu(tBu)-OH, Fmoc-Glu(tBu)-OH, Fmoc-Met-OH, Fmoc-Gln(trt)-OH, Fmoc-Lys(boc)-OH, Fmoc-Ser(tBu)-OH, Fmoc-Le)-OH, Fmoc-Asp(tBu)-OH, Fmoc -Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Phe-OH, Fmoc-Thr(tBu)-OH, Fmoc-Gly-OH, Fmoc-GlutBu()-OH, Fmoc-Gly- Formula 1 below was prepared by adding OH and Fmoc-His(trt)-OH.
[화학식 1][Formula 1]
Fmoc-His(trt)-Gly-Glu(tBu)-Gly-Thr(tBu)-Phe-Thr(tBu)-Ser(tBu)-Asp(tBu)-Leu-Ser(tBu)-Lyc(Boc)-Gln(trt)-Met-Glu(tBu)-Glu(tBu)-Cys(tBu)-Ala-Val-Arg(pbf)-Leu-Phe-Ile-Glu(tBu)-Trp(Boc)-Leu-Lys(Boc)-Asn(trt)-Gly-Gly-Pro-Ser(tBu)-Lys(dde)-트리틸 레진Fmoc-His(trt)-Gly-Glu(tBu)-Gly-Thr(tBu)-Phe-Thr(tBu)-Ser(tBu)-Asp(tBu)-Leu-Ser(tBu)-Lyc(Boc)- Gln(trt)-Met-Glu(tBu)-Glu(tBu)-Cys(tBu)-Ala-Val-Arg(pbf)-Leu-Phe-Ile-Glu(tBu)-Trp(Boc)-Leu-Lys (Boc)-Asn(trt)-Gly-Gly-Pro-Ser(tBu)-Lys(dde)-trityl resin
1-2. 화학식 21-2. Formula 2
화학식 1에 2% NH2NH2*?*H2O를 포함하는 DMF를 첨가하고 dde를 제거하여 화학식 2을 제조하였다.Formula 2 was prepared by adding DMF containing 2% NH 2 NH 2 ***H 2 O to Formula 1 and removing dde.
[화학식 2][Formula 2]
Fmoc-His(trt)-Gly-Glu(tBu)-Gly-Thr(tBu)-Phe-Thr(tBu)-Ser(tBu)-Asp(tBu)-Leu-Ser(tBu)-Lyc(Boc)-Gln(trt)-Met-Glu(tBu)-Glu(tBu)-Cys(trt)-Ala-Val-Arg(pbf)-Leu-Phe-Ile-Glu(tBu)-Trp(Boc)-Leu-Lys(Boc)-Asn(trt)-Gly-Gly-Pro-Ser(tBu)-Lys-트리틸 레진Fmoc-His(trt)-Gly-Glu(tBu)-Gly-Thr(tBu)-Phe-Thr(tBu)-Ser(tBu)-Asp(tBu)-Leu-Ser(tBu)-Lyc(Boc)- Gln(trt)-Met-Glu(tBu)-Glu(tBu)-Cys(trt)-Ala-Val-Arg(pbf)-Leu-Phe-Ile-Glu(tBu)-Trp(Boc)-Leu-Lys (Boc)-Asn(trt)-Gly-Gly-Pro-Ser(tBu)-Lys-trityl resin
1-3. 화학식 31-3. Formula 3
화학식 2에 카프릭산, 및 HOBt 및 DIC를 포함하는 DMF를 첨가하여 화학식 3을 제조하였다.Formula 3 was prepared by adding capric acid and DMF containing HOBt and DIC to Formula 2.
[화학식 3][Formula 3]
Fmoc-His(trt)-Gly-Glu(tBu)-Gly-Thr(tBu)-Phe-Thr(tBu)-Ser(tBu)-Asp(tBu)-Leu-Ser(tBu)-Lyc(Boc)-Gln(trt)-Met-Glu(tBu)-Glu(tBu)-Cys(trt)-Ala-Val-Arg(pbf)-Leu-Phe-Ile-Glu(tBu)-Trp(Boc)-Leu-Lys(Boc)-Asn(trt)-Gly-Gly-Pro-Ser(tBu)-Lys(capric acid)-트리틸 레진Fmoc-His(trt)-Gly-Glu(tBu)-Gly-Thr(tBu)-Phe-Thr(tBu)-Ser(tBu)-Asp(tBu)-Leu-Ser(tBu)-Lyc(Boc)- Gln(trt)-Met-Glu(tBu)-Glu(tBu)-Cys(trt)-Ala-Val-Arg(pbf)-Leu-Phe-Ile-Glu(tBu)-Trp(Boc)-Leu-Lys (Boc)-Asn(trt)-Gly-Gly-Pro-Ser(tBu)-Lys(capric acid)-trityl resin
1-4. 화학식 41-4. formula 4
화학식 3의 보호기를 절단 한 후, 정제하여 화학식 4를 제조하였다.After cleavage of the protecting group of Chemical Formula 3 and purification, Chemical Formula 4 was prepared.
[화학식 4][Formula 4]
His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lyc-Gln-Met-Glu-Glu-Cys-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Lys(capric acid)-OHHis-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lyc-Gln-Met-Glu-Glu-Cys-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp- Leu-Lys-Asn-Gly-Gly-Pro-Ser-Lys(capric acid)-OH
1-5. 화학식 51-5.
화학식 4에 11 당의 구조를 이루는 Bromoacetyl glycan (11 suar) 및 NaOH, 인산 완충액 (Phosphate buffer)을 첨가하여, 화학식 5을 제조하였다.
[화학식 5][Formula 5]
His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lyc-Gln-Met-Glu-Glu-Cys(11 sugar)-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Lys(capric acid)-OHHis-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lyc-Gln-Met-Glu-Glu-Cys(11 sugar)-Ala-Val-Arg-Leu-Phe-Ile- Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Lys(capric acid)-OH
실시예 2. AGM-212(N28C-11 sugar)의 제조Example 2. Preparation of AGM-212 (N28C-11 sugar)
실시예 1의 제조 과정에서 28번째 아미노산인 Fmoc-Asn(tBu)-OH를 Fmoc-Cys(trt)-OH로 대체하여 동일한 방법으로 화학식 6을 제조하였다.
[화학식 6][Formula 6]
His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lyc-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Cys(11 sugar)-Gly-Gly-Pro-Ser-Lys(capric acid)-OHHis-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lyc-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp- Leu-Lys-Cys(11 sugar)-Gly-Gly-Pro-Ser-Lys(capric acid)-OH
실시예 3. AGM-212(N28-11 sugar)의 제조Example 3. Preparation of AGM-212 (N28-11 sugar)
실시예 1의 제조 과정에서 28번째 아미노산인 Fmoc-Asn(tBu)-OH를 도면 2의 11NC-Asn-Fmoc으로 대체하여 동일한 방법으로 화학식 7을 제조하였다.Formula 7 was prepared in the same manner as in Example 1 by replacing the 28th amino acid, Fmoc-Asn(tBu)-OH, with 11NC-Asn-Fmoc in FIG. 2.
[화학식 7][Formula 7]
His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lyc-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn(11 sugar)-Gly-Gly-Pro-Ser-Lys(capric acid)-OHHis-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lyc-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp- Leu-Lys-Asn(11 sugar)-Gly-Gly-Pro-Ser-Lys(capric acid)-OH
실시예 4. AGM-212(E24C-11 sugar)의 제조Example 4. Preparation of AGM-212 (E24C-11 sugar)
실시예 1의 제조 과정에서 24번째 아미노산인 Fmoc-Glu(tBu)-OH를 Fmoc-Cys(trt)-OH로 대체하여 동일한 방법으로 화학식 8을 제조하였다.
[화학식 8][Formula 8]
His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lyc-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Cys(11 sugar)-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Lys(capric acid)-OHHis-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lyc-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Cys (11 sugar )-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Lys(capric acid)-OH
실시예 5. AGM-212(E17C-11 sugar & E24C-11 sugar)의 제조Example 5. Preparation of AGM-212 (E17C-11 sugar & E24C-11 sugar)
5-1. 화학식 95-1. Formula 9
실시예 1의 제조 과정에서 24번째 아미노산인 Fmoc-Glu(tBu)-OH를 Fmoc-Cys(trt)-OH로 대체하여 화학식 9을 제조하였다.In the preparation process of Example 1, Formula 9 was prepared by replacing the 24th amino acid, Fmoc-Glu(tBu)-OH, with Fmoc-Cys(trt)-OH.
[화학식 9][Formula 9]
His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lyc-Gln-Met-Glu-Glu-Cys-Ala-Val-Arg-Leu-Phe-Ile-Cys-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Lys(capric acid)-OHHis-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lyc-Gln-Met-Glu-Glu-Cys-Ala-Val-Arg-Leu-Phe-Ile-Cys-Trp- Leu-Lys-Asn-Gly-Gly-Pro-Ser-Lys(capric acid)-OH
5-2. 화학식 115-2.
화학식 9에 11 당의 구조를 이루는 Bromoacetyl glycan (11 suar) 및 NaOH, 인산 완충액을 첨가하여, 화학식 10을 제조하였다.
[화학식 10][Formula 10]
His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lyc-Gln-Met-Glu-Glu-Cys(11 sugar)-Ala-Val-Arg-Leu-Phe-Ile-Cys(11 sugar)-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Lys(capric acid)-OHHis-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lyc-Gln-Met-Glu-Glu-Cys(11 sugar)-Ala-Val-Arg-Leu-Phe-Ile- Cys(11 sugar)-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Lys(capric acid)-OH
실시예 6. AGM-212(E17C-11 sugar & N28C-11 sugar)의 제조Example 6. Preparation of AGM-212 (E17C-11 sugar & N28C-11 sugar)
6-1. 화학식 116-1.
실시예 1의 제조 과정에서 28번째 아미노산인 Fmoc-Asn(tBu)-OH를 Fmoc-Cys(trt)-OH로 대체하여 화학식 11을 제조하였다.In the preparation process of Example 1,
[화학식 11][Formula 11]
His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lyc-Gln-Met-Glu-Glu-Cys-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Cys-Gly-Gly-Pro-Ser-Lys(capric acid)-OHHis-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lyc-Gln-Met-Glu-Glu-Cys-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp- Leu-Lys-Cys-Gly-Gly-Pro-Ser-Lys(capric acid)-OH
6-2. 화학식 126-2. Formula 12
화학식 11에 11 당의 구조를 이루는 Bromoacetyl glycan (11 suar) 및 NaOH, 인산 완충액을 첨가하여, 화학식 12을 제조하였다.Formula 12 was prepared by adding Bromoacetyl glycan (11 suar), NaOH, and phosphate buffer having an 11 sugar structure to
[화학식 12][Formula 12]
His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lyc-Gln-Met-Glu-Glu-Cys(11 sugar)-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Cys(11 sugar)-Gly-Gly-Pro-Ser-Lys(capric acid)-OHHis-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lyc-Gln-Met-Glu-Glu-Cys(11 sugar)-Ala-Val-Arg-Leu-Phe-Ile- Glu-Trp-Leu-Lys-Cys(11 sugar)-Gly-Gly-Pro-Ser-Lys(capric acid)-OH
실험예 1. 유사체의 GLP-1 수용체 결합력 확인Experimental Example 1. Confirmation of GLP-1 receptor binding ability of analogues
실시예 1 내지 실시예 6에서 제조한 유사체의 GLP-1 수용체에 대한 결합력을 알아보기 위해, luciferase assay system을 사용하였다. Luciferase assay system은 세포의 특정 수용체에 대한 리간드의 결합력을 측정하여 수용체의 활성 정도를 확인할 수 있는 방법이다. In order to examine the binding ability of the analogs prepared in Examples 1 to 6 to the GLP-1 receptor, a luciferase assay system was used. Luciferase assay system is a method that can check the activity level of a receptor by measuring the binding force of a ligand to a specific receptor in a cell.
구체적으로, 섬유아세포주인 CV-1 (1 x 104 cells/ml, 한국세포주은행)을 96well white cell culture plate에 24시간 배양 후, human GLP-1R(pcDNA3.1_hGLP-1R), cAMP response element (CRE, pcDNA3.1_hCRE)를 첨가하여 형질전환(transfection)하였다. 24시간 배양 후, serum이 없는 배지로 교체하여, 16시간 배양 후, 각 유사체를 6시간 동안 처리하였다. 활성화된 GLP-1R에 의해 reporter gene인 luciferase의 발현 정도를 luminometer를 이용하여 정량하여, 그 결과를 표 2에 나타내었다.Specifically, after culturing the fibroblast cell line CV-1 (1 x 10 4 cells/ml, Korea Cell Line Bank) for 24 hours in a 96-well white cell culture plate, human GLP-1R (pcDNA3.1_hGLP-1R), cAMP response element ( CRE, pcDNA3.1_hCRE) was added to transform (transfection). After 24 hours of culture, the medium was replaced with serum-free medium, and after 16 hours of culture, each analogue was treated for 6 hours. The expression level of the reporter gene luciferase by activated GLP-1R was quantified using a luminometer, and the results are shown in Table 2.
표 2에서 확인할 수 있듯이, AGM-212는 Ex4와 동등한 GLP-1R에 대한 활성을 보이며, 11 sugar가 결합된 AGM-212 유사체들은 Ex4 또는 AGM-212보다 다소 감소된 활성을 발견하였다. 당쇄화로 인해 각 유사체들의 활성이 감소되지만 여전히 nM 수준의 결합력을 가짐을 알 수 있었다.As can be seen in Table 2, AGM-212 showed activity against GLP-1R equal to that of Ex4, and AGM-212 analogues with 11 sugars showed slightly reduced activity than Ex4 or AGM-212. Although the activity of each analog was reduced due to glycosylation, it was found that they still had nM-level binding ability.
실험예 2. 유사체의 인슐린 분비능 확인Experimental Example 2. Confirmation of insulin secretion ability of analogues
실시예 1 내지 실시예 6에서 제조한 유사체의 인슐린 분비능을 확인하기 위해, rat islets에 대한 유사체의 당 의존성 인슐린 분비능을 확인하였다. In order to confirm the insulin secretion ability of the analogs prepared in Examples 1 to 6, the glucose-dependent insulin secretion ability of the analogs for rat islets was confirmed.
구체적으로, SD rat (다물사이언스) 8주령의 pancreas를 추출하여, islets을 분리하였다. 분리된 islets을 28 mM glucose에서의 각 유사체를 농도별(10 nM, 100 nM)로 처리 한 후, rat insulin ELISA kit를 이용해 분비된 인슐린 양을 측정하여, 그 결과를 도 1 내지 도 2 및 표 3 내지 표 4에 나타내었다.Specifically, 8-week-old pancreas from SD rats (Damul Science) were extracted and islets were isolated. The isolated islets were treated with each analogue in 28 mM glucose at different concentrations (10 nM, 100 nM), and then the amount of secreted insulin was measured using a rat insulin ELISA kit, and the results are shown in Figs. 1 to 2 and Tables. Tables 3 to 4 show.
도 1 내지 도 2 및 표 3 내지 표 4에서 확인할 수 있듯이, 11 sugar가 결합된 유사체 모두 농도 의존적으로 인슐린 분비를 증진시키며, 또한 Ex4 및 AGM-212보다 증진된 인슐린 분비능을 확인하였다.As can be seen in Figures 1 to 2 and Tables 3 to 4, all of the 11 sugar-conjugated analogs enhanced insulin secretion in a concentration-dependent manner, and also confirmed improved insulin secretion compared to Ex4 and AGM-212.
실험예 3. 유사체의 당부하 효과 확인Experimental Example 3. Confirmation of the glucose load effect of analogues
실시예 1 내지 실시예 4에서 제조한 유사체의 당 부하 효과를 확인하기 위해, 2형 당뇨 질병 마우스 모델인 C57BKS/J dbdb mice (5-7주령, 중앙실험동물)를 16시간 절식 후, 각 유사체들을 10 nmole/kg으로 피하투여하고, 30분 후, 포도당(1.5 g/kg)을 복강으로 투여하였다. 120분 동안, 0, 15, 30, 45, 60, 90, 120분에서의 마우스 꼬리 미정맥에서 추출한 혈액을 이용하여 혈당측정기(acu-check, Roche, Germany)로 혈당을 측정하여, 그 결과를 도 3a 내지 도 3b에 나타내었다. In order to confirm the glucose loading effect of the analogues prepared in Examples 1 to 4, C57BKS/J dbdb mice (5-7 weeks old, central experimental animals), a mouse model for type 2 diabetes, were fasted for 16 hours, and each analogue were subcutaneously administered at 10 nmole/kg, and 30 minutes later, glucose (1.5 g/kg) was intraperitoneally administered. For 120 minutes, blood glucose was measured with a blood glucose meter (acu-check, Roche, Germany) using blood extracted from the tail vein of the mouse at 0, 15, 30, 45, 60, 90, and 120 minutes, and the results were It is shown in Figures 3a to 3b.
도 3a 내지 도 3b에서 확인할 수 있듯이, 모든 AGM-212 유사체가 Ex4 및 AGM-212 동등한 당부하 효능을 보였다. 이 결과는, 당쇄화된 AGM-212 유사체들이 Ex4의 생물학적인 활성을 가지고 있음을 의미한다. As can be seen in Figures 3a to 3b, all AGM-212 analogs showed equivalent glucose-loading efficacy to Ex4 and AGM-212. This result means that the glycosylated AGM-212 analogs have the biological activity of Ex4.
실험예 4. 유사체의 약동력학 시험Experimental Example 4. Pharmacokinetic test of analogues
실시예 2 내지 실시예 3에서 제조한 유사체의 약동력학(pharmacokinetics) 시험을 실시하였다. 야생형 C57BL/6J mice(male, 5-6주령, n=5)을 이용, 각 유사체들을 50 nmole/kg으로 피하 투여 후, 각 0, 0.5, 1, 2, 4, 8, 10, 12, 14, 24시간에 혈액을 추출하였다. 추출한 혈액의 혈장을 분리하여 Exendin-4 EIA를 이용하여 정량 분석을 진행하였다. 결과 분석은 winnolin 프로그램을 이용하여 Pharmacokinetics parameter를 결정하여, 그 결과를 도 4 및 표 5에 나타내었다. The pharmacokinetics of the analogs prepared in Examples 2 to 3 were tested. Using wild-type C57BL/6J mice (male, 5-6 weeks old, n=5), each analog was subcutaneously administered at 50 nmole/kg, and then 0, 0.5, 1, 2, 4, 8, 10, 12, 14 , blood was extracted at 24 h. Plasma was separated from the extracted blood and quantitative analysis was performed using Exendin-4 EIA. For the analysis of the results, Pharmacokinetics parameters were determined using the winnolin program, and the results are shown in FIG. 4 and Table 5.
도 4 및 표 5에서 확인할 수 있듯이, AGM-212(N28-11 sugar)가 AGM-212와 유사한 반감기를 나타내었으며, AGM-212(N28C-11 sugar)의 경우, Ex4보다는 증진된 반감기가 관찰되었으나, AGM-212(N28-11 sugar)보다는 다소 감소된 수준을 보임을 확인하였다. 이 결과는 당쇄화가 되었을 때, 체내 반감기에는 영향을 주지 않는 것으로 보임을 알 수 있다.As can be seen in Figure 4 and Table 5, AGM-212 (N28-11 sugar) showed a half-life similar to that of AGM-212, and in the case of AGM-212 (N28C-11 sugar), an improved half-life was observed than Ex4, but , it was confirmed that the level was somewhat lower than that of AGM-212 (N28-11 sugar). It can be seen from this result that when glycosylated, the half-life in the body does not appear to be affected.
실험예 5. 유사체의 면역원성 시험Experimental Example 5. Immunogenicity test of analogues
당쇄화 AGM-212 유사체에 대한 면역원성 시험을 하기 위해, 야생형 C57BL/6J mice(male, 6주령, 을 이용, 각 Ex4와 AGM-212(N28C-11 sugar)를 1 mg/kg으로 Freund's complete adjuvant(sigma)를 첨가하여 일주일에 한번씩 총 세 번을 피하 투여하였다. 혈액을 추출하여, antidrug antibody assay kit를 이용하여 생성된 항체를 정량 분석하여, 그 결과를 도 5에 나타내었다. In order to test the immunogenicity of glycosylated AGM-212 analogues, wild-type C57BL/6J mice (male, 6 weeks old) were administered with Freund's complete adjuvant of Ex4 and AGM-212 (N28C-11 sugar) at 1 mg/kg each. (sigma) was added and administered subcutaneously three times a week, blood was extracted, and the antibody produced was quantitatively analyzed using an antidrug antibody assay kit, and the results are shown in FIG.
도 5에서 확인할 수 있듯이, Ex4를 투여한 군에서는 Ex4에 대한 lgG의 항체가 약 10 pg/ml이 형성된 반면에, 당쇄화 AGM-212 유사체를 투여한 군에서는 형성된 항체가 검출되지 않음을 확인하였다. 이 결과는 당쇄화 AGM-212 유사체가 당쇄화로 인해 이의 면역원성이 개선되었음을 의미한다.As can be seen in FIG. 5, in the group administered with Ex4, about 10 pg/ml of IgG antibody to Ex4 was formed, whereas in the group administered with glycosylated AGM-212 analog, it was confirmed that no antibody was detected. . This result means that the immunogenicity of glycosylated AGM-212 analogues was improved due to glycosylation.
실험예 6. 유사체의 용해도 시험Experimental Example 6. Solubility test of analogues
당쇄화된 유사체는 당의 결합으로 증진된 용해도(solubility)를 가질 수 있기 때문에, 당쇄화 AGM-212 유사체에 대한 용해도 시험을 수행하였다. AGM-212(N28C-11 sugar) 및 AGM-212(E17C-11 sugar & N28C-11 sugar)를 각각 10 mg/ml로 H2O 및 PBS(phosphate buffered saline)에서의 용해도를 HPLC를 이용하여 진행하여, 그 결과를 표 6에 나타내었다. Since the glycosylated analogues can have enhanced solubility by linking sugars, a solubility test was performed on the glycosylated AGM-212 analogues. Solubility of AGM-212 (N28C-11 sugar) and AGM-212 (E17C-11 sugar & N28C-11 sugar) at 10 mg/ml, respectively, in H 2 O and PBS (phosphate buffered saline) was conducted using HPLC. So, the results are shown in Table 6.
표 6에서 확인할 수 있듯이, Ex4는 모든 용매에서 10 mg/ml의 용해도를 갖는데, AGM-212의 경우, H2O에서는 다소 감소된 용해도를 갖음을 알 수 있었고, PBS에서는 Ex4 대비 약 0.5배 이상의 용해도를 나타내었다. 당쇄화 유사체의 경우, 모든 용매에서 AGM-212보다는 증진된 용해도를 보이며, 11 sugar가 하나 및 두개로 결합된 유사체의 용해도를 비교할 때, 결합된 당의 수의 증가로 인해, 보다 증진된 용해도를 가짐을 발견하였다.As can be seen in Table 6, Ex4 has a solubility of 10 mg/ml in all solvents. In the case of AGM-212, it was found that the solubility was slightly reduced in H 2 O, and about 0.5 times higher than Ex4 in PBS. Solubility was indicated. In the case of glycosylated analogues, they show improved solubility compared to AGM-212 in all solvents, and when comparing the solubility of analogues with one and two 11 sugars, they have more enhanced solubility due to the increase in the number of linked sugars. found
<110> ANYGEN CO., LTD
<120> Glycosylated exenatide analogs and uses thereof
<130> PN190190P1
<150> KR 10-2019-0098911
<151> 2019-08-13
<160> 1
<170> KoPatentIn 3.0
<210> 1
<211> 39
<212> PRT
<213> Artificial Sequence
<220>
<223> Exenatide
<400> 1
His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu
1 5 10 15
Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly Gly Pro Ser
20 25 30
Ser Gly Ala Pro Pro Pro Ser
35
<110> ANYGEN CO., LTD
<120> Glycosylated exenatide analogs and uses thereof
<130> PN190190P1
<150> KR 10-2019-0098911
<151> 2019-08-13
<160> 1
<170> KoPatentIn 3.0
<210> 1
<211> 39
<212> PRT
<213> artificial sequence
<220>
<223> Exenatide
<400> 1
His Gly Glu Gly Thr Phe Thr Ser Asp Leu Ser Lys Gln Met Glu Glu
1 5 10 15
Glu Ala Val Arg Leu Phe Ile Glu Trp Leu Lys Asn Gly
Claims (16)
상기 엑세나타이드 유사체의 C-말단의 아미노산이 Lys로 치환되어 지방산이 접합 (conjugation)되며,
상기 서열번호 1의 아미노산 서열로 이루어진 엑세나타이드의 17, 24 및 28번째 위치로 이루어진 군에서 선택된 1종 이상의 위치의 아미노산이 Cys로 치환되어 당류가 결합 또는 28번째 위치의 아미노산에 당류가 결합된 것인,
당쇄화 엑세나타이드 유사체.In the exenatide analog in which six amino acids at the C-terminus of the amino acid sequence of exenatide consisting of the amino acid sequence of SEQ ID NO: 1 are deleted,
The amino acid at the C-terminus of the exenatide analog is substituted with Lys to conjugate fatty acids,
One or more amino acids selected from the group consisting of the 17th, 24th and 28th positions of the exenatide of the amino acid sequence of SEQ ID NO: 1 are substituted with Cys to bind a saccharide or a saccharide is bound to the amino acid at the 28th position will,
Glycosylated exenatide analogues.
[구조식 1]
[구조식 2]
[Structural Formula 1]
[Structural Formula 2]
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| KR101768446B1 (en) * | 2014-03-21 | 2017-08-17 | 애니젠 주식회사 | Novel Exenatide Analogs and Uses thereof |
| WO2017189342A1 (en) * | 2016-04-26 | 2017-11-02 | Merck Sharp & Dohme Corp. | Insulin dimer-incretin conjugates |
| KR102493143B1 (en) * | 2019-08-13 | 2023-01-30 | 애니젠 주식회사 | Glycosylated exenatide analogs and uses thereof |
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| Chem Sci, 7(4): 2492-2500 (2016.01.29.)* |
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| KR20210019965A (en) | 2021-02-23 |
| KR102419566B1 (en) | 2022-07-12 |
| KR102496719B1 (en) | 2023-02-07 |
| KR20210019966A (en) | 2021-02-23 |
| KR20210019977A (en) | 2021-02-23 |
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