JP2020127420A - 新規なペプチド - Google Patents
新規なペプチド Download PDFInfo
- Publication number
- JP2020127420A JP2020127420A JP2020081677A JP2020081677A JP2020127420A JP 2020127420 A JP2020127420 A JP 2020127420A JP 2020081677 A JP2020081677 A JP 2020081677A JP 2020081677 A JP2020081677 A JP 2020081677A JP 2020127420 A JP2020127420 A JP 2020127420A
- Authority
- JP
- Japan
- Prior art keywords
- peptide
- dentin
- pulp
- disease
- tissue
- 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.)
- Granted
Links
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Abstract
Description
本発明は、新規なペプチドに関するもので、より具体的には、本発明は、象牙質または歯髄組織の再生促進用及び象牙質知覚過敏症の治療用の新規なペプチド、前記ペプチドをコードするポリヌクレオチド、前記ポリヌクレオチドを含む発現ベクター、前記ペプチドを含む象牙質疾患または歯髄疾患の予防または治療用の薬学的組成物、前記ペプチドを含む象牙質疾患または歯髄疾患の予防または改善用の医薬部外品組成物、ならびに前記ペプチドを含む象牙質疾患または歯髄疾患の予防または改善用の健康機能性食品組成物に関する。
歯髄は、歯の内部にある歯髄腔を占めている柔らかい結合組織であって、神経と血管が豊富に分布しており、象牙質の表面まで至る。歯髄に生じる障害を歯髄疾患という。
K−Y−R1−R2−R3−R4−R5−R6−R7−R8(一般式1)
式中、
R1が、アルギニン(R)、リジン(K)またはグルタミン(Q)であり;
R2が、アルギニン(R)またはグルタミン(Q)であり;
R3、R4、及びR5が、それぞれアルギニン(R)またはリジン(K)であり;
R6が、アスパラギン(N)またはセリン(S)であり;ならびに
R7及びR8が、それぞれリジン(K)またはチロシン(Y)である。
本発明者らは、象牙質疾患または歯髄疾患をより効果的に治療できる剤を開発するために様々な研究を行った結果、10個のアミノ酸からなる新規なペプチドを開発した。
K−Y−R1−R2−R3−R4−R5−R6−R7−R8(一般式1)
式中、
R1が、アルギニン(R)、リジン(K)またはグルタミン(Q)であり;
R2が、アルギニン(R)またはグルタミン(Q)であり;
R3、R4、及びR5が、それぞれアルギニン(R)またはリジン(K)であり;
R6が、アスパラギン(N)またはセリン(S)であり;ならびに
R7及びR8が、それぞれリジン(K)またはチロシン(Y)である。
もよい。
K−Y−R1−R2−R3−R4−R5−R6−R7−R8(一般式1)
式中、
R1が、アルギニン(R)、リジン(K)またはグルタミン(Q)であり;
R2が、アルギニン(R)またはグルタミン(Q)であり;
R3、R4、及びR5が、それぞれアルギニン(R)またはリジン(K)であり;
R6が、アスパラギン(N)またはセリン(S)であり;ならびに
R7及びR8が、それぞれリジン(K)またはチロシン(Y)である。
本発明者らは、象牙質または歯髄組織の再生促進効果を示すペプチド(配列番号1)を9−フルオレニルメチルオキシカルボニル(Fmoc)法で合成し、前記合成されたペプチドのアミノ酸を置換して各グループのペプチドを合成した(表1〜12)。
実施例2−1:DSPP(象牙質シアロホスホタンパク質)プロモーター活性に及ぼす、象牙質または歯髄組織の再生促進用及び象牙質知覚過敏症の治療用のペプチドの効果
まず、マウス由来の象牙芽細胞であるMDPC−23細胞を、10%FBSを含むDMEM培地中で5%のCO2及び37℃の条件で培養した。
実施例2−1で培養したMDPC−23細胞を、実施例1で合成された各グループのペプチドで処理して、48時間培養した後、前記MDPC−23細胞で発現される象牙芽細胞分化マーカーであるDspp遺伝子のmRNAレベルを測定し、測定されたDspp mRNAレベルの、対照群で測定されたDspp mRNAレベルに対する比をそれぞれ算出した(表13〜24)。また、各グループのペプチドで測定されたDspp mRNAレベルの平均値を、グループ間で比較した(図1b)。このとき、本発明のペプチドで処理されていないMDPC−23細胞を対照群として使用した。
実施例2−2の結果から、本発明のペプチドは、Dspp mRNAレベルを増加させることができ、特に、グループ11及び12のペプチドは、Dspp mRNAレベルを少なくとも3倍以上増加させうることが分かった。
まず、ソウル大学歯科病院で成人10人(18〜22歳)の知恵歯からヒト歯髄幹細胞を分離した。詳細には、すべての実験は、施設内審査委員会で承認を受けた後に患者の同意を得て行った。Jung HSら(J Mol Histol.(2011))の方法に基づいて知恵歯を切断して歯髄を露出させ、鉗子で歯髄組織を分離した。分離された各歯髄組織を剃刀で小片に切り分け、60mmの皿に入れてカバースリップで覆った後、DMEM培地で培養して、培養歯髄細胞を取得した。
実施例3−1:6週間飼育された動物に由来する移植組織の形態学的分析
2×106細胞数の歯髄細胞に100mgの象牙質代用品を加えて、0.5%フィブリンゲルと混合してインプラントを作製した。このとき、象牙質代用品としてヒドロキシアパタイト/リン酸三カルシウム(HA/TCP)セラミックパウダー(Zimmer、USA)を用い、前記フィブリンゲルは、10μgのグループ11のペプチド(配列番号87)、グループ12のペプチド(配列番号96)、2μgのBMP−2を含んで作製した。前記作製されたインプラントを、免疫システムが破損されたマウス(NIH-bg-nu-xid;Harlan Laboratories、Indianapolis、IN)の皮下組織に移植して、マウスを6週間飼育した後、インプラントから形成された象牙質/歯髄様組織を摘出した。摘出された組織を4%パラホルムアルデヒドで固定し、10%EDTA(pH7.4)で脱灰させてパラフィンに包埋し、ヘマトキシリン−エオシン(H−E)(Vector Labs)で染色して、象牙質/歯髄様組織のレベルを評価した(図2)。このとき、本発明のペプチドを含まないインプラントを対照群として使用した。
コラーゲンは、象牙質及び骨に最も豊富に存在する有機基質であり、無機質を沈着させ、象牙質の再生に重要な役割を果たすことが知られている。
実施例3−1で摘出された各組織における、象牙芽細胞特異的分化マーカー遺伝子であるDSP及び骨芽細胞特異的分化マーカーであるBSPの発現レベルを評価するために、免疫染色分析を行った。
インプラントが移植されたマウスを12週間飼育することを除いて、実施例3−1と同様に、象牙質/歯髄様組織のレベルを評価した(図5)。
実施例3−4で摘出された各組織のコラーゲンタンパク質産生レベルを調べるために、Polysciences社のMasson’s TrichromeStain Kit(Cat. 25088-100)を用いて、前記組織をコラーゲン染色(マッソントリクローム染色)に供した(図6)。このとき、本発明のペプチドを含まないインプラントが移植された組織を対照群として使用した。
実施例3−1で摘出された組織の代わりに実施例3−4で摘出された各組織を用いたことを除いて、実施例3−3と同様に、免疫染色分析を行った(図7)。このとき、本発明のペプチドを含まないインプラントが移植された組織を対照群として使用した。
実施例3−4で摘出された組織において、インプラントに含まれた歯髄細胞が象牙芽細胞に分化されたかどうかを、走査型電子顕微鏡を用いて調べた(図8)。このとき、本発明のペプチドを含まないインプラントが移植された組織を対照群として使用した。
天然の歯の象牙質壁及び空いている歯髄空間は、歯髄細胞による象牙質/歯髄様組織の再生に特異的な局所環境を作ることが知られている(Huang GT,et al.(2010) Tissue engineering. Part A 16(2):605-615)。このことから、歯根管空間での象牙質/歯髄様組織の形成を評価した。
間接歯髄覆罩術モデルにおいて新規なペプチドが生理的象牙質(第三象牙質)の形成に及ぼす効果を調べるために、その象牙質再生能を評価した。
直接歯髄覆罩術モデルにおいて新規なペプチドが生理的象牙質(第三象牙質)の形成に及ぼす効果を調べるために、象牙質再生能を評価した。
Claims (14)
- 下記一般式1のアミノ酸配列を含み、配列番号1〜96のいずれか一つのアミノ酸配列からなり、N末端またはC末端のアセチル化、アミド化またはメチル化と、D−アミノ酸の導入と、CH2−NH、CH2−S、CH2−S=OまたはCH2−CH2を含むペプチド結合修飾と、バックボーン修飾と、側鎖修飾とのうちの少なくともいずれかの修飾がなされている、象牙質または歯髄組織の再生促進用及び象牙質疾患または歯髄疾患の治療用のペプチド:
K−Y−R1−R2−R3−R4−R5−R6−R7−R8(一般式1)
式中、
R1が、アルギニン(R)、リジン(K)またはグルタミン(Q)であり;
R2が、アルギニン(R)またはグルタミン(Q)であり;
R3、R4、及びR5が、それぞれアルギニン(R)またはリジン(K)であり;
R6が、アスパラギン(N)またはセリン(S)であり;ならびに
R7及びR8が、それぞれリジン(K)またはチロシン(Y)である。 - 請求項1に記載のペプチドをコードする、ポリヌクレオチド。
- 請求項2に記載のポリヌクレオチドを含む、発現ベクター。
- 請求項1に記載のペプチドを含む、象牙質疾患または歯髄疾患の予防または治療用の薬学的組成物。
- 前記ペプチドのリピートを連結することにより作製されたポリペプチドを含む、請求項4に記載の薬学的組成物。
- 象牙質疾患または歯髄疾患に対する治療効果を有する薬物に結合された前記ペプチドの複合体を含む、請求項4に記載の薬学的組成物。
- 薬学的に許容可能な担体、賦形剤、または希釈剤をさらに含む、請求項4に記載の薬学
的組成物。 - 前記象牙質疾患または歯髄疾患が、象牙質知覚過敏症、歯髄充血、歯髄炎、歯髄変性または歯髄の壊死、及び壊疽性歯髄である、請求項4に記載の薬学的組成物。
- 請求項1に記載のペプチドを含む、象牙質疾患または歯髄疾患の予防または改善用の医薬部外品組成物。
- 口腔用消毒マウスウォッシュ、口腔衛生用品、歯みがき粉、デンタルフロス、または口腔用軟膏である、請求項9に記載の医薬部外品組成物。
- 請求項1に記載のペプチドを含む、象牙質疾患または歯髄疾患の予防または改善用の健康機能性食品組成物。
- 飲料、茶、香辛料、ガム、または菓子の製造に用いられる、請求項11に記載の健康機能性食品組成物。
- 請求項1に記載のペプチドを含む組成物をヒトを除く対象に投与する段階を含む、象牙質疾患または歯髄疾患を予防または治療する方法。
- 請求項1に記載のペプチドを含む組成物をヒトを除く対象に投与する段階を含む、象牙質または歯髄組織の再生を促進する方法。
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KR101956578B1 (ko) * | 2018-05-09 | 2019-03-11 | 주식회사 하이센스바이오 | 상아질 지각과민증 완화를 위한 구강 청결용 조성물 |
KR102006862B1 (ko) * | 2019-01-07 | 2019-08-02 | 주식회사 하이센스바이오 | 신규한 펩타이드 |
KR102037969B1 (ko) * | 2019-07-25 | 2019-10-29 | 주식회사 하이센스바이오 | 신규한 펩타이드 |
RU2729428C1 (ru) * | 2020-03-24 | 2020-08-06 | Федеральное государственное бюджетное учреждение науки Институт химии твердого тела Уральского отделения Российской академии наук | Средство для лечения пародонтита и способ лечения пародонтита |
KR102500280B1 (ko) * | 2020-06-09 | 2023-02-15 | 주식회사 하이센스바이오 | 치주질환 또는 탈구성 외상 치아의 예방 또는 치료용 약학 조성물 |
KR102522134B1 (ko) * | 2022-09-15 | 2023-04-21 | 주식회사 하이센스바이오 | Cpne7 유래 펩타이드를 포함하는 상아질 접착용 조성물 및 치수복조용 조성물 |
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Cited By (2)
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US11390648B2 (en) | 2017-12-28 | 2022-07-19 | Hysensbio | Peptide |
US11905337B2 (en) | 2017-12-28 | 2024-02-20 | Hysensbio | Peptide |
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MY197825A (en) | 2023-07-19 |
CN108239142B (zh) | 2021-11-05 |
EP3369741A4 (en) | 2019-09-18 |
HK1254601A1 (zh) | 2019-07-26 |
AU2018271360A1 (en) | 2018-12-20 |
US10844092B2 (en) | 2020-11-24 |
MX2019007152A (es) | 2019-10-14 |
TWI749415B (zh) | 2021-12-11 |
AU2017359581A1 (en) | 2018-07-19 |
WO2018124425A1 (ko) | 2018-07-05 |
RU2719434C1 (ru) | 2020-04-17 |
SG10202109234YA (en) | 2021-10-28 |
US20190153033A1 (en) | 2019-05-23 |
US20180179254A1 (en) | 2018-06-28 |
JP6715446B2 (ja) | 2020-07-01 |
KR101772449B1 (ko) | 2017-08-30 |
US10428110B2 (en) | 2019-10-01 |
CN108239142A (zh) | 2018-07-03 |
BR112019013106A2 (pt) | 2019-12-17 |
TWI710578B (zh) | 2020-11-21 |
JP2019513003A (ja) | 2019-05-23 |
AU2017359581B2 (en) | 2019-02-07 |
SG11201804006QA (en) | 2018-08-30 |
TW201823264A (zh) | 2018-07-01 |
EP3369741A1 (en) | 2018-09-05 |
JP7224042B2 (ja) | 2023-02-17 |
TW202014429A (zh) | 2020-04-16 |
AU2018271360B2 (en) | 2020-04-16 |
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