JP5030078B2 - ボンベシン様ペプチド受容体を活性化するペプチド、およびその利用 - Google Patents
ボンベシン様ペプチド受容体を活性化するペプチド、およびその利用 Download PDFInfo
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- JP5030078B2 JP5030078B2 JP2006038503A JP2006038503A JP5030078B2 JP 5030078 B2 JP5030078 B2 JP 5030078B2 JP 2006038503 A JP2006038503 A JP 2006038503A JP 2006038503 A JP2006038503 A JP 2006038503A JP 5030078 B2 JP5030078 B2 JP 5030078B2
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- 239000000843 powder Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000000473 propyl gallate Substances 0.000 description 1
- 235000010388 propyl gallate Nutrition 0.000 description 1
- 229940075579 propyl gallate Drugs 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 230000004853 protein function Effects 0.000 description 1
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- GHBFNMLVSPCDGN-UHFFFAOYSA-N rac-1-monooctanoylglycerol Chemical compound CCCCCCCC(=O)OCC(O)CO GHBFNMLVSPCDGN-UHFFFAOYSA-N 0.000 description 1
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- FQENQNTWSFEDLI-UHFFFAOYSA-J sodium diphosphate Chemical compound [Na+].[Na+].[Na+].[Na+].[O-]P([O-])(=O)OP([O-])([O-])=O FQENQNTWSFEDLI-UHFFFAOYSA-J 0.000 description 1
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- SLBXZQMMERXQAL-UHFFFAOYSA-M sodium;1-dodecoxy-4-hydroxy-1,4-dioxobutane-2-sulfonate Chemical group [Na+].CCCCCCCCCCCCOC(=O)C(S(O)(=O)=O)CC([O-])=O SLBXZQMMERXQAL-UHFFFAOYSA-M 0.000 description 1
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- GGHPAKFFUZUEKL-UHFFFAOYSA-M sodium;hexadecyl sulfate Chemical compound [Na+].CCCCCCCCCCCCCCCCOS([O-])(=O)=O GGHPAKFFUZUEKL-UHFFFAOYSA-M 0.000 description 1
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- 238000006277 sulfonation reaction Methods 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- DHCDFWKWKRSZHF-UHFFFAOYSA-N sulfurothioic S-acid Chemical compound OS(O)(=O)=S DHCDFWKWKRSZHF-UHFFFAOYSA-N 0.000 description 1
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- 238000010998 test method Methods 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- 235000019818 tetrasodium diphosphate Nutrition 0.000 description 1
- 239000001577 tetrasodium phosphonato phosphate Substances 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- 229960002663 thioctic acid Drugs 0.000 description 1
- YODZTKMDCQEPHD-UHFFFAOYSA-N thiodiglycol Chemical compound OCCSCCO YODZTKMDCQEPHD-UHFFFAOYSA-N 0.000 description 1
- 229950006389 thiodiglycol Drugs 0.000 description 1
- 229940035024 thioglycerol Drugs 0.000 description 1
- 125000003396 thiol group Chemical group [H]S* 0.000 description 1
- UIERETOOQGIECD-ONEGZZNKSA-N tiglic acid Chemical compound C\C=C(/C)C(O)=O UIERETOOQGIECD-ONEGZZNKSA-N 0.000 description 1
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- 229940042585 tocopherol acetate Drugs 0.000 description 1
- 125000002088 tosyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C([H])([H])[H])S(*)(=O)=O 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
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- 230000010474 transient expression Effects 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 235000011178 triphosphate Nutrition 0.000 description 1
- 239000001226 triphosphate Substances 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 125000002221 trityl group Chemical group [H]C1=C([H])C([H])=C([H])C([H])=C1C([*])(C1=C(C(=C(C(=C1[H])[H])[H])[H])[H])C1=C([H])C([H])=C([H])C([H])=C1[H] 0.000 description 1
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- 239000000439 tumor marker Substances 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 238000000108 ultra-filtration Methods 0.000 description 1
- 230000013948 uterine smooth muscle contraction Effects 0.000 description 1
- 239000004474 valine Substances 0.000 description 1
- 230000009278 visceral effect Effects 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
- 235000004835 α-tocopherol Nutrition 0.000 description 1
- 235000021247 β-casein Nutrition 0.000 description 1
Images
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-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
- C07K7/086—Bombesin; Related peptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Diabetes (AREA)
- Peptides Or Proteins (AREA)
- Genetics & Genomics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
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Description
Anastasi, A., Erspamer, V., and Bucci, M. Archives of Biochemistry and Biophysics, 148, 443-446, 1972 McDonald, T.J., Joernvall, H., Nillson, G., Vagne, M., Ghatei, M., Bloom, S.R., and Mutt, V. Biochemical and Biophysical Research communication, 90, 227-233, 1979 Reeve, J.R. Jr., Walsh, J.H., Chew, P., Clark, B., Hawke, D., and Shivery, J.E. Journal of Biological Chemistry, 258, 5582-5588, 1983 Minamino, N., Kangawa, K., and matsuo, H. Biochemical and Biophysical Research communication, 114, 541-548. 1983 向井秀仁, 宗像英輔, 化学と生物, 学会出版センター, 28, 152-161, 1990 Corjay, M.H., Dobazanski, D.J., Way, J.M., Viallet, J., Shapira, H., Worland, P., Sausville, E.A., and Battey, J.F. Journal of Biological Chemistry, 266, 18771-18779, 1991 Fathi, Z., Corjay, M.H., Shapira, H., Wada, E., Benya, R., Jensen, R., Viallet, J., Sausville, E.A., and Battey, J.F. Journal of Biological Chemistry, 268, 5979-5984, 1993 Ohki-hamazaki, H., Watase, K., Yamamoto, K., Ogura, H., Yamano, M., Yamada, K., Maeno, H., Imaki, J., Kikuyama, S., Wada, E., and Wada, K. Nature, 390, 165-169, 1997
即ち、本発明者らは、BRS-3を選択的に活性化するペプチド性リガンドを発見し、これにより本発明を完成するに至った。
(1)下記式で表され、かつボンベシン受容体サブタイプ3のアゴニストとして作用することを特徴とするペプチド:
X1−X2−Trp−Ala−X3−Gly−X4
(式中、X1、X2、X3、およびX4は、任意に含まれていてもよいアミノ酸残基、またはアミノ酸配列である。)
(2)X3が、Cys、Val、またはPheのいずれかである、(1)に記載のペプチド。
(3)X4が、Ser-Phe-Met、またはHis-Phe-Metである、(1)または(2)に記載のペプチド。
(4)X2が、AlaまたはLeuである、(1)〜(3)のいずれかに記載のペプチド。
(5)X1が、Lys-Lys-Arg-Lys-Tyr(配列番号:1)、Tyr、pGlu(ピログルタミン酸)、Ile-Ile-Asn-Leu-Glu(配列番号:2)、またはLeu-Gluのいずれかである、(1)〜(4)のいずれかに記載のペプチド。
(6)以下の(a)または(b)のペプチド:
(a)配列番号:3、21、24、25、26、27、28、29、30、31、32、33、38、54、55、57または58に記載のアミノ酸配列からなるペプチド、
(b)配列番号:3、21、24、25、26、27、28、29、30、31、32、33、38、54、55、57または58に記載のアミノ酸配列において1若しくは複数のアミノ酸が置換、欠失、挿入および/または付加されたアミノ酸配列からなり、かつボンベシン受容体サブタイプ3のアゴニストとして作用することを特徴とするペプチド。
(7)カルボキシル末端がアミド化されたことを特徴とする、(1)〜(6)のいずれかに記載のペプチド。
(8)ボンベシン受容体サブタイプ3の選択的アゴニストとして作用することを特徴とする、(1)〜(7)のいずれかに記載のペプチド。
(9)(1)〜(7)のいずれかに記載のペプチドをコードしているDNA。
(10)(9)に記載のDNAを含むベクター。
(11)(10)に記載のベクターが導入された形質転換体。
(12)(11)に記載の形質転換体を培養または育種し、該形質転換体細胞またはその培養上清から組換えタンパク質を回収する工程を含む、(1)〜(7)のいずれかに記載のペプチドの製造方法。
(13)(1)〜(8)のいずれかに記載のペプチドを対象に投与する工程を含む、対象においてボンベシン受容体サブタイプ3を活性化させる方法。
(14)(9)に記載のDNA、(10)に記載のベクター、または(11)に記載の形質転換体のいずれかを対象に投与する工程を含む、対象においてボンベシン受容体サブタイプ3を活性化させる方法。
(15)(1)〜(8)のいずれかに記載のペプチドを対象に投与する工程を含む、対象における肥満症を治療または予防する方法。
(16)(9)に記載のDNA、(10)に記載のベクター、または(11)に記載の形質転換体のいずれかを対象に投与する工程を含む、対象における肥満症を治療または予防する方法。
(17)(1)〜(8)のいずれかに記載のペプチドを有効成分として含有する、肥満症を予防または治療するための薬剤。
(18)(9)に記載のDNA、(10)に記載のベクター、または(11)に記載の形質転換体のいずれかを有効成分として含有する、肥満症を予防または治療するための薬剤。
(19)(1)〜(8)のいずれかに記載のペプチドに結合する抗体。
(20)モノクローナル抗体である(19)に記載の抗体。
(21)(1)〜(8)のいずれかに記載のペプチド、または、(19)もしくは(20)に記載の抗体を含有する、腫瘍細胞の増殖を検出するためのマーカー。
(22)(1)〜(8)のいずれかに記載のペプチド、または、(19)もしくは(20)に記載の抗体を含有する、代謝病を検出するためのマーカー。
本発明のペプチドの一つの態様として、好ましくは下記式で表されるペプチドを挙げることが出来る。
X1−X2−Trp−Ala−X3−Gly−X4
式中、X1、X2、X3、およびX4は、任意に含まれていてもよいアミノ酸残基、またはアミノ酸配列であり、本発明のペプチドと機能的に同等である限り、アミノ酸の配列構成については特に限定をされない。「任意に含まれていてもよい」とは、その位置に相当するアミノ酸が何も存在しない場合も含まれる。
上記の検出は、該ペプチドまたは抗体に標識物質を結合させ、当業者に公知の方法で行うことが可能である。
ペプチド性GPCRリガンドは、前駆体から特異的切断ならびに修飾を受けて初めて活性を持つ成熟体となることから、これを発見し同定するためには、以下の三つの工程が必要になる。
(1)ヒトゲノム配列〈以下に一覧としてリストアップ〉からGPCRのペプチド性リガンドを有する前駆体配列を予測すること。
(2)前駆体から生成されるペプチド成熟体を予測すること。
(3)予測したペプチド成熟体配列をモチーフとして、ゲノム配列へのマッピングおよび、既知蛋白質配列の検索により、ペプチド成熟体候補を増加させること。
最初にヒトゲノム配列上で、low-complexity 領域や、リピート領域をマスクするための前処理を行った。次にSWISSPROTより、既知ペプチド性GPCRリガンドを有する前駆体配列(以下、既知ペプチド性リガンド前駆体配列)を検索して抽出した。そして次の独立した3つのステップ<1>,<2>,<3>により前駆体候補を予測した。
使用したDBを以下に一覧として記載する。
(A) nr 2005/05/29バージョン。Homo sapiensのみを対象。
(B) NCBIヒトゲノムアノテーション (BUILD35.1)
(a)protein.fa (annotated proteins)
(b)Gnomon_prot.fsa (ab initio protein predictions)
(C) Ensemblヒトゲノムアノテーション (BUILD35.1)
(a)Homo_sapiens.NCBI35.may.pep.fa (the super-set of all translations
resulting from Ensembl known or novel gene predictions)
(D) UCSCヒトゲノムアノテーション (BUILD35.1)
(a)knownGenePep.txt (Protein coding genes based on proteins from
SWISS-PROT, TrEMBL, and TrEMBL-NEW
and their corresponding mRNAs from GenBank)
(b)twinscanPep.txt (Translations of Twinscan gene predictions into
corresponding amino acid sequences)
(c)genscanPep.txt (Translations of Genscan gene predictions into
corresponding amino acid sequences)
(E) DIGITized Genes (BUILD34)
(a)chrN.pep (N: 1-22,X,Y,)
(F) H-invDB release 1.8
(a)orf_all.fa
上記の(1)で同定した前駆体配列の中から、長さが数残基から十数残基程度であって、C末端側にトリプシン様酵素による切断モチーフ(Gly-Lys-Lys, Gly-Arg-Arg, Gly-Lys-Arg, Gly-Arg-Lys, Gly-Lys, Gly-Arg, Lys-Lys, Arg-Arg, Lys-Arg, Arg-Lys, Lys, Argのいずれか)を持つ配列、あるいは終止コドンで終わる配列を全て切り出してリストアップした。
上記(2)でリストアップ済みのペプチドリガンド候補配列をモチーフとして、再びヒトゲノム配列へのマッピングと既知蛋白質配列への検索を行った。本発明においては、モチーフとしてボンベシン様ペプチド最小活性単位を使用した。
Trp-Ala-X-Gly(配列番号:65)
を用いた。また詳細なモチーフとしては、以下に記載の配列を使用した。
Trp-Ala-X-Gly-[Ser / His]-[Leu / Phe]-Met(配列番号:66)
Trp-Ala-X-Gly-[Ser / His]-[Leu / Phe]-[Met / Asp / Glu](配列番号:67)
Trp-Ala-X-Gly-[Ser / His]-[Leu / Ile / Phe]-[Met / Asp / Glu](配列番号:68)
[Leu / Ile / Asp / Glu]-Trp-Ala-X-Gly-Ser-[Leu / Ile / Phe]-Met(配列番号:69)
[Leu / Ile / Asp / Glu]- Trp-Ala-[Val / Thr]-Gly-[Ser / His / Thr]-[Leu / Ile / Phe / Val]-[Met / Asp / Glu](配列番号:70)
例えば[Leu / Ile / Asp / Glu]- Trp-Ala-[Val / Thr]-Gly -[ Ser / His / Thr]-[ Leu / Ile / Phe / Val]-[ Met / Asp / Glu] (配列番号:70)の8残基のモチーフを想定し、各ヒットで何残基一致するかを調べ、一致度=一致残基数とした。(Trp, Ala, Glyは全てのヒットで一致するので加点から除外)。
Trp-Ala-Leu-Gly-Ser-Leu-Met(配列番号:10)
Trp-Ala-Pro-Gly-Ser-Leu-Met(配列番号:11)
Trp-Ala-Gln-Gly-Ser-Leu-Met(配列番号:12)
Trp-Ala-Thr-Gly-Ser-Leu-Met(配列番号:13)
Trp-Ala-Cys-Gly-Ser-Phe-Met(配列番号:14)
Trp-Ala-Lys-Gly-Ser-Leu-Met(配列番号:15)
Trp-Ala-Pro-Gly-Ser-Phe-Met(配列番号:16)
Trp-Ala-Val-Gly-Ser-Phe-Met-NH2(配列番号:17)
Trp-Ala-Ser-Gly-Ser-Leu-Met(配列番号:18)
Trp-Ala-Gly-Gly-His-Phe-Met(配列番号:19)
Trp-Ala-Met-Gly-Ser-Leu-Met(配列番号:20)
Trp-Ala-Phe-Gly-His-Phe-Met-NH2(配列番号:21)
が最小活性単位の候補として予測された(図1)。
実施例1により予測された最小活性単位を含む配列をヒトゲノム配列から抽出し、抽出した配列およびその鎖長をかえた誘導体の化学合成を行った。設計したペプチドのアミノ酸配列を、配列番号:21〜33(図3−A)、配列番号:34〜53(図3−B)、および配列番号:3、38、54〜64(図3−C)に示す。
Boc法によるペプチド合成において、カルボキシル末端が遊離のカルボン酸の場合固相担体には PAM 樹脂を、アミド体の場合はp-methyl-benzhydrylamine樹脂を用い、α-amino 基の保護基にBoc 基を用い固相合成した。またBoc-アミノ酸の側鎖保護基としてArgにはtosyl基、 Asp には cyclohexyl 基、Cysには4-methylbenzyl基、Gluにはbenzyl ester基、Hisには2,4-dinitrophenyl (Dnp)基、Lysには2-chlorobenzyloxycarbonyl基、Serおよび Thr には benzyl 基、Tyrには2-bromobenzyloxycarbonyl基を用いた。最初に Boc-X- 樹脂(X は合成したいペプチドの C 末端アミノ酸)を 50 % TFA で処理し、N 末端の Boc 基を切断、続いて Boc-X の導入量に対し 2.5 当量の Boc- アミノ酸を DCC-HOBt 法で縮合させた。数時間後、Kaisar のニンヒドリンテストによって反応が完了しているかどうかを確認し、反応が充分でない場合は再度縮合反応を行なった。このように Boc 基の切断と保護アミノ酸の縮合反応を繰り返して C 末端より順次ペプチド鎖を延長し、保護ペプチド樹脂を得た。ただし、Trp のインドール環を保護するために、Trp 残基導入後の Boc 基の切断には 2 % エタンジチオールを含む 50% TFA を使用した。得られた保護ペプチド樹脂の脱保護および樹脂からの脱離は、無水フッ化水素処理により行なった。すなわち、保護ペプチド樹脂1g あたりアニソール(0.5 ml)、チオアニソール、エタンジチオール、硫化メチル(各 1 ml )存在下、10 ml の無水フッ化水素で氷冷下 1 時間処理してペプチドを樹脂から脱離し、同時に保護基を除去した。反応後直ちに HF を真空下で除去し、ペプチドおよび樹脂混合物をジエチルエーテルで洗浄した後、60% アセトニトリルによりペプチドを抽出し、減圧濃縮後凍結乾燥して粗ペプチドを得た。ただし、保護ペプチド樹脂に His が含まれている場合は 、Dnp 基をチオフェノール(20 mmol/mmol Dnp 基)で 1 時間反応させて除去した後、N 末端の Boc 基を切断、無水フッ化水素処理を行った。
Fmoc 法によるペプチド合成においては、固相担体に カルボキシル末端が遊離のカルボン酸の場合は Wang 樹脂を、アミド体の場合はRink amide樹脂を用いて固相合成した。アミノ酸の保護基としてα-アミノ基には Fmoc 基を、側鎖の保護には Asn、Cys、GlnおよびHisに triphenylmethyl ( Trt )基、Ser、ThrおよびTyrにtert-butyl( t-Bu ) 基、GluおよびAspにtert-butyl ester基、Argに 4-methoxy-2,3,6-trimethylbenzenesulfonyl ( Mtr )基あるいは2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl(Pbf)基、LysおよびTrpには tert-butyloxycalbonyl ( Boc ) 基を用いた。まずWang樹脂あるいはRink amide樹脂をdichloromethane(DCM)中で膨潤させた後、これと2当量のDCC、0.2当量の dimethylaminopyridine ( DMAP )、Fmocアミノ酸をN,N'-dimethylformamide ( DMF ) 中において1時間反応させ Fmocアミノ酸-樹脂を得た。ペプチド鎖の伸長は Fmoc-アミノ酸-樹脂を25 % ピペリジン-DMF中で約30分処理して Fmoc基を除去した後、導入されたC末端アミノ酸に対して2.5当量のFmoc-アミノ酸、HOBt、DCCならびに、0.5当量のN,N',N''-diisopropylethylamine ( DIEA )、あるいは2.5当量のFmoc-アミノ酸、HOBt、2.25等量のHBTUならびに、4.5当量のDIEAを加えて30分〜数時間縮合する操作を繰り返すことで行なった。Fmoc基の脱離および縮合反応の進行は、微量の樹脂を反応容器より取り出してニンヒドリンテストを行なって確認した。得られた保護ペプチド-樹脂の脱保護および樹脂からの脱離はスカベンジャーとしてフェノール、チオアニソール、エタンジチオールを含むTFA 溶液( TFA : フェノール :チオアニソール:エタンジチオール:水=82.5:5:5:2.5:5 )で3時間処理することにより行なった。反応終了後に反応混合液を濃縮除去し、 1 M酢酸を用いてペプチドの抽出を行ない樹脂を濾別した。その後ジエチルエーテルによる洗浄を5回行ないスカベンジャーを除去し減圧濃縮した後、凍結乾燥することで粗ペプチドを得た。
合成ペプチドの精製は逆相ODSカラム( 20 × 250 mm )を用いた RP-HPLC によって行った。精製は、0.1% TFA 存在下でアセトニトリルの直線的濃度勾配をかけて流速 5 ml /min で溶出を行い、214 nm の吸収を指標に主なピークを分取し、これを凍結乾燥することで精製ペプチドを得た。精製ペプチドの純度は、ODS(4.5 × 150 mm)カラムを使用した分析RP-HPLC により確認した。ペプチドの精製同様に、0.1% TFA 存在下でアセトニトリルの直線的濃度勾配をかけて流速 1 ml /min で溶出を行い、214 nm の吸収で検出した。またMALDI-TOF MS装置を用いて質量分析し、目的の質量数であることを確認した。次に、精製したペプチドを 2% フェノール、2% チオグリコール酸を含む 6 N 塩酸中で 110 ℃、24 時間加水分解し、加水分解物をアミノ酸分析計によって分析することでペプチドのアミノ酸組成を確認するとともに、その含有量を定量した。定量したペプチドは 100 nmol/tube で分注し、凍結乾燥後測定時まで冷凍保存した。またこれらは水に難溶性であるため、ジメチルスルホキシド(DMSO)に溶解し DMSO の終濃度が 0.1% となるようにした。その際この濃度で、それぞれの反応に影響がみられないことを確認した。
NMB受容体(NMBR)、GRP受容体(GRPR)ならびにBRS-3を発現するHEK293細胞の作製を下記の工程により行った。
HEK293 細胞あるいはBRS-3安定発現HEK293細胞(BRS3/HEK293 stable、後述)の培養は、10%熱非働化ウシ胎児血清(FBS)含む DMEM 培地(10% FBS-DMEM)中で37 ℃、 CO2 濃度 5 %の条件下静置して行った。細胞培養には直径10 cmのcollagen-coated dishを用い、細胞がコンフルエントになるたびに継代した。すなわち、コンフルエントに細胞が増殖したdishの培地を吸引し除いた後PBSで洗浄し、つづいて0.025% Trypsin-EDTAを室温で1 分反応させ接着した細胞を回収した(trypsin-EDTA処理)。これに1 mlのtrypsin inhibitorを加えてtrypsinを不活性化した後、細胞懸濁液を15 mlの遠心管に移し、PBSで細胞懸濁液を15 mlにフィルアップして遠心(800 rpm, 4 min)、上清を吸引して除いた後、PBS 10 ml中に懸濁し細胞数を計測した。この細胞懸濁液をふたたび遠心、上清を吸引し、最後に1.0×106細胞/10 mlとなるよう10% FBS-DMEMに懸濁し、dishに播種した。
コンフルエントに増殖したHEK293細胞dishの培地を吸引し除いた後、dish 1枚あたり5 mlのPBSで洗浄、0.025% Trypsin-EDTAを室温で1 分反応させ細胞を脱接着した(trypsin-EDTA処理)。これに1 mlのtrypsin inhibitorを加えてtrypsinを不活性化した後、この細胞懸濁液を15 mlの遠心管に移し、PBSで細胞懸濁液を15 mlにフィルアップして遠心(800 rpm、4 分)、上清を吸引して除いた後、PBS 10 ml中に懸濁し細胞数を計測した。この細胞懸濁液をふたたび遠心、上清を吸引し、計測した細胞数より計算してdish1枚あたり6.0 − 7.0 ×106細胞/ 10 mlとなるよう10% FBS-DMEMに懸濁し、collagen-coated dishに播種、37 ℃、 5%CO2で一晩培養した。24 時間後検鏡により培養密度がサブコンフルエントになったことを確認の上、NMBR遺伝子(cDNAを配列番号:72に、アミノ酸配列を配列番号:73に示す)、GRPR遺伝子(cDNAを配列番号:74に、アミノ酸配列を配列番号:75に示す)、またはBRS-3遺伝子(cDNAを配列番号:76に、アミノ酸配列を配列番号:77に示す)を組み込んだ細胞発現ベクターpcDNA3.1(pcDNA/NMBR、pcDNA/GRPRならびにpcDNA/BRS-3)12 μg 相当量を900μl のOPTI-MEM培地で希釈した溶液に45μlのLipofectamine 2000を900 μlのOPTI-MEM培地で希釈したものを静かに加え、室温で20分インキュベートし、これをHEK293細胞のdishに加え37 ℃、 5%CO2で一晩培養した。この後上述したようにtrypsin-EDTA処理により細胞を回収し、1 dishから回収した細胞を2 dish に再播種し、24 時間後活性評価に使用した(後述)。
コンフルエントに増殖したHEK293細胞dishの培地を吸引し除いた後、dish 1枚あたり5 mlのPBSで洗浄、上記の場合と同様にtrypsin-EDTA処理により細胞を回収し、細胞数を計測した。この細胞懸濁液をふたたび遠心、上清を吸引し、計測した細胞数より計算してdish1枚あたり6.0 - 7.0 ×106細胞/ 10mlとなるよう10% FBS-DMEMに懸濁し、collagen-coated dishに播種、37 ℃、5%CO2で一晩培養した。24 時間後検鏡により培養密度がサブコンフルエントになったことを確認の上、BRS-3遺伝子を組み込んだジェネティシン耐性遺伝子を持つpcDNA3.1細胞発現ベクター12 μg 相当量を900 μl のOPTI-MEM培地で希釈した溶液に45 μlのLipofectamine 2000を900 μlのOPTI-MEM培地で希釈したものを静かに加え、室温で20分インキュベートし、これをHEK293細胞のdishに加え37 ℃、 5%CO2で一晩培養した。この後dishの培地を吸引して除き、ジェネティシンを含む10% FBS-DMEM培地で2週間培養し、再びtrypsin-EDTA処理により生育した細胞コロニーを回収し、これを96ウエルプレートに1ウエル1細胞になるように播種し、RT-PCRでBRS-3遺伝子の発現を確認するとともにNMBによって細胞内カルシウム濃度が上昇する細胞を選択(評価法は後述)、これをBRS-3安定発現細胞(BRS3/HEK293 stable)とした。
HEK293細胞に発現したボンベシン様ペプチド受容体NMBR、GRPRならびにBRS-3を活性化するリガンドペプチドの活性は、細胞内カルシウム濃度上昇活性により評価した。
実施例2において化学合成したペプチドおよび誘導体について以下の工程により、ボンベシン様ペプチド受容体活性化能の評価を行った。実施例3において作製した各細胞を本評価方法に用いた。本評価方法の概念図を図2に示す。
まず始めに、BRS-3を安定発現したHEK293細胞に対する各合成ペプチドのBRS-3活性化能の評価を行った。
上記活性の確認されたペプチドのうち、BN3-001-07(配列番号:28)、BN3-001-10(配列番号:31)、BN3-001-12(配列番号:33)、BN3-006-01(配列番号:38)、BN3-006-05(配列番号:57)、BN3-006-06(配列番号:3)、天然のボンベシン様ペプチドであるNMB、GRP-10、およびボンベシンについて、ボンベシン様ペプチド受容体NMBR、GRPR、またはBRS-3の活性化能を評価した。
Claims (11)
- 以下の(a)または(b)のペプチド:
(a)配列番号:3、21、24、25、26、27、28、29、30、31、32、33、38、54、55、57または58に記載のアミノ酸配列からなるペプチド、
(b)配列番号:3、21、24、25、26、27、28、29、30、31、32、33、38、54、55、57または58に記載のアミノ酸配列において1のアミノ酸が置換、欠失、挿入および/または付加されたアミノ酸配列からなり、かつボンベシン受容体サブタイプ3のアゴニストとして作用することを特徴とするペプチド。 - カルボキシル末端がアミド化されたことを特徴とする、請求項1に記載のペプチド。
- ボンベシン受容体サブタイプ3の選択的アゴニストとして作用することを特徴とする、請求項1又は2に記載のペプチド。
- 請求項1又は2に記載のペプチドをコードしているDNA。
- 請求項4に記載のDNAを含むベクター。
- 請求項5に記載のベクターが導入された非ヒト形質転換体。
- 請求項6に記載の非ヒト形質転換体を培養または育種し、該非ヒト形質転換体またはその培養上清から組換えタンパク質を回収する工程を含む、請求項1〜3のいずれかに記載のペプチドの製造方法。
- 請求項1〜3のいずれかに記載のペプチドを有効成分として含有する、肥満症を予防または治療するための薬剤。
- 請求項1〜3のいずれかに記載のペプチドに結合する抗体。
- モノクローナル抗体である請求項9に記載の抗体。
- 請求項1〜3のいずれかに記載のペプチド、または、請求項9もしくは10に記載の抗体を含有する、肥満症を検出するためのマーカー。
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