JP2019521089A - 乳酸菌由来のp8蛋白質及びその抗癌剤としての使用 - Google Patents
乳酸菌由来のp8蛋白質及びその抗癌剤としての使用 Download PDFInfo
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- JP2019521089A JP2019521089A JP2018560069A JP2018560069A JP2019521089A JP 2019521089 A JP2019521089 A JP 2019521089A JP 2018560069 A JP2018560069 A JP 2018560069A JP 2018560069 A JP2018560069 A JP 2018560069A JP 2019521089 A JP2019521089 A JP 2019521089A
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- disease
- colon
- protein
- lactic acid
- large intestine
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Abstract
Description
実施例1−1.乳酸菌由来の蛋白質の精製
多様な種類の乳酸菌培養上澄液または菌体破砕液を大腸癌細胞株のDLD−1に処理して抗癌活性を確認した。そのうち、抗癌活性が最も良いラクトバチルスラムノサス(Lactobacillus rhamnosus、KCTC12202BP)菌体破砕液を選別した。
実施例1−1の方法で精製されたP8蛋白質をクマシーブルー−250染色後、マルチ−トフ質量分析(MALDI−TOF、Matrix Assisted Laser Desorption Ionization Time Of Flight Mass spectrometry)を行って「未究明蛋白質LGG_02452[ラクトバチルスラムノサス]」というアイディーを算出し、前記蛋白質をPVDFメンブレンに転移し、N−末端アミノ酸シーケンシングにより同定した結果、N末端アミノ酸配列はA−T−V−D−P−E−K−T−L−Fであることを確認した。前記結果を図3に示した。
実施例1−1で精製されたP8蛋白質の活性部位を追跡するために、P8蛋白質の配列と類似の乳酸菌由来の蛋白質を探索し、その結果を表3に記載した。P8蛋白質と表3に記載の蛋白質間の配列相同性を分析して導出された活性部位3箇所の配列を表4に記載した。前記乳酸菌由来の蛋白質間の活性部位の配列共有模式図を図4に記載した。
大腸癌細胞株DLD−1細胞を96ウェル−プレートに1×104cells/ウェルの密度で培養し、実施例1−3の活性部位1〜3(配列番号8〜10)を10μg/mlの濃度で添加した。陰性対照群は、蛋白質の精製時に用いた緩衝溶液である0.1%PBSを使用した。これを24時間培養した後、細胞生存率測定用キット(Dojindo Cell count kit WST−8)をウェルあたり10μlずつ処理して、2時間反応させた。これをマイクロプレートリーダー(Microplate reader、amersham、Biorad、米国、日本)を用いて450nmで吸光度を測定し、測定値を細胞生存率(Cell survival rate)として算出した。その結果、陰性対照群に比べて、活性部位1〜3を処理した実験群で大腸癌細胞株DLD−1の細胞成長が有意に抑制されたことを確認した。
実施例2−1.細胞生存率の確認
大腸癌細胞株DLD−1とHT−29細胞それぞれを96ウェル−プレートに1×104cells/ウェルの密度で培養し、実施例1のP8蛋白質を0.39μg/ml〜100μg/mlの濃度で添加した。陰性対照群は、蛋白質の精製時に用いた緩衝溶液である0.1%PBSを使用した。これを24時間培養した後、細胞生存率測定用キット(Dojindo Cell count kit WST−8)をウェルあたり10μlずつ処理して、2時間反応させた。これをマイクロプレートリーダー(Microplate reader、amersham、Biorad、米国、日本)を用いて450nmで吸光度を測定し、測定値を細胞生存率(Cell survival rate)として算出した。前記結果を図5に示した。
大腸癌細胞株DLD−1細胞を6ウェル−プレートに1.5×106cells/ウェルの密度で培養し、実施例1のP8蛋白質を1μg/ml、または10μg/mlの濃度で添加した。これを24時間から48時間培養した後、リン酸緩衝溶液で2回洗浄し、LIVE/DEAD生存性/細胞毒性キット(LIVE/DEAD viability/cytotoxicity staining kit)1ml処理後、20〜40分間反応させた。前記染色によって生きた細胞は緑色、死んだ細胞は赤色に染色される。前記細胞を蛍光顕微鏡下で確認して生存性の抑制程度を確認し、その結果を図6に示した。実験結果、大腸癌細胞にP8蛋白質処理時、陰性対照群(Cont.)に比べて細胞生存率が減少することが分かり、処理されたP8蛋白質の濃度が増加するほど、またはP8蛋白質処理時間が増加するほど、大腸癌細胞株の生存能力が阻害されることを確認した。
実施例1のP8蛋白質の細胞毒性の有無を確認するために、NIH3T3細胞(mouse embryonic fibroblast cell)で大量発現させたP8蛋白質と、陽性対照群としてBSA(bovine serum albumin)の細胞毒性実験を行った。
大腸癌細胞のDLD−1細胞に、実施例1のP8蛋白質を1μg/mlの濃度で1日、3日、または7日を毎日処理した後、それぞれの細胞を6ウェル−プレートに分注した。
実施例3−1.大腸癌異種移植モデルの製造
ヒト由来の大腸癌細胞株(DLD−1)をヌードマウスの皮下に移植して異種移植モデル(xenograft model)を製造し、これを用いて実施例1のP8蛋白質の抗癌活性を評価した。
実施例3−1の方法で製造された大腸癌異種移植モデルを表5のようにグループ化し、週2回ずつ4週間、計8回腹腔に薬物を投与した。
atggcaacag tagatcctga aaagacattg
tttctcgatg aaccaatgaa caaggtattt
gactggagca acagcgaagc acctgtacgt
gatgcgctgt gggattatta catggaaaag
aacagccgtg ataccatcaa gactgaagaa
gaaatgaaac cagtcctaga catgtccgac
gatgaggtca aagccctagc agaaaaggtt
ctcaagaagt aa
配列番号2(Lactobacillus rhamnosus、PRT)
Met Ala Thr Val Asp Pro Glu Lys Thr Leu
Phe Leu Asp Glu Pro Met Asn Lys Val Phe
Asp Trp Ser Asn Ser Glu Ala Pro Val Arg
Asp Ala Leu Trp Asp Tyr Tyr Met Glu Lys
Asn Ser Arg Asp Thr Ile Lys Thr Glu Glu
Glu Met Lys Pro Val Leu Asp Met Ser Asp
Asp Glu Val Lys Ala Leu Ala Glu Lys Val
Leu Lys Lys
配列番号3(Lactobacillus acidophilus、PRT)
Met Ala Asp Glu Ile Ile Lys Thr Ala Leu
Leu Asp Arg His Met Lys Glu Ala Phe Asp
Trp Ser Asp Ser Asp Met Pro Val Arg Asp
Ala Leu Trp Asp Tyr Phe Met Glu Lys Asn
Gly Glu Asp Met Leu Pro Phe Leu Arg Asp
Thr Met Lys Thr Glu Lys Asp Ser Asp Glu
Lys Ile Glu Ala Phe Val Asn Glu Asn Leu
Lys Lys
配列番号4(Lactobacillus paracasei、PRT)
Met Ala Ser Val Asp Pro Glu Lys Thr Leu
Phe Leu Asp Glu Pro Met Asn Lys Val Phe
Asp Trp Ser Asp Ser Glu Ala Pro Val Arg
Asp Ala Leu Trp Asp Tyr Tyr Met Glu Lys
Asn Ser Arg Asp Thr Ile Lys Thr Glu Glu
Glu Met Lys Pro Val Leu Asp Met Ser Asp
Asp Glu Val Lys Ala Leu Ala Glu Lys Val
Leu Lys Lys
配列番号5(Lactobacillus plantarum、PRT)
Met Ala Ala Ala Val Glu Met Asn Ser Met
Leu Asp Glu Lys Met Thr Asp Val Phe Asp
Trp Ser Asp Ser Lys Leu Pro Val Arg Asp
Ala Ile Trp Asn His Phe Met Asp Ala Asp
Ser His Asp Thr Asp Lys Thr Ala Asp Glu
Val Ala Pro Tyr Met Ser Met Asp Glu Ala
Lys Leu Lys Ser Glu Val Glu Lys Leu Leu
Lys Ala
配列番号6(Pediococcus pentosaceus、PRT)
Met Ala Thr Thr Leu Lys Thr Glu Leu Leu
Asp Gln Lys Met Thr Glu Val Phe Asp Trp
Ser Asn Asp Gln Thr Pro Leu Arg Asp Ala
Met Trp Asn His Val Met Asp Asp Asn Gly
His Asp Thr Met Lys Thr Ile Ala Glu Ala
Lys Lys Trp Glu Asn Met Asn Asp Ala Glu
Leu Lys Lys Thr Ala Glu Gln Met Leu Lys
配列番号7(Lactobacillus brevis、PRT)
Met Ala Val Val Glu Lys Thr Ala Leu Leu
Asp Glu Lys Met Asn Glu Val Phe Asp Trp
Ser Asp Ser Lys Glu Pro Val Arg Asp Ala
Leu Trp Asn His Phe Met Glu Ser Asn Gly
His Asn Thr Asp Glu Thr Glu Ala Ser Met
Lys Glu Ile Asp Ala Lys Ser Asp Ala Asp
Val Arg Ser Tyr Val Glu Asp Asn Leu Lys
Lys
配列番号8(Lactobacillus rhamnosus、PRT)
Ala Thr Val Asp Pro Glu Lys Thr Leu Phe
Leu Asp Glu Pro Met Asn Lys Val Phe Asp
Trp Ser Asn Ser Glu
配列番号9(Lactobacillus rhamnosus、PRT)
Met Asn Lys Val Phe Asp Trp Ser Asn Ser
Glu Ala Pro Val Arg Asp Ala Leu Trp Asp
Tyr Tyr Met Glu Lys Asn Ser Arg Asp Thr
Ile Lys Thr
配列番号10(Lactobacillus rhamnosus、PRT)
Ala Pro Val Arg Asp Ala Leu Trp Asp Tyr
Tyr Met Glu Lys Asn Ser Arg Asp Thr Ile
Lys Thr Glu Glu Glu Met Lys Pro Val Leu
Met Ser Asp Asp Glu Val Lys Ala Leu Ala
Glu Lys Val Leu Lys Lys
atggcaacag tagatcctga aaagacattg
tttctcgatg aaccaatgaa caaggtattt
gactggagca acagcgaagc acctgtacgt
gatgcgctgt gggattatta catggaaaag
aacagccgtg ataccatcaa gactgaagaa
gaaatgaaac cagtcctaga catgtccgac
gatgaggtca aagccctagc agaaaaggtt
ctcaagaagt aa
配列番号2(Lactobacillus rhamnosus、PRT)
Met Ala Thr Val Asp Pro Glu Lys Thr Leu
Phe Leu Asp Glu Pro Met Asn Lys Val Phe
Asp Trp Ser Asn Ser Glu Ala Pro Val Arg
Asp Ala Leu Trp Asp Tyr Tyr Met Glu Lys
Asn Ser Arg Asp Thr Ile Lys Thr Glu Glu
Glu Met Lys Pro Val Leu Asp Met Ser Asp
Asp Glu Val Lys Ala Leu Ala Glu Lys Val
Leu Lys Lys
配列番号3(Lactobacillus acidophilus、PRT)
Met Ala Asp Glu Ile Ile Lys Thr Ala Leu
Leu Asp Arg His Met Lys Glu Ala Phe Asp
Trp Ser Asp Ser Asp Met Pro Val Arg Asp
Ala Leu Trp Asp Tyr Phe Met Glu Lys Asn
Gly Arg Asp Thr Met Lys Thr Glu Glu Asp
Met Leu Pro Phe Leu Lys Asp Ser Asp Glu
Lys Ile Glu Ala Phe Val Asn Glu Asn Leu
Lys Lys
配列番号4(Lactobacillus paracasei、PRT)
Met Ala Ser Val Asp Pro Glu Lys Thr Leu
Phe Leu Asp Glu Pro Met Asn Lys Val Phe
Asp Trp Ser Asp Ser Glu Ala Pro Val Arg
Asp Ala Leu Trp Asp Tyr Tyr Met Glu Lys
Asn Ser Arg Asp Thr Ile Lys Thr Glu Glu
Glu Met Lys Pro Val Leu Asp Met Ser Asp
Asp Glu Val Lys Ala Leu Ala Glu Lys Val
Leu Lys Lys
配列番号5(Lactobacillus plantarum、PRT)
Met Ala Ala Ala Val Glu Met Asn Ser Met
Leu Asp Glu Lys Met Thr Asp Val Phe Asp
Trp Ser Asp Ser Lys Leu Pro Val Arg Asp
Ala Ile Trp Asn His Phe Met Asp Ala Asp
Ser His Asp Thr Asp Lys Thr Ala Asp Glu
Val Ala Pro Tyr Met Ser Met Asp Glu Ala
Lys Leu Lys Ser Glu Val Glu Lys Leu Leu
Lys Ala
配列番号6(Pediococcus pentosaceus、PRT)
Met Ala Thr Thr Leu Lys Thr Glu Leu Leu
Asp Gln Lys Met Thr Glu Val Phe Asp Trp
Ser Asn Asp Gln Thr Pro Leu Arg Asp Ala
Met Trp Asn His Val Met Asp Asp Asn Gly
His Asp Thr Met Lys Thr Ile Ala Glu Ala
Lys Lys Trp Glu Asn Met Asn Asp Ala Glu
Leu Lys Lys Thr Ala Glu Gln Met Leu Lys
配列番号7(Lactobacillus brevis、PRT)
Met Ala Val Val Glu Lys Thr Ala Leu Leu
Asp Glu Lys Met Asn Glu Val Phe Asp Trp
Ser Asp Ser Lys Glu Pro Val Arg Asp Ala
Leu Trp Asn His Phe Met Glu Ser Asn Gly
His Asn Thr Asp Glu Thr Glu Ala Ser Met
Lys Glu Ile Asp Ala Lys Ser Asp Ala Asp
Val Arg Ser Tyr Val Glu Asp Asn Leu Lys
Lys
配列番号8(Lactobacillus rhamnosus、PRT)
Ala Thr Val Asp Pro Glu Lys Thr Leu Phe
Leu Asp Glu Pro Met Asn Lys Val Phe Asp
Trp Ser Asn Ser Glu
配列番号9(Lactobacillus rhamnosus、PRT)
Met Asn Lys Val Phe Asp Trp Ser Asn Ser
Glu Ala Pro Val Arg Asp Ala Leu Trp Asp
Tyr Tyr Met Glu Lys Asn Ser Arg Asp Thr
Ile Lys Thr
配列番号10(Lactobacillus rhamnosus、PRT)
Ala Pro Val Arg Asp Ala Leu Trp Asp Tyr
Tyr Met Glu Lys Asn Ser Arg Asp Thr Ile
Lys Thr Glu Glu Glu Met Lys Pro Val Leu
Asp Met Ser Asp Asp Glu Val Lys Ala Leu
Ala Glu Lys Val Leu Lys Lys
Claims (25)
- 配列番号8、9、および10で表されるアミノ酸配列から構成されたグループより選択されたいずれか1つ以上のアミノ酸配列を含む蛋白質。
- 前記蛋白質は、配列番号2で表される、請求項1に記載の蛋白質。
- 前記蛋白質は、乳酸菌由来であることを特徴とする、請求項1に記載の蛋白質。
- 前記乳酸菌は、ラクトバチルスラムノサス(Lactobacillus rhamnosus)、ラクトバチルスアシドフィルス(Lactobacillus acidophilus)、ラクトバチルスパラカゼイ(Lactobacillus paracasei)、ラクトバチルスプランタルム(Lactobacillus plantarum)、ペディオコッカスペントサセウス(Pediococcus pentosaceus)、およびラクトバチルスブレビス(Lactobacillus brevis)からなるグループより選択されたいずれか1つ以上である、請求項3に記載の蛋白質。
- 前記乳酸菌は、ラクトバチルスラムノサス(Lactobacillus rhamnosus)である、請求項4に記載の蛋白質。
- 請求項1に記載の蛋白質を有効成分として含む、大腸疾患の予防または治療用薬学組成物。
- 前記大腸疾患は、大腸癌、大腸ポリープ、大腸炎、虚血性腸疾患、赤痢、腸内血管異形成、憩室症、過敏性大腸症候群、およびクローン病から構成されるグループより選択されたいずれか1つ以上である、請求項6に記載の大腸疾患の予防または治療用薬学組成物。
- 前記大腸疾患は、大腸癌である、請求項7に記載の大腸疾患の予防または治療用薬学組成物。
- 請求項1に記載の蛋白質を有効成分として含む、大腸疾患の予防または改善用食品組成物。
- 前記大腸疾患は、大腸癌、大腸ポリープ、大腸炎、虚血性腸疾患、赤痢、腸内血管異形成、憩室症、過敏性大腸症候群、およびクローン病から構成されるグループより選択されたいずれか1つ以上である、請求項9に記載の大腸疾患の予防または改善用食品組成物。
- 前記大腸疾患は、大腸癌である、請求項10に記載の大腸疾患の予防または改善用食品組成物。
- 請求項1に記載の蛋白質を発現するように構築されたベクター。
- 請求項12に記載のベクターを含む、ヒトを除いた形質転換体。
- 前記形質転換体は、乳酸菌である、請求項13に記載の形質転換体。
- 前記乳酸菌は、ペディオコッカスペントサセウス(Pediococcus pentosaceus)である、請求項14に記載の形質転換体。
- 請求項13に記載の形質転換体を有効成分として含む、大腸疾患の予防または治療用薬学組成物。
- 前記形質転換体は、乳酸菌である、請求項16に記載の大腸疾患の予防または治療用薬学組成物。
- 前記乳酸菌は、ペディオコッカスペントサセウス(Pediococcus pentosaceus)である、請求項17に記載の大腸疾患の予防または治療用薬学組成物。
- 前記大腸疾患は、大腸癌、大腸ポリープ、大腸炎、虚血性腸疾患、赤痢、腸内血管異形成、憩室症、過敏性大腸症候群、およびクローン病から構成されるグループより選択されたいずれか1つ以上である、請求項16に記載の大腸疾患の予防または治療用薬学組成物。
- 前記大腸疾患は、大腸癌である、請求項19に記載の大腸疾患の予防または治療用薬学組成物。
- 請求項13に記載の形質転換体を有効成分として含む、大腸疾患の予防または改善用食品組成物。
- 前記形質転換体は、乳酸菌である、請求項21に記載の大腸疾患の予防または改善用食品組成物。
- 前記乳酸菌は、ペディオコッカスペントサセウス(Pediococcus pentosaceus)である、請求項22に記載の大腸疾患の予防または改善用食品組成物。
- 前記大腸疾患は、大腸癌、大腸ポリープ、大腸炎、虚血性腸疾患、赤痢、腸内血管異形成、憩室症、過敏性大腸症候群、およびクローン病から構成されるグループより選択されたいずれか1つ以上である、請求項21に記載の大腸疾患の予防または改善用食品組成物。
- 前記大腸疾患は、大腸癌である、請求項24に記載の大腸疾患の予防または改善用食品組成物。
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KR101915951B1 (ko) * | 2018-01-09 | 2018-11-07 | 주식회사 쎌바이오텍 | P8 단백질을 발현 및 분비하는 위장관 질환 치료 약물 전달용 미생물 및 그를 포함하는 위장관 질환 예방 또는 치료용 약제학적 조성물 |
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JP7134261B2 (ja) | 2019-09-11 | 2022-09-09 | セル バイオテック カンパニー リミテッド | 乳酸菌由来p8タンパク質の発現コンストラクトを含む大腸疾患の治療または予防用組成物 |
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US11213565B2 (en) | 2022-01-04 |
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WO2018097402A1 (ko) | 2018-05-31 |
US20190201481A1 (en) | 2019-07-04 |
KR20180060228A (ko) | 2018-06-07 |
DK3453718T3 (da) | 2021-04-19 |
EP3453718B1 (en) | 2021-03-31 |
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