JP6422046B2 - Stx2阻害4価ペプチドおよびこのStx2阻害4価ペプチドを含む治療薬 - Google Patents
Stx2阻害4価ペプチドおよびこのStx2阻害4価ペプチドを含む治療薬 Download PDFInfo
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- JP6422046B2 JP6422046B2 JP2014013815A JP2014013815A JP6422046B2 JP 6422046 B2 JP6422046 B2 JP 6422046B2 JP 2014013815 A JP2014013815 A JP 2014013815A JP 2014013815 A JP2014013815 A JP 2014013815A JP 6422046 B2 JP6422046 B2 JP 6422046B2
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- tet
- peptide
- stx2
- inhibitory
- stx2d
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Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
用して、Stx2dおよびStx2cのBサブユニットのグロボ3糖結合部位を標的とした新規な阻害ペプチドを提供することを課題としている。
配列番号1:Met-Met-Met-Arg-Arg-Arg-Arg(MMMRRRR)
配列番号2:Leu-Met-Ala-Arg-Arg-Arg-Arg(LMARRRR)
配列番号3:Met-Met-Val-Arg-Arg-Arg-Arg(MMVRRRR)
配列番号4:Met-Met-Ser-Arg-Arg-Arg-Arg(MMSRRRR)
配列番号5:Gln-Met-Ala-Arg-Arg-Arg-Arg(QMARRRR)
配列番号6:Ile-Met-Ala-Arg-Arg-Arg-Arg(IMARRRR)
のうちの1種が結合したものである。
1)シート上に合成する配列既知4価ペプチドライブラリーのデザイン
これまでに、本発明者らは、多価型ペプチドライブラリー法を用い、Stx1a Bサブユニットに存在するグロボ3糖結合部位、サイト1を標的として、4価ペプチドから構成されるStx1a阻害ペプチド;MMA-tet(化学式2に示す多価型ペプチドライブラリーの構造中、-XXXX-部の配列が、MMARRRR(配列番号10)のもの)を開発している(特許文献1)。
Stx2d BサブユニットのAsn16を標的として結合するペプチドモチーフを取得するために、Stx2d BサブユニットのAsn16のAla置換体(N16A)を作成し、スクリーニングに使用した。
MMVRRRR(配列番号3)
MMSRRRR(配列番号4)
MMMRRRR(配列番号1)
KMARRRR(配列番号8)
LMARRRR(配列番号2)
QMARRRR(配列番号5)
IMARRRR(配列番号6)
RMARRRR(配列番号9)
このうち、I125-Stx2d Bサブユニット/ I125-Stx2d BサブユニットN16Aの結合比に着目したところ、特にMMMRRRRならびにLMARRRRが高い値を示すことが明らかとなった。
2)に示した9種のモチーフをそれぞれ図1(化学式2)の-XXXX-部に組み入れ、9種の新規ペプチド性化合物(以下、MMK-tet,MMV-tet,MMS-tet,MMM-tet,KMA-tet, LMA-tet, QMA-tet, IMA-tet、RMA-tetと記載する)を合成した。なお、図1(化学式2)で例示するペプチドは、末端にMA(Met−Ala)を有しているが、これは、スクリーニングのために導入したものである。
そこで、本発明のStx2阻害4価ペプチドのMMM-tetおよびLMA-tetとMMA-tetとについて、Stx2cの細胞毒性に対する阻害効果を検討した。具体的には、Stx2c(80 pg/ml)とベロ細胞を、各濃度のペプチド性化合物(MMM-tet、LMA-tet、MMA-tet)存在下37℃で72時間培養し、細胞の生存率をWST-1 Cell Counting kit(Wako)にて測定することによって評価した。
Claims (4)
- Stx2dまたはStx2cに結合して毒性を阻害するStx2阻害4価ペプチドであって、3つのリジン(Lys)が結合して形成された以下の分子核構造
- スペーサーは、炭素数4〜10の炭化水素鎖を有することを特徴とする請求項1のStx2阻害4価ペプチド。
- Stx2dまたはStx2cに起因する疾患の治療薬であって、請求項1または2のStx2阻害4価ペプチドを含有することを特徴とする治療薬。
- 治療対象となる疾患が、腸管出血性大腸菌感染症であることを特徴とする請求項3の治療薬。
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