JP2022538545A - Romo1由来抗菌ペプチドおよびその変異体 - Google Patents
Romo1由来抗菌ペプチドおよびその変異体 Download PDFInfo
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- JP2022538545A JP2022538545A JP2021575444A JP2021575444A JP2022538545A JP 2022538545 A JP2022538545 A JP 2022538545A JP 2021575444 A JP2021575444 A JP 2021575444A JP 2021575444 A JP2021575444 A JP 2021575444A JP 2022538545 A JP2022538545 A JP 2022538545A
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- 239000004474 valine Substances 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 239000003981 vehicle Substances 0.000 description 1
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Abstract
Description
アルギニン(Arg、R)、リシン(Lys、K)、ヒスチジン(His、H)、セリン(Ser、S)、トレオニン(Thr、T)、グルタミン(Gln、Q)、アスパラギン(Asp、N)、メチオニン(Met、M)、ロイシン(Leu、L)、イソロイシン(Ile、I)、バリン(Val、V)、フェニルアラニン(Phe、F)、トリプトファン(Trp、W)、チロシン(Tyr、Y)、アラニン(Ala、A)、グリシン(Gly、G)、プロリン(Pro、P)、システイン(Cys、C)、アスパラギン酸(Asp、D)、グルタミン酸(Glu、E)、ノルロイシン(Nle)
実施例1.Romo1由来ペプチドの抗菌活性の確認および最適なペプチドの探索
Romo1タンパク質は2個のアルファヘリックス(α-helix)を含んでいる。本発明者らは、親水性および疎水性の二面性を有する2番目アルファヘリックス(α-helix2)領域を合成し、バクテリア殺菌最小濃度測定法(minimum bactericidal concentration:MBC)を利用してその抗菌活性を確認し、これをKU-5279(Romo1タンパク質の52-79アミノ酸領域)と名付けた。次いで、人体適用に有利であり、抗菌活性に優れたペプチドを探索するために、Romo1タンパク質の52-79アミノ酸領域において任意のアミノ酸を基準として連続するアミノ酸配列を含む数種のペプチドを合成して、バクテリア殺菌最小濃度測定法により各ペプチドの抗菌活性を比較確認した(各ペプチドの情報は下記表1参照)。前記各ペプチドのバクテリア殺菌最小濃度測定法を利用した抗菌活性の確認は、具体的には下記のように行われた。
2-1.多様な細菌に対する抗菌活性の確認
前記実施例1で抗菌活性を確認したRomo1タンパク質の52-79アミノ酸領域またはその一部領域を含むペプチドが殺菌力を発揮する細菌の種類を確認するために、前記表1に示した合成ペプチドのうちKU-5878を代表に選定して、下記表2に示した細菌に対する抗菌活性をバクテリア殺菌最小濃度測定法を利用して測定した。バクテリア殺菌最小濃度測定法は、前記実施例1の方法と同一である。
In vitroにおける抗菌活性を確認したKU-5878ペプチドがin vivo、特に動物の血管内での細菌に対する殺菌力を効果的に発揮するかを確認するために、グラム陽性菌としては黄色ブドウ状球菌、グラム陰性菌としては緑膿菌、多剤耐性菌としてはメタシリン耐性黄色ブドウ状球菌および多剤耐性緑膿菌を代表に選定して、下記の実験を行った。
前記実施例2-2に続き、in vivoにおけるKU-5878ペプチドの抗菌活性を確認するために、グラム陽性菌としては黄色ブドウ状球菌、グラム陰性菌としては緑膿菌、クレブシエラニューモニエ、およびアシネトバクターバウマニ、多剤耐性菌としては多剤耐性緑膿菌、メチシリン耐性黄色ブドウ状球菌、多剤耐性クレブシエラニューモニエ、多剤耐性アシネトバクターバウマニを選定して、下記の実験を行った。
前記実施例1および2でグラム陽性、グラム陰性、および多剤耐性細菌に対する殺菌力を確認したRomo1タンパク質の52-79アミノ酸領域またはその一部領域を含むペプチドが個体に適用可能であるかを確認するために、その毒性を測定しようとした。以下の実験では、前記表1に示した合成ペプチドのうちKU-5878を代表に選定して、その毒性を確認した。
ヒトの血管内皮細胞由来細胞株であるヒューベック細胞を96-ウェルマイクロプレートに培養し、MTT(3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliurn bromide)試薬は2mg/mlの濃度でPBSに溶かした後、0.2μm membrane filterで滅菌濾過して用意した。対照群としてPBSを使用した。
血液赤血球をPBSで希釈した後、900gで10分間3回繰り返し遠心分離して洗浄した。前記希釈した赤血球溶液(10%v/v PBS)を96-ウェルマイクロプレートに100μlずつ分注し、KU-5878、KU-5878-K4、KU-5878-K4-D、メリチン、マガイニン2、またはダプトマイシンを添加し、200μlとなるようにPBSで満たして、37℃のインキュベーション(incubation)で1時間培養して反応させた。次いで、前記反応溶液の上層液を分離し、分光光度計を用いて550nmの波長で吸光度を測定した。対照群としてPBSと0.1%トリトンX-100(Triton X-100)溶液を使用した。
In vitroにおける無毒性を確認したKU-5878ペプチドがin vivo、特に動物(個体)の血管に注射した時、個体に毒性を呈しないかを確認するために、10週齢の雄マウス(C57BL/6)の尾静脈にKU-5878を100mg/kgの濃度で投与した。この時、注射用量の最大体積は150μlであった。注射後1時間マウスの行動を観察し、以後、24時間間隔で12日間マウスの体重変化を測定した。
4-1.配列番号16のアミノ酸配列を含むKU-5878変異体の抗菌活性の確認
次いで、より抗菌活性に優れたペプチドを探索するために、KU-5878の親水性残基を含むアミノ酸を正電荷を含んでいるリシン(K)またはアルギニン(R)に置換した後、その変異体の抗菌活性をバクテリア殺菌最小濃度測定法を利用して比較確認した。実験は前記実施例1と同様の方法で行った。KU-5878変異体の具体的な情報および各細菌に対するMBC値は下記表4に示した。
前記実施例4-1で抗菌活性を確認したKU-5878変異体が殺菌力を発揮する細菌の種類を確認するために、前記表4に示したKU-5878変異体のうちKU-5878-K4を代表に選定して、下記表5に示した細菌に対する抗菌活性をバクテリア殺菌最小濃度測定法を利用して測定した。バクテリア殺菌最小濃度測定法は前記実施例1の方法と同様に行った。
前記実施例4-1でKU-5878の親水性残基を正電荷を含むアミノ酸に置換する場合にも、その抗菌活性が維持されるか、より優れた抗菌活性を示すことを確認し、次いで、KU-5878の疎水性残基を含み残基の構造が類似するメチオニン(M)またはイソロイシン(I)を親水性または残基の構造が異なるアミノ酸に置換した後、抗菌活性を殺菌最小濃度測定法を利用して比較確認した。実験は前記実施例1と同様の方法で行った。KU-5878変異体の具体的な情報および各細菌に対するMBC値は下記表6に示した。
次いで、KU-5878の抗菌活性に相応するか、それを上回る抗菌活性を有するKU-5878変異体を探索するために、KU-5878において疎水性残基を含むフェニルアラニン(F)を親水性または残基の構造が異なるアミノ酸に置換した後、抗菌活性を殺菌最小濃度測定法を利用して比較確認した。実験は前記実施例1と同様の方法で行った。KU-5878変異体の具体的な情報および各細菌に対するMBC値は下記表7に示した。
前記実施例4-4に続き、KU-5878においてアラニン(A)またはグリシン(G)をそれぞれグリシンまたはアラニンに置換した後、抗菌活性を殺菌最小濃度測定法を利用して比較確認した。実験は前記実施例1と同様の方法で行った。KU-5878変異体の具体的な情報および各細菌に対するMBC値は下記表8に示した。
前記実施例1~5に続き、KU-5878およびKU-5878-K4を構成するアミノ酸をD-型アミノ酸に置換したペプチド(KU-5878-D(all)およびKU-5878-K4-D)を合成してその抗菌活性を比較確認した。KU-5878-K4-Dは、KU-5878-K4において59番、62番、63番、66番リシンアミノ酸残基をD-形態のアミノ酸に置換したペプチドであり、KU-5878-D(all)は、KU-5878のすべてのアミノ酸をD-形態のアミノ酸に置換したペプチドである。
KU-5878の優れた抗菌活性とより高い安定性を有するペプチドを探索するために、KU-5878のC-末端をアミデーション(amidation)後、ペプチドの抗菌活性をバクテリア殺菌最小濃度測定法を利用して比較確認した。実験は前記実施例1と同様の方法で行った。KU-5878変異体の具体的な情報および各細菌に対するMBC値は下記表10に示した。
KU-5878(配列番号13)のアミノ酸配列に対して1個のアミノ酸を欠損させた変異体を作製し、抗菌活性を評価した。抗菌活性評価は下記表11に開示されている。
KU-5878(配列番号13)のアミノ酸配列に対して1つのアミノ酸を欠損させ、抗菌活性を評価した。抗菌活性評価は下記表12に開示されている。
KU-5878(配列番号13)のアミノ酸配列に対して1つのアミノ酸を置換させ、抗菌活性を評価した。抗菌活性評価は下記表13に開示されている。
U-5878-T59Kアミノ酸配列に対してQ62K、S63K、T66Kの置換を順次に追加し、抗菌活性を評価した。抗菌活性評価は下記表14に開示されている。
KU-5878のC末端にアミノ酸の繰り返し配列を追加し、抗菌活性度を評価した。下記表15によれば、KU-5878のC末端にR(arginine)繰り返し配列またはK(lysine)配列を付加すると抗菌活性が増加した。
Claims (10)
- 配列番号1で表されるアミノ酸配列で構成されたRomo1タンパク質の配列のうち52~62番目アミノ酸領域から選択される任意の1つのアミノ酸を基準として連続した18個のアミノ酸配列を含む抗菌ペプチド。
- 前記ペプチドは、配列番号2~12、14、および15からなる群より選択されるいずれか1つのアミノ酸配列を含むことを特徴とする、請求項1に記載の抗菌ペプチド。
- 前記ペプチドは、N-末端またはC-末端が変異(modification)したものであって、前記変異は、ペギレーション(PEGylation)、アセチレーション(acetylation)、カルボキシレーション(carboxylation)、リピデーション(lipidation)、またはアミデーション(amidation)であることを特徴とする、請求項1に記載の抗菌ペプチド。
- 配列番号16、30、40、および45のいずれか1つのアミノ酸配列からなる、抗菌ペプチド。
- 前記配列番号16は、配列番号17~29からなる群より選択されたいずれか1つのアミノ酸配列であり、
前記配列番号30は、配列番号31~39からなる群より選択されたいずれか1つのアミノ酸配列であり、
前記配列番号40は、配列番号41~44からなる群より選択されたいずれか1つのアミノ酸配列であり、
前記配列番号45は、配列番号46~47からなる群より選択されるいずれか1つのアミノ酸配列である、
請求項4に記載の抗菌ペプチド。 - 前記ペプチドは、N-末端、C-末端、または任意のアミノ酸が変形(modification)されたものであって、
前記変異は、ペギレーション(PEGylation)、アセチレーション(acetylation)、カルボキシレーション(carboxylation)、リピデーション(lipidation)、またはアミデーション(amidation)であることを特徴とする、請求項4に記載の抗菌ペプチド。 - 配列番号13のアミノ酸配列;または
配列番号13のアミノ酸配列に対して、下記の(a)~(h)の少なくとも1つのアミノ酸置換を含む配列からなる抗菌ペプチド:
(a)1番目アミノ酸KをRに置換、
(b)2番目アミノ酸TをKまたはRに置換、
(c)5番目アミノ酸QをKまたはRに置換、
(d)6番目アミノ酸SをK、R、またはHに置換、
(e)9番目アミノ酸TをKまたはRに置換、
(f)10番目アミノ酸FをWに置換、
(g)16番目アミノ酸IをLに置換、
(h)20番目アミノ酸IをGまたはLに置換。 - 前記抗菌ペプチドは、少なくとも1つのメチオニンがノルロイシンまたはイソロイシンに置換された、
請求項7に記載の抗菌ペプチド。 - 3、4、5、7、8、9、11、17、18、および19番目アミノ酸のいずれか1つが欠損;または3または4番目アミノ酸、および7または8番目アミノ酸が欠損した、
請求項7に記載の抗菌ペプチド。 - 前記抗菌ペプチドは、C末端に連結されたアミノ酸配列をさらに含み、
前記C末端に連結されたアミノ酸配列は、RまたはKが1~3個繰り返す配列からなるものである、
請求項7に記載の抗菌ペプチド。
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