JP2018507259A - 抗微生物ペプチド - Google Patents
抗微生物ペプチド Download PDFInfo
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- JP2018507259A JP2018507259A JP2017562150A JP2017562150A JP2018507259A JP 2018507259 A JP2018507259 A JP 2018507259A JP 2017562150 A JP2017562150 A JP 2017562150A JP 2017562150 A JP2017562150 A JP 2017562150A JP 2018507259 A JP2018507259 A JP 2018507259A
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Abstract
Description
未変性セクロピンAおよびBSAと比較して向上したOMN6の安定性
プロテイナーゼK(ProtK)を、未変性セクロピンA(CecA)およびウシ血清アルブミン(BSA)に対するOMN6の安定性を評価するために用いた(図1Aを参照)。10μgのそれぞれのタンパク質を、指定したように5〜20ngの間のProtKの濃度を増加して、37℃で2時間インキュベートした。試料を、100℃で5分間沸騰させて15%アクリルアミドゲル上に分離した。ゲルを、次いでクーマシーブルーで染色して過剰な染料を一晩かけて除去した。結果は、20ngのProtKが、CecAおよびBSAを完全に分解するのに十分であったことを明確に示す(レーン:それぞれ3、9)。見て分かるように、OMN6は、ProtKタンパク質分解から保護されており分解されなかった(レーン:6)。結果は、5ngの低濃度でのProtKが、CecAおよびBSAを部分的に分解するのに十分であったことも示す(レーン:それぞれ2、8)。レーン2において、CecAバンドは、レーン1における未処置の試料バンドよりも弱かった。レーン8において、部分的分解の証拠である、分解されたBSAのフラグメントが、検出された。OMN6は、ProtKによって全く分解されなかった。これらの結果は、OMN6は、遺伝子操作後、その未変性形態である、セクロピンAよりも安定であることを証明する。上述と同じ実験系を、ProtKによるタンパク質分解性分解に対するOMN2、OMN7およびOMN11の安定性を評価するために用いた(図1Bを参照)。指定したような、いずれの場合にも、結果は、OMNペプチドがProtKによって分解されないことを示す。ペプチドは、それぞれのペプチドについて現れたバンドの同等の強度から見て分かるように安定である。
図2A:OMN6は、未変性ペプチドセクロピンAより強力な抗微生物作用を発揮する。
アッセイを、本発明のペプチドOMN6に対して未変性ペプチドセクロピンA(CecA)の抗微生物活性を比較するために実行した。大腸菌細菌を、12.5μMの濃度のCecAまたはOMN6と共に17〜20時間培養した。細菌の増殖を、分光光度法によって600nmで連続的に観測した。細菌増殖が進行するにつれて、OD600nm値は上昇し、かつ増殖が阻害された場合はOD600nm値は一定のままである。結果は、12.5μMの濃度において、遺伝子操作されたペプチドOMN6は、強い抗微生物作用を発揮しかつ実験の全継続期間である、17時間より長く細菌増殖を完全に阻害したことを明確に示す。より高濃度においても細菌増殖は、同様に全面的に阻害された(データは示さず)。対照的に、細菌を12.5μMのCecAと共に同実験条件下でインキュベートした場合、増殖の有意の阻害はなかった。細菌は、10時間後にCecAの阻害効果を完全に克服した。次いで細菌を引き続き繁殖させてCTRL群のものと同様の密度に増殖させた。総合すればこれらの結果は、OMN6が、新しくかつその未変性の対応するCecAより強力な抗微生物剤であることを強く示唆するために役立つ。
タンパク質分解性分解に対するOMN6/CecAの感受性を評価して活性への安定性の影響を判定した。未変性ペプチド−CecAおよび改変ペプチド−OMN6を、20ngのプロテイナーゼK(ProtK)と共に37℃で2時間インキュベートした(それぞれ、左の棒および右の棒)。500,000CFU/mlの大腸菌を、ProtKで前処置したCecAまたはOMN6と共に18時間インキュベートした。インキュベーション後、細菌生存をOD600nmにおける吸収および寒天プレート上のCFU数によって判定した。
OMN6処置は、細菌細胞溶解および細胞から囲繞している培地へのGFPの漏出に繋がる。
ペプチドが発揮する注目に値する抗微生物作用を達成する作用機序(MOA)を判定および評価するために、以下の実験を実施した:GFPuv大腸菌細菌は、誘導すると緑色蛍光タンパク質(GFP)を発現する株である。GFP蛍光は、395/509nmで検出され得る一方で、生存細菌は、600nmにおける吸光度(OD600)によって検出さ得る。
OMN2、OMN6、OMN7およびOMN11は、HEK293細胞において細胞毒性を呈さない。
ヒト胎児由来腎臓293細胞(HEK293)は、潜在的な有害物質の副作用を評価するためのモデル細胞株として広く受け入れられているヒト由来細胞である。HEK293細胞を、80%培養密度まで培養して増加濃度のOMN2、OMN6、OMN7およびOMN11に導入した。CTRL群はDDWで処置した。
OMN6は、ヒト初代赤血球(Human Primary Erythrocytes)で細胞毒性を呈さない。
本発明のペプチドは、特に創傷または他の損傷した組織において作用することが意図されるので、患者の血液との直接接触が発生し得る。したがって、OMN6がヒト初代赤血球への細胞毒性を有するかどうかを評価するために実験を実施した。これらの細胞は、形質膜への損傷に対してそれらを保護するためのいかなる防御反応機序もなくかつそのために真核細胞での細胞毒性を評価するための標準モデルである。測定されたパラメーターは、ヒト赤血球における、溶血、赤血球死を引き起こすOMN6の能力であった。実験は、こうした試験を実施するために病院職員によって日常的に用いられるABX PENTRA DF120装置を用いてヒト血液試料で実施した。結果は、細胞の溶血が発生しなかったことを示す。赤血球は、OMN6と接触することの結果として死滅しなかった。実験の初めの細胞の数は、実験群のいずれにおいても実験の期間全体を通して変化せずかつ細胞の数/mmlは、CTRL群と実験群との間で異ならなかった(表4)。
In−Vitroでの感受性および耐性細菌へのOMNペプチド最小阻害濃度(MIC)値
ペプチドのMIC値を判定するために、種々の細菌の増殖および阻害を、本発明のペプチドでの処置後に観測した(表6)。大腸菌細菌を、0.8〜200μMの増加濃度においてOMN6ありまたはなしでおよびウシ胎児血清10%ありまたはなしで17〜20時間培養した。細菌の増殖を、分光光度法によって600nmで連続的に観測した。細菌増殖が進行するにつれて、OD600nm値は上昇し、かつ増殖が阻害された場合はOD600nm値は一定のままである。
In−Vitroでの感受性および耐性細菌へのOMNペプチド最小殺菌濃度(MBC)値
ペプチドの最小殺菌濃度(MBC)値を判定するために、種々の細菌株のコロニー形成を、本発明のペプチドでの処置後に観測および判定した。多剤耐性A.バウマニ細菌を、図6および実施例6に詳述するように、増加濃度のOMN6ありまたはなしで培養した。このあとすぐに、それぞれの実験群の試料を、必要に応じて1×104から1×106に希釈し、さらに、試料を適切な培地−寒天プレート上に平板培養した。全てのプレートを、37℃で24〜48時間インキュベートした。コロニーを計数し、平板培養に先立って、元の試料におけるCFU/mlを計算して判定した。インキュベーション後の、プレートの実施例を、図7において示し、画像の左側のプレートは、DDWで処置したCTRL試料でありかつ画像の右側のプレートは、その中に指定されるように、増加濃度のOMN6が示される。結果は、CTRL群における細菌の大量増殖を示し、0.62μMおよび1.25μMの濃度群においてCTRL、ならびにOMN6における増殖の阻害は検出されない。2.5μM、5μMおよび10μMのOMN6で処置した群においてプレートは透明であり、すなわちコロニーが無い。
マウスモデルにおけるOMN6抗微生物ペプチド予備安全性
毒性効果があるかどうかを評価および定量化するために抗微生物ペプチドOMN6をマウスに投与した。OMN6ペプチド(C195H332N56O49S3)を、表9に詳述した濃度および群に従って局所に投与した。
1.マウス(1群当り6匹)に群の明細に従って第1日目に単回用量投与を与えた(表9)。全ての群におけるマウスの死亡と共に食物および水消費(体重分析)を、処置後4日間観測した。5日間の試行の終わりに、動物をと殺した。
2.赤血球溶血分析のために、遊離Hgb(ヘモグロビン)アッセイを、全ての群からの全ての試料で、第5日目に実施した。
3.水/食物の入手しやすさ、温度および他の条件は、5日間の試行全体で群間で変更しないままであった。
4.赤血球溶血分析を、ヘモグロビンアッセイキット(Sigma−Aldrich、3Plaut St.、イスラエル、レホヴォト)によって実施した。
1.マウス(1群当り6匹)に群の明細に従って第1日目に単回用量投与を与えた(表10)。全ての群におけるマウスの死亡と共に食物および水消費(体重分析)を、処置後3日間観測した。4日間の試行の終わりに、動物をと殺した。
2.赤血球溶血分析のために、遊離Hgb(ヘモグロビン)アッセイを、全ての群からの全ての試料で、第4日目に実施した。
3.水/食物の入手しやすさ、温度および他の条件は、4日間の試行全体で群間で変更しないままであった。
4.赤血球溶血分析を、ヘモグロビンアッセイキット(Sigma−Aldrich、3 Plaut St.イスラエル、レホヴォト)によって実施した。
大腸菌でのマウスモデル皮下感染におけるOMN6有効性
動物:重量16〜20gの健常な成体雌マウスを用いた。CD−I非近交系(Harlan Breeding Labs、イスラエル、エルサレム)を、全ての実験において用いた。動物を、5〜10匹の群で檻に入れて食物(Ralston Purina)および水は自由に維持した。
Claims (33)
- セクロピンファミリーのメンバーのアミノ酸配列と同一または類似である、コアアミノ酸配列を含むペプチドであって、前記コアアミノ酸配列が、N末端基によってN末端において延長されおよび/またはC末端基によってC末端において延長されており、かつ前記N末端基および/または前記C末端基が同一または異なるまたは空白でありかつ分子間共有結合によって環状ペプチドまたはホモマルチマーアセンブリを形成するために共有結合を形成する能力がある、ペプチド。
- 前記セクロピンファミリーの前記メンバーが、AMP CMIV、セクロピンA、セクロピンB、セクロピンB2、セクロピンD、セクロピンIA、およびセクロピンP1の群に属する、請求項1に記載のペプチド。
- 前記環状ペプチドが、トポロジーが頭−尾、側鎖−側鎖、頭−側鎖または側鎖−尾または主鎖−主鎖または側鎖−主鎖または頭−主鎖または尾−主鎖である、前記トポロジーを有する、請求項1に記載のペプチド。
- 前記共有結合が、酸化的および/または酸性の生理学的条件下で形成される、請求項1に記載のペプチド。
- 前記セクロピンファミリーの前記メンバーの前記アミノ酸配列が、17〜144個のアミノ酸を含む、請求項1に記載のペプチド。
- 前記セクロピンファミリーのメンバーの前記コアアミノ酸配列が、配列番号12〜22に示されている通りである、請求項1に記載のペプチド。
- 前記コアアミノ酸配列が、配列番号12〜22に示されている前記アミノ酸配列に対して少なくとも70%、75%、80%、85%、90%、95%または99%の配列同一性を有する、請求項1に記載のペプチド。
- 前記コアアミノ酸配列が、1つまたは複数の位置における置換、保存的アミノ酸置換、保存的に修飾された配列変異体、欠失、および/または挿入を含む、請求項1に記載のペプチド。
- 前記C末端基および/または前記N末端基が、システイン、システイン誘導体、システインを含有するアミノ酸配列またはチオール部分を含む基あるいはそれらの任意の組み合わせのうちの1つまたは複数を含む、請求項1に記載のペプチド。
- 前記C末端基および/または前記N末端基が、システイン、システイン誘導体、システインを含有するアミノ酸配列または任意の他のチオール部分を含む基からなる群からそれぞれ選択される、請求項1に記載のペプチド。
- 前記N末端基が、アミノ酸配列メチオニン−システイン、メチオニン−システイン誘導体、メチオニン誘導体−システインまたはメチオニン誘導体−システイン誘導体を含みかつ前記C末端基が、システインまたはシステイン誘導体である、請求項1に記載のペプチド。
- 前記C末端基が、アミノ酸配列メチオニン−システイン、メチオニン−システイン誘導体、メチオニン誘導体−システインまたはメチオニン誘導体−システイン誘導体を含みかつ前記N末端基が、システインまたはシステイン誘導体である、請求項1に記載のペプチド。
- 前記共有結合が、ジスルフィド結合である、請求項1に記載のペプチド。
- 前記共有結合が、アミド、ラクタムまたはペプチド結合である、請求項1に記載のペプチド。
- 前記N末端基および前記C末端基が、環状ペプチドを形成するように共有結合している、請求項1に記載のペプチド。
- 前記ペプチドが、前記分子間共有結合が、前記ペプチドの前記N末端基から追加の同一ペプチドの前記N末端またはC末端基までの間で形成されるようにあるいは前記分子間共有結合が、前記ペプチドの前記C末端基から追加の同一ペプチドの前記N末端またはC末端基までの間で形成されるように生理学的膜内で自己組織化される、請求項1に記載のペプチド。
- 前記ペプチドが、配列番号1〜11のうちのいずれかに示されている通りである、請求項1に記載のペプチド。
- 前記ペプチドが、配列番号1〜11に示されているアミノ酸配列に対して少なくとも70%、75%、80%、85%、90%、95%または99%の配列同一性であるアミノ酸配列を有する、請求項1に記載のペプチド。
- 前記ペプチドが、配列番号6に示されている通りである、請求項1に記載のペプチド。
- 前記ペプチドが、配列番号6に示されているアミノ酸配列に対して少なくとも70%、75%、80%、85%、90%、95%または99%の配列同一性であるアミノ酸配列を有する、請求項1に記載のペプチド。
- 請求項1〜20のいずれか一項に記載のペプチドをコードする核酸配列。
- 請求項21に記載の核酸を含むベクター。
- 請求項1〜20のいずれか一項に記載のペプチドまたは請求項21に記載の核酸を含む医薬組成物。
- 感染を治療する方法であって、請求項1〜20のいずれか一項に記載のペプチドまたは請求項23に記載の医薬組成物を、それを必要とする対象に投与するステップを含む方法。
- 対象における感染を治療するための薬物の製造における請求項1〜20のいずれか一項に記載のペプチドまたは請求項23に記載の医薬組成物の使用。
- 前記感染が、細菌、ウイルスおよび/または真菌感染である、請求項24に記載の方法または請求項25に記載の使用。
- 前記医薬組成物が、液体、クリーム、ゲル、ペースト、粉末、エマルション、軟膏、リニメント、ローション、経皮システム、注射流体、懸濁液、パッチフィルム貼付剤または噴霧液の形態である、請求項23に記載の医薬組成物。
- カプセルまたは錠剤の形態である、請求項23に記載の医薬組成物。
- 前記組成物または前記ペプチドが、1種または複数の追加の抗炎症性活性薬剤と共に投与される、請求項21に記載の組成物、または請求項1〜18のいずれか一項に記載のペプチド。
- 抗生物質製剤に対する微生物の固有の耐性または獲得耐性を克服する方法であって、前記微生物を、請求項1〜20のいずれか一項に記載のペプチドまたは請求項23に記載の医薬組成物に接触させるステップを含む方法。
- 前記微生物が、大腸菌、肺炎桿菌、緑膿菌、サルモネラ血清型チフス菌、アシネトバクター−バウマニ、腸内細菌科種のメンバー、シュードモナス属種、サルモネラ属種、またはアシネトバクター属種、あるいは任意のそれらの組み合わせである、請求項30に記載の方法。
- 創傷を、請求項1〜20のいずれか一項に記載のペプチドまたは請求項23に記載の医薬組成物と接触させるステップを含む、創傷を殺菌する方法。
- 前記創傷が、水疱創傷、軟組織創傷、皮膚膿瘍、外科的創傷、縫合傷、汚染傷、火傷、褥瘡性潰瘍、鬱血性潰瘍、下肢潰瘍、足部潰瘍、静脈性潰瘍、糖尿病性潰瘍、虚血性潰瘍、圧迫潰瘍、経口感染、歯周疾患、中間層熱傷、または全層性熱傷である、請求項32に記載の方法。
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