JP6625071B2 - 慢性疼痛用のナトリウムチャネルを標的とする非麻薬性crmp2ペプチド - Google Patents
慢性疼痛用のナトリウムチャネルを標的とする非麻薬性crmp2ペプチド Download PDFInfo
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- JP6625071B2 JP6625071B2 JP2016573711A JP2016573711A JP6625071B2 JP 6625071 B2 JP6625071 B2 JP 6625071B2 JP 2016573711 A JP2016573711 A JP 2016573711A JP 2016573711 A JP2016573711 A JP 2016573711A JP 6625071 B2 JP6625071 B2 JP 6625071B2
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
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- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
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Description
本願は、2014年3月7日に出願した米国特許仮出願第61/949,456号に基づく優先権と、その利益を主張するものであり、この出願は、参照によりその全体が本明細書に援用される。
〔技術分野〕
本開示は、ペプチド、特には、非麻薬性鎮痛性ペプチド、及び慢性疼痛の治療方法を含むその使用方法に関する。
〔背景技術〕
全世界で約15億人が、様々な病因の慢性疼痛を患っている。疼痛は、戦場で負傷した兵士及び退役軍人の障害の主因である。急性及び慢性疼痛は、一般人の比率を大きく上回る比率で、軍人と退役軍人を苦しめている。不朽の自由作戦またはイラクの自由作戦の退役軍人の限定的コホート研究では、81.5%が慢性疼痛を経験したことが明らかになった。全退役軍人の30%近くが、持続的な慢性疼痛を治療してもらいたいと考えている。
〔発明の概要〕
本明細書では、電位依存性ナトリウムチャネルアイソフォーム1.7(Nav1.7)を調節するペプチドを開示する。特に、開示するペプチドは、コラプシン応答メディエータタンパク質2(CRMP2)の低分子ユビキチン様修飾因子(SUMO)化によるNav1.7機能のトラフィッキングを阻止、阻害及び/または低下させるとともに、慢性疼痛状態(例えば、熱傷痛、関節痛、腸の炎症、一部のがん性疼痛及び糖尿病性神経障害のようなある種の神経損傷に付随する神経炎症)などの疼痛の管理を含む、Nav1.7によって調節される障害、状態及び疾患を緩和するのに用いることができる。
(a)GRKKRRQRRRPPQ(配列番号3)、
(b)RQIKIWFQNRRMKWKK(配列番号4)、
(c)LLIILRRRIRKQAHAHSK(配列番号5)、
(d)RGGRLSYSRRRFSTSTGR(配列番号6)、
(e)RRRRRRRRR(配列番号7)、
(f)GRRRRRRRRRPPQ(配列番号8)、
(g)AAVALLPAVLLALLAP(配列番号9)、
(h)KLALKLALKALKAALKLA(配列番号10)、
(i)TRRQRTRRARRNR(配列番号11)、
(j)PLSSIFSRIGDP(配列番号12)、
(k)MALNLGWLLALFVTMWTDVGLCKKRPKP(配列番号13)、
(l)AGYLLGKINLKALAALAKKIL(配列番号14)、または
(m)PLSSIFSRIGDP(配列番号15)
というアミノ酸配列を有する細胞透過性モチーフのような細胞透過性モチーフを更に含む。
〔図面の簡単な説明〕
図1A〜1C:CRMP2は、保存された負電荷SUMO化モチーフ(NDSM)コンセンサス配列を含む。(図1A)可逆性のSUMOサイクルと、CRMP2などの修飾タンパク質の一般的な結果は次の通りである。(i)SUMO化は、標的とそのパートナーとの相互作用を妨げることができるが、この場合の相互作用は、SUMO化が存在しないときのみに発生し得るものである。(ii)SUMO化によって、相互作用パートナーに対する結合部位をもたらすことができる。(iii)SUMO化によって、修飾した標的の立体構造変化をもたらすことができる。CRMP2では、これらのシナリオのうちのどれが生じるのかは不明である。(図1B)齧歯類動物CRMP1〜5の配列(それぞれ、配列番号16、配列番号2、配列番号17、配列番号18及び配列番号19)の短い領域を整列させたものであり、CRMPのSUMO化コンセンサスモチーフが黄色でハイライトされている。その基準モチーフの端側(右側)に隣接する負電荷酸性部分の存在は、更にストリンジェントなNDSMに適合する。数字は、ラットCRMP2のアミノ酸残基を指す。(図1C)。球(矢印)によって識別されるSUMO化モチーフ残基を有するCRMP2の構造図である。明確にするために、CRMP2四量体のうちの3つのモノマーのみが示されている。
配列表に列挙されている核酸配列及びアミノ酸配列は、37C.F.R.1.822に定義されているように、ヌクレオチド塩基の標準的な略記とアミノ酸の3文字表記を用いて示されている。各核酸配列の1本の鎖しか示されていないが、示されている鎖を参照することによって、相補鎖が含まれるものと理解する。添付の配列表では、以下のとおりである。
配列番号2は、例示的なペプチドCSM−1Lのコンセンサスアミノ酸配列であり、
配列番号3〜15は、例示的な細胞透過性モチーフのアミノ酸配列であり、
配列番号16は、CRMP1の部分アミノ酸配列であり、
配列番号17は、CRMP3の部分アミノ酸配列であり、
配列番号18は、CRMP4の部分アミノ酸配列であり、
配列番号19は、CRMP5の部分アミノ酸配列であり、かつ
配列番号20は、ラットCRMP2の完全なアミノ酸配列である。
〔発明を実施するための形態〕
I.序論
疼痛シグナル伝達は典型的には、情報を中枢神経系(CNS)に伝える末梢神経系の感覚ニューロンに由来する。これらの末梢感覚ニューロンの興奮性が変化すると、病的な疼痛感覚が生じることがある。電位依存性ナトリウムチャネル(VGSC、Nav)は、活動電位の発生及び伝播を調節する重要な決定因子であるため、ナトリウムチャネル機能の変化は、神経興奮性及び疼痛シグナル伝達に重大な影響を及ぼすことがある。Nav1.7アイソフォームは、末梢神経系において、後根神経節、三叉神経節及び交感神経節を含む、侵害受容性疼痛に関連する神経節内で優先的に発現する。疼痛シグナルの伝達を担う侵害受容ニューロンでは、上記のチャネルは、刺激に応じて活動電位を発生させるのに必要な電流閾値を調節する。
別途示されない限り、技術用語は、従来の用法に従って用いられている。別段の説明のない限り、本明細書で用いられている全ての技術用語及び科学用語は、本開示の属する技術分野に精通する者が一般的に理解しているものと同じ意味を有する。文脈によって明確に別段に示されている場合を除き、「a」、「an」及び「the」という単数形の用語には、複数形の指示物が含まれる。本開示の実施または試験の際には、本明細書に記載されているものと同様または同等の方法及び材料を用いることができるが、好適な方法及び方法が後述されている。
本明細書には、コラプシン応答メディエータタンパク質2(CRMP2)の低分子ユビキチン様修飾因子(SUMO)化によるNav1.7機能のトラフィッキングを調節するCRMP2 SUMO化モチーフ(CSM−1)のペプチドが開示されており、これらのペプチドを用いて、Nav1.7によって調節される障害、状態及び疾患を調整することができる。炎症性及び神経病性疼痛状態を含む、急性疼痛及び慢性疼痛などの疼痛を伴う状態を治療するために、これらのペプチドを調製かつ使用する方法を提供する。また、有効量の鎮痛性分子、すなわち開示されているペプチドを血流に投与することによって、個体に対して鎮痛又は疼痛の緩和をもたらす方法も開示されている。特定の態様では、がんによる疼痛を治療する方法を開示する。パーキンソン病、アルツハイマー病、ピック病及び慢性疲労症候群などの神経状態を治療及び阻止、または改善する方法、ならびに情緒または気分障害を治療する方法も提供する。特定の実施形態では、本開示のペプチドは、KMDというアミノ酸配列を含み、典型的には、3〜18アミノ酸長、より好ましくは5〜8アミノ酸長である。
(a)GRKKRRQRRRPPQ(配列番号3)、
(b)RQIKIWFQNRRMKWKK(配列番号4)、
(c)LLIILRRRIRKQAHAHSK(配列番号5)、
(d)RGGRLSYSRRRFSTSTGR(配列番号6)、
(e)RRRRRRRRR(配列番号7)、
(f)GRRRRRRRRRPPQ(配列番号8)、
(g)AAVALLPAVLLALLAP(配列番号9)、
(H)KLALKLALKALKAALKLA(配列番号10)、
(i)TRRQRTRRARRNR(配列番号11)、
(j)PLSSIFSRIGDP(配列番号12)、
(k)MALNLGWLLALFVTMWTDVGLCKKRPKP(配列番号13)、
(l)AGYLLGKINLKALAALAKKIL(配列番号14)または
(m)PLSSIFSRIGDP(配列番号15)
というアミノ酸配列のうちの1つ以上を有する細胞透過性モチーフに結合している。
本開示の組成物は、製薬学的に許容可能な担体/賦形剤を更に含んでよく、これらには、本明細書で使用する場合、製薬学的に許容可能な担体/賦形剤には、所望の特定の剤形に適するようなあらゆる溶剤、希釈剤またはその他の液体ビヒクル、分散補助剤、懸濁補助剤、表面活性剤、等張化剤、増粘剤または乳化剤、保存剤、固体結合剤、潤滑剤などが含まれる。E.W.MartinのRemington’s Pharmaceutical Sciences第21版、(Mack Publishing Co.,Easton,Pa.,2005)には、製薬学的に許容可能な組成物の調合で用いる様々な担体、及びそれらの担体を調製するための既知の技法が開示されている。従来の任意の担体媒体が、望ましくないいずれかの生物学的作用をもたらしたり、さもなければ製薬学的に許容可能な組成物の他の任意の構成成分(複数可)との相互作用を有害な形で生じさせたりすることなどによって、本発明の化合物と不適合である場合を除き、その担体媒体の使用は、本開示の範囲内に含まれるものと考えられる。製薬学的に許容可能な担体として機能することができる物質のいくつかの例としては、イオン交換体、アルミナ、ステアリン酸アルミニウム、レシチン、血清タンパク質(ヒト血清アルブミンなど)、緩衝物質(リン酸、グリシン、ソルビン酸またはソルビン酸カリウム、飽和植物脂肪酸の部分グリセリド混合物など)、水、塩または電解質(硫酸プロタミン、リン酸水素二ナトリウム、 リン酸水素カリウム、塩化ナトリウム、亜鉛塩など)、コロイダルシリカ、三ケイ酸マグネシウム、ポリビニルピロリドン、ポリアクリル酸塩、ワックス、ポリエチレン−ポリオキシプロピレンブロックポリマー、羊毛脂、糖、デンプン、セルロース及びその誘導体、トラガント末、麦芽、ゼラチン、タルク、賦形剤(ココアバター及び座薬ワックスなど)、油(ラッカセイ油、綿実油、ベニ花油、ゴマ油、オリーブ油、コーン油及び大豆油など)、グリコール(プロピレングリコールまたはポリエチレングリコールなど)、エステル(オレイン酸エチル及びラウリン酸エチルなど)、寒天、緩衝剤(水酸化マグネシウム及び水酸化アルミニウムなど)、アルギン酸、パイロジェンフリー水、等張食塩水、リンゲル液、エチルアルコール及びリン酸緩衝液、ならびにその他の非毒性適合性潤滑剤(ラウリル硫酸ナトリウム及びステアリン酸マグネシウムなど)、ならびに着色剤、放出剤、コーティング剤、甘味剤、矯味矯臭剤、付香剤、保存剤、ならびに抗酸化剤が挙げられるが、これらに限らず、これらは、調合者の判断に従って、本発明の組成物中に存在させることができる。
本開示のペプチド、組成物及び製剤は、Nav1.7によって調節される障害状態及び疾患の予防及び/または治療に有用であり、その障害、状態及び疾患としては、急性及び慢性疼痛、侵害受容性疼痛、がん性疼痛、神経痛、筋肉痛、熱傷痛、関節痛、腸の炎症疼痛、骨痛及び骨粗しょう症の疼痛、ならびに炎症性疼痛(ある種の神経損傷(例えば、糖尿病性神経障害)に付随する神経炎症など)が挙げられるが、これらに限らない。本ペプチドの一部として治療可能なその他の状態としては、パーキンソン病、アルツハイマー病、ピック病及び慢性疲労症候群のような神経障害が挙げられる。開示されているペプチドを用いて、うつ病、PTSD、不安神経症、耽溺及び強迫性障害のような情緒及び気分障害も治療することができる。開示されているペプチドを用いて、外傷性脳損傷に付随する疼痛も治療することができる。いくつかの例では、開示されているペプチドを用いて、片頭痛に付随する疼痛を治療する。いくつかの例では、開示されている組成物は、物質使用障害(SUD)またはオピオイド治療剤を投与することができないその他の状態/疾患を患っているか又は発症する可能性がある対象に投与する。
本明細書に開示されている方法では、Nav1.7によって調節される障害、状態及び/または疾患を患っている対象に、本明細書に記載されている組成物を含む医薬組成物を有効量(治療有効量など)投与する。Nav1.7によって調節される障害、状態及び/または疾患に付随する1つ以上の徴候または症状を抑制または軽減するために、開示されている医薬組成物の治療有効量を定めるアッセイが、本明細書に記載されている(例えば、実施例を参照のこと)。
Nav1.7によって調節される例示的な障害、状態及び疾患としては、急性及び慢性疼痛、侵害受容性疼痛、がん性疼痛、神経痛、筋肉痛、熱傷痛、関節痛、腸の炎症疼痛、骨痛及び骨粗しょう症の疼痛、炎症性疼痛(ある種の神経損傷(例えば糖尿病性神経障害)に付随する神経炎症など)、神経障害(例えば、パーキンソン病、アルツハイマー病、ピック病及び慢性疲労症候群)、情緒及び気分障害(例えば、うつ病、PTSD、不安神経症、耽溺及び強迫性障害)、外傷性脳損傷に付随する疼痛、片頭痛に付随する疼痛、ならびに/または物質乱用障害が挙げられるが、これらに限らない。
〔実施例〕
実施例1
材料及び方法
この実施例では、本明細書に記載されている試験で用いた材料及び方法を示す。
触覚過敏:ベースラインのフォンフライ試験(von Frey testing)の前に、吊るした金網ケージ内で、ラットを30分、順化する(神経結紮前、神経結紮後、偽手術前または偽手術後)。化合物またはビヒクルの投与後(t=0)、最初の60分間は、以前から用いられている上げ下げ法(参照により本明細書に援用されるChaplan et al.,J.Neurosci.Methods.53,55−63(1994))を用いて、15分間隔で7秒間、左後足(SNLと同じ側)の足底面に垂直にプローブされた較正済みフォンフライフィラメント(0.4〜15.0g)に対する反応を評価する。その足を上げること、その足を舐めること、または声を出すことは、較正済みフィラメントに対する陽性反応として計数する。既に報告されているようなDixonのノンパラメトリック法(参照により本明細書に援用されるLargent−Milnes,T.M.,et al.British Journal of Pharmacology 161,986−1001(2010))を用いて、足退避閾値をグラム単位で計算する。反対側の足では、試験を行わなかったのは、負傷している動物が、負傷している側よりも、負傷していない足の方に体重をかけるためである。
CRMP2由来の抗侵害受容性非麻薬性ペプチドによる慢性疼痛の治療
この実施例によって、CRMP2由来の抗侵害受容性非麻薬性ペプチドが慢性疼痛を治療する能力が示されている。特に、(1)CRMP2のSUMO化が、Nav1.7の電流密度及び表面トラフィッキングにとって重要であること、(2)CRMP2 SUMO化モチーフ(CSM)ペプチドが、Nav1.7の膜表面へのトラフィッキング及び電流密度を阻止すること、及び(3)Nav1.7の電流を低下させる、CRMP2のSUMO化に影響を及ぼす操作が、炎症性及び神経病性疼痛のモデルにおいて、オピオイドで見られる望ましくない副作用を起こすことなく、抗侵害受容性であることを本発明者は発見した。現時点では、慢性疼痛を抑えるための持続可能な治療が不足していることを考えれば、本明細書に報告されている発見は、革新的かつ非常に重要なことであるのみならず、早急に必要とされることでもある。
Nav1.7チャネルは、望ましくない副作用を起こさない選択的及び特異的アンタゴニストの設計が実現されていない慢性疼痛を研究する際の分子標的である。Nav1.7は、DRGで見られるが、中枢神経系では見られず、肢端紅痛症、発作性激痛症及び糖尿病性神経障害のような衰弱性慢性疼痛状態に関連付けられているが、製薬会社及び薬学会は、この特有の慢性疼痛標的を活用してこなかった。Nav1.7は、慢性末梢炎症及び末梢神経損傷の動物モデルにおいて、アップレギュレートされて、慢性疼痛を促進する。本発明では、低分子ユビキチン様修飾を用いてNav1.7のトラフィッキングを調節するCRMP2を変化させて、慢性炎症及び神経損傷の状態において、末梢ニューロンの表面におけるNav1.7の発現レベルを変化させるように、試験を設計する。この機構は、Nav1.7のトラフィッキングを低下させるが、密接な関係がある他のナトリウムチャネル(Nav1.1またはNav1.3チャネルなど)では低下させないことが示されている。加えて、本明細書中に示される試験により、この経路における新規ペプチド(tat−CSM−1S)が、神経損傷後に、熱痛覚過敏と機械刺激痛覚過敏の両方を有意に軽減する一方で、運動活動への影響または障害の明確な徴候が見られないことが示されている。したがって、開示されている新規化合物の薬理は、(a)十分に認められている神経病性疼痛モデル(坐骨神経部分損傷(SNI))及び慢性炎症性疼痛モデル(後肢中のフロイント完全アジュバント(CFA))における抗熱痛覚過敏及び抗機械刺激痛覚過敏についてインビボで試験し、(b)用量反応及び経時的反応のデータを収集し、(c)神経病性疼痛用として現在入手可能な薬剤(モルヒネ及びガバペンチン)と比較し、(d)無傷のラット及び損傷ラットから採取した後根神経節(DRG)及び脊髄であって、試験化合物またはビヒクルで処理したDRG及び脊髄のNav1.7レベル及びCRMP2レベルを調べ、(e)DRG及び脊髄組織に対して、プロテオミクスベースの分析も行って、損傷の代替的な標的及び/またはバイオマーカーを特定し、(f)ロータロッドを用いて鎮静/運動作用を調べ、かつ(g)場所条件付け嗜好性(CPP)を用いて、依存性傾向を調べる。いずれの試験でも、雄スプラーグドーリーラット(Harlan、175〜225g)を用いる。いずれの試験も盲検で行い、薬剤/ビヒクルを髄腔内経路(作用部位での試験)及び鼻腔内経路(BBB透過のための全身投与)で投与する。気道、特に鼻は、薬物送達を向上させる機会を提供する。多くの薬剤は、鼻腔から迅速かつ効率的に吸収されるので、経鼻経路は、クリーゼの治療(例えば疼痛及び悪心)に用いることができる。徐放性生分解性ナノ粒子中のペプチドの直接的な鼻腔−脳送達は、CNS生物学的利用能を高めるのに有効な治療経路であるとともに、現役勤務の戦闘状況下にある軍人向けの、関連性の高い送達経路と考えられる。
侵害受容を抑える方法
この実施例では、急性疼痛、慢性疼痛、侵害受容性疼痛、がん性疼痛、神経疼痛、筋肉疼痛、熱傷痛、関節痛、腸の炎症疼痛、骨痛及び/若しくは骨粗しょう症の疼痛、炎症性疼痛、またはこれらの組み合わせを患う恐れがあるかまたは患っている対象などにおいて、侵害受容を抑える方法を説明する。いくつかの例では、対象は、パーキンソン病、アルツハイマー病、ピック病及び/または慢性疲労症候群などの神経障害を患う恐れがあるかまたは患っている。いくつかの例では、対象は、うつ病、PTSD、不安神経症、耽溺及び強迫性障害などの情緒及び/または気分障害を患う恐れがあるかまたは患っている。
Claims (14)
- コラプシン応答メディエータタンパク質2(CRMP2)の低分子ユビキチン様修飾因子(SUMO)化による電位依存性ナトリウムチャネル1.7(Nav1.7)機能のトラフィッキングを阻止することができる、3〜20個のアミノ酸からなる単離ポリペプチドであって、前記3〜20個のアミノ酸が、KMDというアミノ酸配列を含み、
前記ペプチドが、GKMDENQというアミノ酸配列(配列番号1、CSM−1S)を含む、前記単離ポリペプチド。 - 前記ペプチドが、WDKAVVTGKMDENQFVAVというアミノ酸配列(配列番号2、CSM−1L)を含む、請求項1に記載の単離ペプチド。
- 細胞透過性モチーフを更に含む、請求項1または2に記載の単離ポリペプチド。
- 前記細胞透過性モチーフが、
(a)GRKKRRQRRRPPQ(配列番号3)、
(e)RRRRRRRRR(配列番号7)、
(f)GRRRRRRRRRPPQ(配列番号8)、
(i)TRRQRTRRARRNR(配列番号11)、
(j)PLSSIFSRIGDP(配列番号12)、または
(m)PLSSIFSRIGDP(配列番号15)
というアミノ酸配列を有する、請求項3に記載の単離ポリペプチド。 - 請求項1〜4のいずれか1項に記載の単離ポリペプチドと、製薬学的に許容可能な担体とを含む組成物。
- 請求項1〜4のいずれか1項に記載のポリペプチドをコードする核酸配列を含むベクター。
- 請求項6に記載のベクターを含む細胞。
- 非ヒトである対象に、請求項1〜4のいずれか1項に記載の単離ポリペプチド、または請求項5に記載の組成物を有効量投与し、それによって、前記対象の侵害受容を抑えることを含む、侵害受容の抑制方法。
- 前記投与が、静脈内、髄腔内、腹腔内、皮下、経口、経皮、硬膜外または舌下投与を含む、請求項8に記載の方法。
- 前記対象が、急性疼痛、慢性疼痛、侵害受容性疼痛、がん性疼痛、神経疼痛、筋肉疼痛、熱傷痛、関節痛、腸の炎症疼痛、骨痛及び/若しくは骨粗しょう症の疼痛、炎症性疼痛、またはこれらの組み合わせを患う恐れがあるかまたは患っている、請求項8または9に記載の方法。
- 前記対象が、パーキンソン病、アルツハイマー病、ピック病及び/または慢性疲労症候群などの神経障害を患う恐れがあるかまたは患っている、請求項8または9に記載の方法。
- 前記対象が、うつ病、外傷後ストレス障害(PTSD)、不安神経症、耽溺及び強迫性障害などの情緒及び/または気分障害を患う恐れがあるかまたは患っている、請求項8または9に記載の方法。
- 非ヒトの細胞を、有効量の、請求項1〜4のいずれか1項に記載の単離ポリペプチド、または請求項5に記載の組成物と接触させ、それによって、電位依存性ナトリウムチャネル1.7(Nav1.7)の活性を調節することを含む、電位依存性ナトリウムチャネル1.7(Nav1.7)の活性の調節方法。
- 前記調節が、コラプシン応答メディエータタンパク質2(CRMP2)の低分子ユビキチン様修飾因子(SUMO)化による電位依存性ナトリウムチャネル1.7(Nav1.7)機能のトラフィッキングを阻止、阻害及び/または未処置細胞で生じるトラフィッキングと比べて低下させることを含む、請求項13に記載の方法。
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