JP6574412B2 - 癌治療の新たな手法としてのp53凝集の構造に基づくペプチド阻害剤 - Google Patents
癌治療の新たな手法としてのp53凝集の構造に基づくペプチド阻害剤 Download PDFInfo
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- JP6574412B2 JP6574412B2 JP2016513091A JP2016513091A JP6574412B2 JP 6574412 B2 JP6574412 B2 JP 6574412B2 JP 2016513091 A JP2016513091 A JP 2016513091A JP 2016513091 A JP2016513091 A JP 2016513091A JP 6574412 B2 JP6574412 B2 JP 6574412B2
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- 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
- C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
- C07K14/4711—Alzheimer's disease; Amyloid plaque core protein
-
- 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
- C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
- C07K14/4746—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used p53
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- G16B20/00—ICT specially adapted for functional genomics or proteomics, e.g. genotype-phenotype associations
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Description
本出願は、ASCII形式で電子的に提出された配列表を含み、参照により本明細書にその全体が組み込まれる。2014年5月8日に作成されたそのASCIIコピーは、58086−364665_SL.txtという名前が付けられ、24,636バイトの大きさである。
コンセンサス配列
によって表される阻害性ペプチド、またはその活性変異体。
[本発明1002]
コンセンサス配列
によって表される本発明1001の阻害性ペプチド、またはその活性変異体。
[本発明1003]
コンセンサス配列
で構成される、本発明1001の阻害性ペプチド。
[本発明1004]
コンセンサス配列
で構成される、本発明1001の阻害性ペプチド。
[本発明1005]
以下の配列:
のうちの1つを含む、本発明1001の阻害性ペプチド。
[本発明1006]
任意にリンカー配列を介して、細胞透過性ペプチド(CPP)に融合される、本発明1001の阻害性ペプチドまたはその活性変異体を含むCPP阻害剤。
[本発明1007]
コンセンサス配列
によって表される本発明1006のCPP、またはその活性変異体。
[本発明1008]
本発明1001〜1007のいずれかの阻害性ペプチドまたはCPPと、薬学的に許容される担体と、を含む、薬学的組成物。
[本発明1009]
p53と、本発明1001〜1007のいずれかの阻害性ペプチドまたはCPPとを含む、複合体。
[本発明1010]
異常な立体構造を有するp53タンパク質分子の立体構造を修復するための方法であって、
前記異常な立体構造を有する前記p53分子を、有効量の本発明1001〜1007のいずれかの阻害性ペプチドまたはCPP阻害剤と接触させることを含み、
前記接触したp53が、修復された立体構造を有し、
前記修復された立体構造を有する前記p53分子が、アポトーシスの誘発、細胞増殖の阻害、及び/または腫瘍縮小の誘発から選択される活性を呈する、前記方法。
[本発明1011]
異常な立体構造を有するp53に起因する細胞の増殖を予防及び/または阻害するための方法であって、前記細胞を、有効量の本発明1001〜1007のいずれかの阻害性ペプチドまたはCPP阻害剤と接触させることを含む、前記方法。
[本発明1012]
異常な立体構造を有するp53に関連する癌を有する対象を治療するための方法であって、前記対象に、有効量の本発明1008の薬学的組成物を投与し、それにより、前記対象における癌細胞の増殖を阻害すること、および/または前記対象の腫瘍を縮小させることを含む、前記方法。
[本発明1013]
癌を発症しやすくするp53をコードする突然変異遺伝子を有する対象を治療するための方法であって、前記対象に、合計で有効量の本発明1008の薬学的組成物を含む複数の用量を投与し、それにより、前記対象における腫瘍の発症を予防することを含む、前記方法。
[本発明1014]
p53の凝集を低減または阻害するための方法であって、p53アミロイドプロトフィラメントを、有効量の本発明1001〜1007のいずれかの阻害性ペプチドまたはCPP阻害剤と接触させることを含む、前記方法。
[本発明1015]
p53の凝集を阻害する阻害性ペプチドを同定するためのコンピュータ実施方法であって、
標的ポリペプチド由来のp53セグメントTIITLE(SEQ ID NO:20)もしくはLTIITLE(SEQ ID NO:21)のジッパー形成配列または前記ジッパー形成配列の鏡体を含む、鋳型ペプチド配列を同定するステップであって、前記ジッパー形成配列が凝集して立体ジッパーになる、前記ステップと、
コンピュータ上で、前記鋳型ペプチド配列と好ましい立体及びエネルギー分子間相互作用を形成する少なくとも1つの相補的ペプチド配列を設計するステップであって、前記相互作用が前記立体ジッパーの上端または下端の一方または両方で生じる、前記ステップと、
前記相補的配列、前記相補的配列の鏡体、前記相補的配列のペプチド模倣物、及び前記相補的配列の前記鏡体のペプチド模倣物から成る群から選択される、候補阻害性ペプチド化合物を同定するステップと
を含む、前記方法。
[本発明1016]
容器内にパッケージ化された、本発明1001〜1007のいずれかの阻害性ペプチドまたはCPPを含むキット。
[本発明1017]
本発明1001〜1007のいずれかの阻害性ペプチドまたはCPPを作製する方法であって、それを化学的に合成するか、またはそれを組換えで生成することを含む、前記方法。
[本発明1018]
本発明1001〜1007のいずれかの阻害性ペプチドまたはCPPをコードする、発現ベクター。
によって表される阻害性ペプチド(例えば、単離されたペプチド)、またはその活性変異体である。1つの実施形態では、阻害性ペプチドは、コンセンサス配列
によって表されるか、またはその活性変異体である。阻害性ペプチドは、コンセンサス配列
で構成されてもよく、またはコンセンサス配列
で構成されてもよい。本発明の実施形態では、阻害性ペプチドは、表1に列挙される阻害性ペプチド配列のうちのいずれかで構成され得るか、またはそれを含み得る。つまり、ペプチドは、
であり得る。活性変異体を含む、先行の配列を有する阻害性ペプチドは、本明細書において「本発明の阻害性ペプチド」と称されることもある。
によって表されるか、またはその活性変異体である。このコンセンサス配列によって包含される配列を含むCPP阻害剤またはその活性変異体は、本明細書において「本発明のCPP阻害剤」と称されることもある。
異常な立体構造を有するp53分子を、有効量の本発明の阻害性ペプチドまたはCPP阻害剤と接触させることを含み、
その接触したp53が、修復された立体構造を有し、
修復された立体構造を有するp53分子が、アポトーシスの誘発、細胞増殖の阻害、及び/または腫瘍縮小の誘発から選択される活性(例えば、修復された活性)を呈する。
標的ポリペプチド由来のp53セグメントTIITLE(SEQ ID NO:20)もしくはLTIITLE(SEQ ID NO:21)のジッパー形成配列または当該ジッパー形成配列の鏡体を含む、鋳型ペプチド配列を同定するステップであって、当該ジッパー形成配列が凝集して立体ジッパーになる、ステップと、
コンピュータ上で、当該鋳型ペプチド配列を用いて好ましい立体及びエネルギー分子間相互作用を形成する少なくとも1つの相補的ペプチド配列を設計するステップであって、当該相互作用が当該立体ジッパーの上端または下端の一方または両方で生じる、設計するステップと、
当該相補的配列、当該相補的配列の鏡体、当該相補的配列のペプチド模倣物、及び当該相補的配列の当該鏡体のペプチド模倣物から成る群から選択される、候補阻害性ペプチド化合物を同定するステップと、を含む。
表1の阻害剤配列は、表の2列目の上から下へ向かってSEQ ID NO:4〜SEQ ID NO:17、10、及び18である。CPP阻害剤配列は、表の3列目の上から下に向かってSEQ ID NO:22〜SEQ ID NO:35、28、及び36である。
である。別の実施形態では、コンセンサス配列は、
である。残基番号1、6、及びより少ない程度に番号3は、鋳型構造との最も少ない接触を有し、このため、7個の残基のうち最も可変である。
LEUを置換し得る非天然アミノ酸:
Fmoc−L−シクロヘキシルグリシン 161321−36−4
Fmoc−L−フェニルグリシン 102410−65−1
Fmoc−4−ヒドロキシ−D−フェニルグリシン 178119−93−2
Fmoc−L−α−t−ブチルグリシン 132684−60−7
Fmoc−シクロペンチル−Gly−OH 220497−61−0
Fmoc−L−2−インダニルグリシン 205526−39−2
THRを置換し得る非天然アミノ酸:
Fmoc−Thr(tBu)−OH 71989−35−0
Fmoc−(RS)−2−アミノ−3−
ヒドロキシ−3−メチルブタン酸 105504−72−1
ILEを置換し得る非天然アミノ酸:
Fmoc−アロ−Ile−OH 251316−98−0
Boc−N−Me−アロ−Ile−OH 136092−80−3
Fmoc−Homoleu−OH 180414−94−2
GLUを置換し得る非天然アミノ酸:
Fmoc−γ−カルボキシ−L−グルタミン酸 111662−64−7
Fmoc−L−α−アミノスベリン酸 218457−76−2
ARGを置換し得る非天然アミノ酸:
Fmoc−Nω−ニトロ−L−アルギニン 58111−94−7
Fmoc−L−シトルリン 133174−15−9
TYRを置換し得る非天然アミノ酸:
Fmoc−3−アミノ−L−チロシン 726181−70−0
Fmoc−3−ニトロ−L−チロシン 136590−09−5
Fmoc−3−メトキシ−L−チロシン
Fmoc−3−ヨード−L−チロシン 134486−00−3
Fmoc−3−クロロ−L−チロシン 478183−58−3
Fmoc−3,5−ジブリモ−L−チロシン 201484−26−6
LYSを置換し得る非天然アミノ酸:
Fmoc−Lys(レトロ−Abz−Boc)−OH 159322−59−5
Fmoc−Lys(Mca)−OH 386213−32−7
Fmoc−(Nδ−4−メチルトリチル)−L−オルニチン 343770−23−0
N−α−Fmoc−N−ε−(d−ビオチン)−L−リジン 146987−10−2
(1)1つの実施形態は、癌特異的プロテアーゼによるタンパク質分解切断後のみ細胞に進入することができる活性化可能なCPPであるACPPを使用する、Roger Tsien及び共同作業者によって説明される手法(Olson et al,PNAS 2010)の修正である。この実施形態では、阻害剤は、目的とする癌によって主に発現されるプロテアーゼに特異的な配列を利用して特定の癌型を標的とする。
(2)別の実施形態は、Hatakeyama及び共同作業者によって提唱される戦略(Hatakeyama et al,PNAS 2011)の修正である。これらの著者は、癌血管系マーカーであるアネキシン1に結合する炭水化物模倣ペプチドIF7(配列IFLLWQR(SEQ ID NO:82))を使用して、標的化癌細胞送達を得た。この実施形態では、好適な腫瘍血管系マーカー結合ペプチドは、本発明のCPP阻害剤に融合される。
(3)別の実施形態では、阻害剤は、ナノ粒子とコンジュゲートされる。様々な好適なナノ粒子のうちのいずれかは、当業者には明らかだろう。これらには、例えば、空のボールトシェル、リポソーム、高分子ナノ粒子、デンドリマー等が挙げられる。
p53凝集は、p53不活性化の指標として癌細胞中で測定される(Xu et al,2011;Lasagna−Reeves et al,2013)。スクリーニングは、例えば、以下の従来の方法のうちの1つを使用して、阻害剤の有無に関係なく存在する凝集体の総量の変化に対して実施される。
・ 市販のアミロイド立体構造特異的抗体、例えば、A11及びOCを使用する細胞の免疫染色
・ チオフラビンT及びCongo Red等のアミロイド特異的色素による細胞の染色
・ OCまたはA11抗体を使用する細胞ライセート上でのドットブロット
・ 高分子量p53凝集体の存在/不在を確認するための、p53特異的抗体を使用する、細胞ライセート上でのウェスタンブロットと連結したネイティブページゲル
・ 異常にまたは正常に折り畳まれたp53の間を識別することができる異なる市販のp53抗体を使用する細胞の免疫染色
記載されたように、p53機能は、典型的には、凝集によって阻害される(Xu et al,2011;Lasagna−Reeves et al,2013)。p53不活性化及び再活性化は、以下の従来の手法を用いて、異なる濃度の阻害剤の存在下で試験される。
・ RT−PCRまたはRNAseqによるいくつかのp53標的の転写物を定量化することによって測定されるp53の転写活性の修復
・ タンパク質レベルでいくつかのp53標的をウェスタンブロットを介して検出することによって、測定されるp53の転写活性の修復
・ 軟寒天培養コロニー形成アッセイによる、細胞増殖スクリーニングを抑止する阻害剤の能力
・ BrdU取り込みまたはKi67染色の低減による、細胞増殖スクリーニングを抑止する阻害剤の能力
・ MTTまたはMTSアッセイにより測定される、細胞死を誘発する阻害剤の能力
・ カスパーゼアポトーシスキットまたはFACSと組み合わされたアネキシンV染色により測定される、アポトーシスを誘発する阻害剤の能力
p53の線維形成セグメントの原子構造の特定に基づいて、本発明者らは、合理的に、インビトロでの凝集を減退させる一連の阻害剤を設計した。本発明者らは、p53の成長する凝集体を「キャップする」ペプチド阻害剤を設計した。ZipperDBアルゴリズム(Goldschmidt et al.2010)を使用して、本発明者らは、配列ILTIITL(SEQ ID NO:2)を同定したXu et al.,2011によって突然変異体p53凝集に重要であるとも報告された領域における、結晶化可能アミロイド形成セグメントを同定した。本発明者らは、p53252−258及びp53253−258セグメントを化学的に合成し、それらを結晶化して、マイクロ結晶学によってそれらの三次元構造を決定した(図1)。構造は、「フェイストゥバック(face−to−back)」(p53252−258に関して)及び「フェイストゥフェイス(face−to−face)」(p53253−258に関して)方向で疎水性側鎖を介して噛み合う平行整列(parallel in−register)のβ鎖及びβシートを有する典型的な立体ジッパーアーキテクチャを示した(Sawaya et al,Nature,2007)。
a. 括弧内の値は、最高解像度シェルに対応する
b. Rmerge=Σ|/−</>|/Σ/
c. Rwork=Σ|Fo−Fc|/ΣFo
d. Rfree=Σ|Fo−Fc|/ΣFo、構造精密化を通して含まれなかった反射を含有するランダム集合を使用して計算される
Claims (12)
- アミノ酸配列:
(R2-16)PILTRITLE(SEQ ID NO: 19)
を含む、請求項1に記載のp53の凝集を阻害するための細胞透過性ペプチド。 - アミノ酸配列:
RRRRRRRRRRPILTRITLE(SEQ ID NO: 22)
を含む、請求項1に記載のp53の凝集を阻害するための細胞透過性ペプチド。 - 請求項1〜3のいずれか1項に記載のp53の凝集を阻害するための細胞透過性ペプチドと、薬学的に許容される担体と、を含む、薬学的組成物。
- 請求項1〜3のいずれか1項に記載のp53の凝集を阻害するための細胞透過性ペプチドを含む、異常な立体構造を有するp53に起因する細胞の増殖を予防及び/または阻害するための薬学的組成物。
- 有効量の請求項4に記載の薬学的組成物を含む、異常な立体構造を有するp53に関連する癌を有する対象を治療するための医薬であって、前記対象における癌細胞の増殖を阻害すること、および/または前記対象の腫瘍を縮小させることを特徴とする、前記医薬。
- 請求項4に記載の薬学的組成物を含む複数の用量を含む、癌を発症しやすくするp53をコードする突然変異遺伝子を有する対象を治療するための医薬であって、前記複数の用量の合計が、請求項4に記載の薬学的組成物の有効量であり、かつ前記医薬が、前記対象における腫瘍の発症を予防することを特徴とする、前記医薬。
- 容器内にパッケージ化された、請求項1〜3のいずれかに記載のp53の凝集を阻害するための細胞透過性ペプチドを含む、異常な立体構造を有するp53に起因する細胞の増殖を予防及び/または阻害するために使用されるキット。
- 請求項1〜3のいずれかに記載のp53の凝集を阻害するための細胞透過性ペプチドを作製する方法であって、それを化学的に合成するか、またはそれを組換えで生成することを含む、前記方法。
- 請求項1〜3のいずれかに記載のp53の凝集を阻害するための細胞透過性ペプチドをコードする、発現ベクター。
- 前記p53の凝集を阻害するための細胞透過性ペプチドが、1〜7個のアミノ酸を含むペプチドリンカーにより前記CPPと結合している、請求項1に記載のp53の凝集を阻害するための細胞透過性ペプチド。
- 2〜16個のアルギニン残基と結合している下記アミノ酸配列:
LTRITLE (SEQ ID NO: 4)
を含む、請求項1に記載のp53の凝集を阻害するための細胞透過性ペプチド。
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US11117930B2 (en) | 2017-02-23 | 2021-09-14 | Adrx, Inc. | Peptide inhibitors of transcription factor aggregation |
US11453701B2 (en) | 2017-08-18 | 2022-09-27 | Adrx, Inc. | Tau aggregation peptide inhibitors |
TW202019398A (zh) * | 2018-06-28 | 2020-06-01 | 張翔毓 | 用於治療或預防構形疾病之方法及藥物篩選方法 |
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