JP5927139B2 - 強力なコンプスタチン類似体 - Google Patents
強力なコンプスタチン類似体 Download PDFInfo
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- JP5927139B2 JP5927139B2 JP2013090484A JP2013090484A JP5927139B2 JP 5927139 B2 JP5927139 B2 JP 5927139B2 JP 2013090484 A JP2013090484 A JP 2013090484A JP 2013090484 A JP2013090484 A JP 2013090484A JP 5927139 B2 JP5927139 B2 JP 5927139B2
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- JP
- Japan
- Prior art keywords
- trp
- tryptophan
- thr
- peptide
- seq
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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- RDTRHBCZFDCUPW-KWICJJCGSA-N 2-[(4r,7s,10s,13s,19s,22s,25s,28s,31s,34r)-4-[[(2s,3r)-1-amino-3-hydroxy-1-oxobutan-2-yl]carbamoyl]-34-[[(2s,3s)-2-amino-3-methylpentanoyl]amino]-25-(3-amino-3-oxopropyl)-7-[3-(diaminomethylideneamino)propyl]-10,13-bis(1h-imidazol-5-ylmethyl)-19-(1h-indol Chemical class C([C@H]1C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CSSC[C@@H](C(N[C@H](C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=2C3=CC=CC=C3NC=2)C(=O)NCC(=O)N[C@@H](CC=2NC=NC=2)C(=O)N1)C(C)C)C(C)C)=O)NC(=O)[C@@H](N)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(N)=O)C1=CN=CN1 RDTRHBCZFDCUPW-KWICJJCGSA-N 0.000 title description 132
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- KVNPSKDDJARYKK-JTQLQIEISA-N 5-methoxytryptophan Chemical compound COC1=CC=C2NC=C(C[C@H](N)C(O)=O)C2=C1 KVNPSKDDJARYKK-JTQLQIEISA-N 0.000 claims description 5
- KGVHCTWYMPWEGN-FSPLSTOPSA-N Gly-Ile Chemical compound CC[C@H](C)[C@@H](C(O)=O)NC(=O)CN KGVHCTWYMPWEGN-FSPLSTOPSA-N 0.000 claims description 4
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- UQTNIFUCMBFWEJ-IWGUZYHVSA-N Thr-Asn Chemical compound C[C@@H](O)[C@H](N)C(=O)N[C@H](C(O)=O)CC(N)=O UQTNIFUCMBFWEJ-IWGUZYHVSA-N 0.000 claims description 4
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Description
本明細書に開示された本発明は国立保険協会(NIH)により交付番号62134に基づく基金の一部が使用されたものであり、米国特許法第202条に従って、米国政府機関が優先権を有することが承認されている。
本発明は、コンプスタチンと比較して、改善された補体阻害活性を有する補体阻害ペプチド、すなわちコンプスタチン(HOOC-ICVVQDWGHHRCT-NH2; 配列番号1)の類似体及び擬態体を提供するものである。
Xaa1 - Cys - Val - Xaa2 - Gln - Asp - Xaa3 - Gly - Xaa4 - His - Arg - Cys - Xaa5 (配列番号:26)
[ 式中、Xaa1 は Ile、Val、Leu、Ac-Ile、Ac-Val、Ac-Leu または Gly-Ileを含むジペプチドであり;
Xaa2 はTrpまたはTrpの類似体であり、ここにTrpの類似体はTrpと比較して疎水性が強いものであるが、但し、Xaa3が Trpの場合は、Xaa2はTrpの類似体であり;
Xaa3はインドール環に化学修飾を含むTrpまたはTrpの類似体であり、ここに化学修飾はインドール環の水素結合能を高めるものであり;
Xaa4はHis、Ala、PheまたはTrpであり;
Xaa5はL-Thr、D-Thr、Ile、Val、Gly、またはThr-Asn若しくはThr-Alaを含むジペプチド、またはThr-Ala-Asnを含むトリペプチドであり、ここに L-Thr、D-Thr、Ile、Val、GlyまたはAsnのいずれかのカルボキシ末端のOH基がNH2基によって任意に置換されていてもよく;かつ2つのCys残基はジスルフィド結合によって結合されている]
を有するペプチドを含む。
(図1)発現コンプスタチン及びその類似体の活性化。補体阻害パーセント対各ペプチド濃度を表した図である。ペプチド濃度はそれぞれ、(四角)Ac-V4W/H9A(配列番号5)、(丸)トリプトファン(配列番号15)、(三角)5−フルオロ−トリプトファン(配列番号16)、(星)6−フルオロ−トリプトファン(配列番号17)、(六角形)5−ヒドロキシ−トリプトファン(配列番号27)、(菱形)7−アザ−トリプトファン(配列番号28)を表している。
本願発明に係る方法及び他の態様に関する様々な用語が明細書及び特許請求の範囲に使われている。このような用語は一般的に使用される意味を呈している。本明細書中、特に定義された用語は、この定義された意味で解釈される。
下記の略語は本明細書及び実施例中において使われる。Ac、アセチル基;NH2、アミド;MALDI、マトリック支援レーザー脱離イオン法;TOF、飛行時間型;ITC、等温滴定熱量測定;HPLC、高速液体クロマトグラフィー;NA、不活性;dT、D−スレオニン;2-Nal、2−ナフチルアラニン;1-Nal、1−ナフチルアラニン;2-Igl、2−インダニルグリシン;Dht、ジヒドロトリプトファン;Bpa、4−ベンゾイル−L−フェニルアラニン;5f-l-W、5−フルオロ−l−トリプトファン;6f-l-W、6−フルオロ−l−トリプトファン;5-OH-W、5−ヒドロキシトリプトファン;5-メトキシ-W、5−メトキシトリプトファン;5-メチル-W、5−メチルトリプトファン;1-メチル-W、1−メチルトリプトファン;アミノ酸に関する略語は3文字表記または一文字表記による命名法を用いる。たとえばトリプトファンであればTrp またはWと表す。
本発明によれば、コンプスタチンの生物学的及び物理化学的特徴についての情報は、親コンプスタチンペプチドと比較して活性化がさらに促進されるコンプスタチン類似体の設計に利用されている。一例では、類似体は少なくとも50倍の活性を備えている。他の態様としては、類似体はコンプスタチンより60、65、70、75、80、85、90、95、100、105、110、115、120、125、130倍またはそれ以上の活性化を有する。さらにまた、実施例において詳述したアッセイを利用したものと比較すると、類似体はコンプスタチンより135、140、145、150、155、160、165、170、175、180、185、190、195、200、205、210、215、220、225、230、235、240、245、250、255、260、265倍またはそれ以上の活性化を有する。
配列番号1と配列番号2を比較すると、N−末端のアセチル化によってコンプスタチン及びその類似体の補体阻害活性が顕著に向上していることがわかる。したがって、ペプチドのアミノ末端でのアシル基の付加、特に限定されるものではないがN−アセチル化が挙げられ、本発明においてはこれが好ましい例であり、ペプチドが合成され調合された場合、特に優れた効果を奏し得る。しかしながら、原核生物または真核生物におけるペプチドをコード化している核酸分子の発現によりまたはインビトロでの転写及び翻訳により予めペプチドを準備してもよい。これらの実施例として、自然界にあるN−末端が利用できる。インビトロまたはインビボにおいて適したコンプスタチン類似体の一例は配列番号15−17によって代表され、それらにおいてN−末端でアセチル基は置換されていないグリシンと置き換わる。配列番号15−17は、以下に詳述するとおり、ペプチド中及びC−末端での修飾を追加的に含むものであり、本明細書中に記載された補体阻害アッセイにおいて、コンプスタチンよりも約45倍から約125倍の活性がある。
コンピューター法(the rank low lying energy sequences)を用いた結果、Tyr と Valが4位においてペプチドの安定化及び活性化を支持する役割があるとして候補に挙げられるのは、以前から明らかであった(Klepeis JL ら、2003)。特に4位のTrp が9位のAlaと組み合わされて親ペプチドよりも何倍も高い活性を示すことは、WO2004/026328に開示されていた(たとえば、配列番号4、5、6の活性化と配列番号2、3を比較する)。WO2004/026326にもまた、4位にトリプトファン類似体である2−ナフチルアラニン(配列番号7、8)、1−ナフチルアラニン(配列番号9)、2−インダニルグリシン(配列番号10、11)またはジヒドロトリプトファン(配列番号12)を含むペプチドすべてが、コンプスタチンと比較して5倍から99倍の範囲で補体阻害活性を促進することが開示されていた。さらに、4位にフェニルアラニン類似体を含むペプチド、4−ベンゾイル−L−アラニン(配列番号13)はコンプスタチンよりも49倍高い活性を有していた。
合成方法により産生されたペプチドは、酸の代わりにアミドを有するようカルボキシ末端で一般的に修飾される;この共通の修飾は表1のコンプスタチン(配列番号1)及びいくつかの類似体に見ることができる。確かに実施例において、末端にアミドを含むペプチドは末端に酸を含むペプチド(比較例として例えば配列番号5及び7と配列番号4と8のそれぞれ)より活性を向上させる。したがって、本発明の利用態様としてC末端アミド修飾が好ましい。しかしながら、ある状況ではC末端に酸を用いることは好ましい。このような状況とは、特に限定されるものではないが、溶解度及びインビトロまたはインビボにおけるペプチドコード核酸分子からのペプチドの発現を含む。
コンプスタチンのバクリテア発現
配列NH2−GICVWQDWGAHRCTN−OH (“G(-1)/V4W/H9A/N14”)(配列番号15)を有するコンプスタチン類似体はキチン結合ドメインとDnaBインテイン(New Engl及び Biolabs, Beverly, MA)との融合物として発現された。E.coliについてのペプチド配列及びコドンの利用によって導かれるように、以下の遺伝的コードを用いて、このペプチドに関する下記配列を有する合成遺伝子を得た。該合成遺伝子は下記の配列を有する:
5’ATTTGCGTTTGGCAGGATTGGGGTGCGCACCGTTGCACCAATTAA3’(配列番号29)
5’GGTGGTGCTCTTCCAACGGTATTTGCGTTTGGCAGGA3’(配列番号30)
5’TTGGGGTGCGCACCGTTGCACCAATTAACTGCAGG3’(配列番号31)
3’CAACGTGGTTAATTGACGTCCGC5’(配列番号32)
3’CATAAACGCAAACCGTCCTAACCCCACGCGTGG5’(配列番号33)
5’CGCCTGCAGTTAATTGGT3’(配列番号34)
5’GGTGGTGCTCTTCCAACG3’(配列番号35)
E. coli内におけるコンプスタチンのトリプトファン類似体の発現
トリプトファン誘導体を有するコンプスタチン類似体を発現させるためにpTWIN1−コンプスタチンクローンをER2566 Trp 82栄養要求株に形質転換した。前述したように1 mM L−トリプトファンが補充されたM9最小培地上で発現が行われた。細胞はOD600 0.8から1.0において成長し、その後遠心分離法によって収集し、望ましいトリプトファン類似体2mMを含む新鮮な最小培地中に再懸濁した:前記望ましいトリプトファン類似体は、5−フルオロ−トリプトファン、6−フルオロ−トリプトファン、7−アザ−トリプトファン、または5−ヒドロキシ−トリプトファンであった。発現されたコンプスタチン類似体を実施例1と同様にさらに精製した。
ペプチド合成
ペプチド合成と精製を1996年Sahuら;2000年Sahuら;2005年Mallikらが明記した方法を用いて実行した。簡潔に述べると、Fmocアミド残基及び標準サイドの鎖状保護基を用いたバイオシステムペプチドシンセサイザー(モデル431A)でペプチドを合成した。5%フェノール、5%チオアニソール、5%精製水、2.5%エタンジチオール、82,5%トリフルオロ酢酸(TFA)を含む溶媒混合物中、22℃、3時間かけてペプチドをインキュベートすることによりペプチドを残基から切断した。この反応液をフリットの漏斗に通して濾過し、冷エーテルを用いて沈殿を誘発させた後、0.1% TFAを含む50%アセトニトリル中に溶解した後、凍結乾燥した。
補体阻害アッセイ
免疫複合体による補体系の活性におけるそれらの効果を測定することにより補体系におけるコンプスタチン及びその類似体の阻害活性を決定した。正常な血漿中における卵白アルブミン−抗−卵白アルブミン複合体へのC3の固定の阻害を測定することによって補体活性の阻害を評価した。マイクロタイターウェルを50μl卵白アルブミン(10mg/ml)で2時間25℃(4℃で一晩)被覆した。ウェルを10 mg/ml BSA 200μlで、25℃で1時間飽和させ、その後補体が活性化され得るようにウサギ抗−卵白アルブミン抗体を添加して免疫複合体を形成させた。様々な濃度でのペプチド30μlをそれぞれのウェルに直接加え、続いて血漿の1:80希釈液30μl加えた。30分インキュベートした後、ヤギ抗−ヒトC3 HRP −複合抗体を用いてC3C3b/iC3bのバンドを検出した。ABTSペルオキダーゼ基質加えることによって発色させ、光学的密度を405 nmにて測定した。
C3とコンプスタチン及びその類似体との相互作用の等温滴定熱量測定
VP-ITC マイクロカロリメトリー (Microcal Inc, Northampton, MA)を用いて、等温滴定熱量測定を実行した。これらの実験にはタンパク質濃度3.5-5μM及びペプチド濃度80-200μMを用いた。すべての滴定ではPBS(150 mM NaCとともに10 mMリン酸エステルバッファー、pH 7.4)を用いた。それぞれの実験において、標的タンパク質であるC3を細胞内に入れ、ペプチドをシリンジ内に入れた。すべての実験は25℃で行われ、前記タンパク質が入った細胞内に2μlペプチドを注入した。それぞれの実験において、ペプチドをバッファーに注入する際に代表されるように等温線が減ずることによる希釈熱を考慮して等温線を補正した。その結果生ずる等温線はOrigin 7.0ソフトウェア内で適合され、最小のカイ二乗値を与えたモデルをそれぞれのデータセットに関して適正なものとみなした。結合親和性及びエントロピーをlog Pに対してプロットした。
細菌により発現されたコンプスタチン類似体によりアッセイされたC3−コンプスタチン相互作用におけるトリプトファンの役割
インドール環の化学的性質において異なる4つのトリプトファン類似体をインテイン媒介タンパク質発現系を用いてコンプスタチンに組み込んだ。発現後、ペプチドは培養液2 mg/Lの最終収量にて単一工程で精製された。トリプトファン類似体、5−フルオロ−トリプトファン、6−フルオロ−トリプトファン、7−アザ−トリプトファン、5−ヒドロキシ−トリプトファンをMALDIによって示されるER2566/Trp 82栄養要求株を用いて発現させ、その結果生ずるペプチドを均一に精製した。PHMBと反応しないことによって証明されるように、未変性のコンプスタチン及び類似体をインビボでジスルフィド結合を通して環化した。すべてのペプチドを逆相C18 HPLCカラムで精製した。
C3コンプスタチン相互作用における個々のトリプトファンの役割
4位もしくは7位、または4位かつ7位に選択的に組み込まれた5−フルオロ−トリプトファンや、9位にアラニンを有するようなコンプスタチン類似体を産生するために固相ペプチド合成を用いた。合成はFmoc-5-フルオロ-dl-トリプトファンを用いて行った。この反応では5−フルオロ−d−トリプトファン及び5−フルオロ−l−トリプトファンのエナンチオマーを産生した。3つの異なるペプチドを合成した:それらは4位または7位において独立的に一つの置換基を有する2つのペプチド及び4位及び7位の両者に置換基を有する1つのペプチドである。一置換の場合、5−フルオロ−l−トリプトファン及び5−フルオロ−d−トリプトファン類似体の混合物が生じ得るが、二置換の場合、4つのエナンチオマーの組み合わせの混合物が生じ得る。それぞれのペプチドの混合を逆相HPLCを用いてペプチドエナンチオマーを分離した。V8プロテアーゼにてペプチドを消化し、次いでMALDIを用いて消化産物を分析することにより、エナンチオマーの同定を行った。V8プロテアーゼは、l−アミノ酸の場合に限りAsp残基のC末端側で切断した。質量スペクトルにおける切断産物の同定によりl−エナンチオマーのペプチドが最初に溶出し、続いて、d−型が溶出したことが示されたが、切断されたフラグメントは検出されなかった。
C3によるトリプトファンを媒介としたコンプスタチンの認識に関する熱力学的根拠
等温滴定熱量測定によりペプチドとC3との結合を検証し、それらの活性に関する熱力学的根拠について調べた。すべてのペプチドとC3との相互作用による熱量データは1に近似した化学量論の一組のサイトモデルに適合する。これらのペプチドとC3との結合は1;1の割合で生じると考えられていた。これらの適合から得られた熱力学的パラメーターを表4に示す。Kd値から明白なように、7位にある5−フルオロ−l−トリプトファン置換基及び4位及び7位にある2つの置換基を有するペプチドは、Ac-V4W/H9A(配列番号5)及びAc-V4(5f-l-W)/H9A(配列番号18)類似体に比べて強固な結合を示した。この知見は、補体阻害アッセイ(表3)で観察された相対活性と一致するものであり、結合−活性の相関関係があることを示すものである。
さらなるコンプスタチン類似体
4位のトリプトファン類似体の相互作用。コンプスタチンの4位にあるトリプトファンをバリンに換えるとその活性が45倍となることは実施例5及び6に示した。コンプスタチンがC3に結合している中で4位の残基によって仲介された相互作用の性質をさらに調べるために、4位のトリプトファンをトリプトファン類似体及び2−ナフチルアラニンに換えた。
4位のトリプトファンの代わりに1−メチル−トリプトファンを置換し、7位に5−フルオロ−トリプトファンを置換すると、活性が劇的に上昇したコンプスタチンが産生されたので、4位及び7位に置換基を有するコンプスタチンを産生した。その結果、ペプチド(Ac-V4(1-メチル-W)/W7(5f-l-W)/H9A)(配列番号24)は、単一置換基である1−メチル−トリプトファン(Ac-V4(1-メチル-W)/H9A)(配列番号23)と同じような阻害曲線を描いた(図3、表5)。このペプチドの結合親和性(Kd = 0.017)は熱量測定の結果においてもAc-V4(1-メチル-W)/H9A(配列番号23)と同じような値が観測された。これらの結果から、実験条件下において、4位に1−メチル−トリプトファンが存在する場合、7位の5−フルオロ−トリプトファンは影響を及ぼさないことが示唆される。
コンプスタチンがC3に結合している間に4位の残基により仲介された相互作用の性質をさらに調べるために4位のトリプトファンをトリプトファン類似体である1−ホルミル−トリプトファンに置き換えた。
コンプスタチン類似体のペグ化
コンプスタチンの半減期の延長は慢性治療の使用に効果的である。ペグ化(Veronese ら、2001参照)によって、試験された治療薬としてのペプチドの半減期を延長することができた。ペグ化は、腎臓でのクリアランス、タンパク質分解及び免疫原性の減少を含むさまざまなメカニズムによって循環系から生体分子を排除することを遅延させる能力を有している。腎臓でのクリアランス及びタンパク質分解及び免疫原性を減少させる性質を備えている。ペグ化は、巨大分子、好ましくはリジンの第一級アミンへのPEGポリマーの共有結合を包含する。
コンプスタチン類似体のアルブミン結合タンパク質複合体
Dennisら(2002)は、多様な種類のうち血清アルブミンに対して特異的に高い親和性をもって結合するコア配列DICLPRWGCLW(配列番号37)を有する一連のペプチドを同定した。これらのペプチドは化学量論において1:1の割合で、低分子結合サイトで知られているものと異なる部位でアルブミンに結合した。ペプチドSA21(AcRLIEDICLPRWGCLWEDDNH2;配列番号38)をウサギに急速静注した際に2.3時間という非常に長い半減期を示す。詳細な説明で述べたように、この配列はD3H44という抗組織因子Fabフラグメントに結合するものであるが、この配列によって、SA21の結合親和性と同じような結合親和性をもって、Fabが組織因子1に結合する能力が保持しつつ、Fabフラグメントがアルブミンに結合することを可能にした(Nguyen ら、2006)。野生型のFabフラグメントD3H44と比較すると、アルブミンとの相互作用はマウス及びウサギにおいてインビボでのクリアランスをそれぞれ25倍及び58倍減少させた。半減期はウサギで37倍延びて32.4時間、またマウスで26倍延びて10.4時間となり、これらの動物におけるアルブミンの半減期の25-43%に達した。これらの半減期はFab2の半減期を超え、ペグ化されたFab分子及びイムノアドヘシン及びアルブミン融合に見られる半減期に匹敵する。
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Claims (11)
- Xaa1 - Cys - Val - Xaa2 - Gln - Asp - Xaa3 - Gly - Xaa4 - His - Arg - Cys - Xaa5 (配列番号:26)
[式中、
Xaa1は Ile、Val、Leu、Ac-Ile、Ac-Val、Ac-LeuまたはジペプチドGly-Ileであり;
Xaa2はTrpまたはTrpの類似体であり、該Trpの類似体は、(a)5−フルオロ−l−トリプトファンまたは6−フルオロ−l−トリプトファン、(b)5−メトキシトリプトファンまたは5−メチルトリプトファン、または(c)1−メチルトリプトファンから選ばれ;但し、Xaa3がTrpの場合は、Xaa2は、Trpの類似体であり、Xaa3がTrpの類似体の場合は、Xaa2は、Trpであり;
Xaa3はTrpまたは5−フルオロ−l−トリプトファン若しくは6−フルオロ−l−トリプトファンから選ばれたTrpの類似体であり;
Xaa4はHis、Ala、PheまたはTrpであり;
Xaa5はL-Thr、D-Thr、Ile、Val、Gly、またはジペプチドThr-Asn若しくはThr-Ala、またはトリペプチドThr-Ala-Asnであり、ここに L-Thr、D-Thr、Ile、Val、GlyまたはAsnのいずれかのカルボキシ末端はOH基またはNH2基を含んでいる]
を有するペプチドを含む、補体活性化を阻害することを特徴とする化合物の製造方法であって、該方法が、アミノ酸残基またはその類似体の縮合によりペプチドを合成すること、または該ペプチドをコードするポリヌクレオチドを発現させることを含む、方法。 - 2つのCys残基間のジスルフィド結合の生成によりペプチドを環化することをさらに含むことを特徴とする、請求項1に記載の方法。
- (a)Xaa1のアセチル化、(b)化合物のペグ化および(c)化合物のインビボにおける保持を延長するさらなるペプチド成分を用いた化合物の合成
の1またはそれ以上から選ばれる、化合物の合成後修飾をさらに含むことを特徴とする、請求項1または2に記載の方法。 - Xaa2が1−メチルトリプトファンであり、Xaa4がAlaであり、Xaa5がL-Thrであることを特徴とする、請求項1、2または3に記載の方法。
- 該ペプチドが配列番号:16〜24のいずれかの配列を有することを特徴とする、請求項1、2、3または4のいずれかに記載の方法。
- C3に結合し、かつ補体活性化を阻害するための補体インヒビターの人工培地中または人工培地上での使用であって、該使用は、該C3を、配列:
Xaa1 - Cys - Val - Xaa2 - Gln - Asp - Xaa3 - Gly - Xaa4 - His - Arg - Cys - Xaa5 (配列番号:26)
[式中、
Xaa1は Ile、Val、Leu、Ac-Ile、Ac-Val、Ac-LeuまたはジペプチドGly-Ileであり;
Xaa2はTrpまたはTrpの類似体であり、該Trpの類似体は、(a)5−フルオロ−l−トリプトファンまたは6−フルオロ−l−トリプトファン、(b)5−メトキシトリプトファンまたは5−メチルトリプトファン、または(c)1−メチルトリプトファンから選ばれ;但し、Xaa3がTrpの場合は、Xaa2は、Trpの類似体であり、Xaa3がTrpの類似体の場合は、Xaa2は、Trpであり;
Xaa3はTrpまたは5−フルオロ−l−トリプトファン若しくは6−フルオロ−l−トリプトファンから選ばれたTrpの類似体であり;
Xaa4はHis、Ala、PheまたはTrpであり;
Xaa5はL-Thr、D-Thr、Ile、Val、Gly、またはジペプチドThr-Asn若しくはThr-Ala、またはトリペプチドThr-Ala-Asnであり、ここに L-Thr、D-Thr、Ile、Val、GlyまたはAsnのいずれかのカルボキシ末端はOH基またはNH2基を含んでおり;かつ2つのCys残基はジスルフィド結合によって結合される]
を有するペプチドである補体インヒビターと接触させることを含む、使用。 - 血清、組織または器官における補体活性化を阻害することを含むことを特徴とする、請求項6に記載の使用。
- 生理学的流体の体外シャント中に生じる補体活性化を阻害することを含むことを特徴とする、請求項6に記載の使用。
- 補体活性化の他の阻害剤の同定のための小分子ライブラリーのスクリーニングのための補体インヒビターの使用であって、該使用は、C3またはC3フラグメントへの結合に対して該補体インヒビターと競合する試験化合物の能力を測定することを含み、該補体インヒビターは、配列:
Xaa1 - Cys - Val - Xaa2 - Gln - Asp - Xaa3 - Gly - Xaa4 - His - Arg - Cys - Xaa5 (配列番号:26)
[式中、
Xaa1は Ile、Val、Leu、Ac-Ile、Ac-Val、Ac-LeuまたはジペプチドGly-Ileであり;
Xaa2はTrpまたはTrpの類似体であり、該Trpの類似体は、(a)5−フルオロ−l−トリプトファンまたは6−フルオロ−l−トリプトファン、(b)5−メトキシトリプトファンまたは5−メチルトリプトファン、または(c)1−メチルトリプトファンから選ばれ;但し、Xaa3がTrpの場合は、Xaa2は、Trpの類似体であり、Xaa3がTrpの類似体の場合は、Xaa2は、Trpであり;
Xaa3はTrpまたは5−フルオロ−l−トリプトファン若しくは6−フルオロ−l−トリプトファンから選ばれたTrpの類似体であり;
Xaa4はHis、Ala、PheまたはTrpであり;
Xaa5はL-Thr、D-Thr、Ile、Val、Gly、またはジペプチドThr-Asn若しくはThr-Ala、またはトリペプチドThr-Ala-Asnであり、ここに L-Thr、D-Thr、Ile、Val、GlyまたはAsnのいずれかのカルボキシ末端はOH基またはNH2基を含んでおり;かつ2つのCys残基はジスルフィド結合によって結合される]
を有するペプチドである、使用。 - Xaa2が1−メチルトリプトファンであり、Xaa4がAlaであり、Xaa5がL-Thrであることを特徴とする、請求項6、7、8または9のいずれかに記載の使用。
- 該ペプチドが配列番号:16〜24のいずれかの配列を有することを特徴とする、請求項6、7、8、9または10のいずれかに記載の使用。
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