JPWO2018038168A1 - ヘマグルチニン結合ペプチド、および、これを含むインフルエンザウイルス感染症の予防・治療薬 - Google Patents
ヘマグルチニン結合ペプチド、および、これを含むインフルエンザウイルス感染症の予防・治療薬 Download PDFInfo
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
Abstract
Description
配列番号1:Arg-Arg-Pro-Val-Asn-His-Phe(RRPVNHF)
が、直接またはスペーサーを介して結合した4価ペプチドである。
さらに、本発明のインフルエンザ感染症の予防・治療方法は、上記のインフルエンザ感染症の予防・治療薬を対象(例えば、ヒト、マウス、ラット、モルモット、ウサギ、イヌ、ウマ、サル、ブタ等)に投与することを特徴としている。
多価型ペプチドライブラリースクリーニングにはビーズに固定された状態でのHAが大量に必要となる。そこで、H1N1の亜型インフルエンザウイルス由来HA遺伝子のC末端側にHis-tagを導入した組み替えHAをバキュロウイルス発現系を用いて大量に調製し、Ni-ビーズを用いてビーズ上に固定化した。HAの受容体結合に変異を有するHA変異体作成にあたっては、シアル酸との結合に必須の役割を果たしているLeu194をAlaに置換した変異体、L194A-HAを同様に調製した(図1A)。
スクリーニングに使用する多価型ペプチドライブラリーの構造を図2に示す。図2中の「M」、「A」、「U」はそれぞれMet, Ala, アミノカプロン酸を示している。図2中の「XXXX」はライブラリー部を示し、X (degenerate position)はCys以外の19種のアミノ酸の混合物を使用して合成を行ったことを示している。
配列番号2:His-His-Thr-Lys-Arg-Arg-Arg(HHTKRRR)
配列番号3:Arg-Arg-Arg-Val-Asn-His-His (RRRVNHH)
をHA結合ペプチドモチーフ候補として同定した。
を試みた。
多価型ペプチドのセルロースシート上への合成は、intavis AG社のスポットペプチドシンセサイザーを使用した。
配列番号4:Arg-Arg-Pro-Val-Asn-His-His (RRPVNHH)
配列番号5:Arg-Arg-Arg-Asp-Asn-His-His (RRRDNHH)
配列番号6:Arg-Arg-Ser-Val-Asn-His-His (RRSVNHH)
を次のスクリーニングのための候補配列として決定した。
配列番号7:Arg-Arg-Pro-Val-Asn-His-Asp (RRPVNHD)
配列番号8:Arg-Arg-Pro-Met-Asn-His-His (RRPMNHH)
配列番号9:Arg-Arg-Pro-Val-Asn-His-Asn (RRPVNHN)
配列番号1:Arg-Arg-Pro-Val-Asn-His-Phe (RRPVNHF)
配列番号10:Arg-Arg-Pro-Val-Asn-His-Pro (RRPVNHP)
を最終HA結合配列として決定した。
MDCK細胞に各濃度の阻害薬(実施例3で得られたPVD-tet、PMH-tet、PVN-tet、PVF-tet、PVP-tet)を添加し、30分後にA/PR/8/34インフルエンザウイルスを高力価(MOI=10)で感染させ、24時間培養後の細胞の生存率をWST法にて測定した。
インフルエンザウイルスが感染性を獲得するためには、HAタンパク質がプロテアーゼによって切断を受けてHA1とHA2のサブユニットに開裂し、fusion domainが露出することが必要である。インフルエンザウイルスが気道に感染するのは、気道にはトリプシン様プロテアーゼなどのHA活性化プロテアーゼが局在するためである。一方、PVF-tetはHA結合モチーフとしてRRPVNHF(配列番号1)の配列を持つため、治療薬として使用する際トリプシン様プロテアーゼによってポジション1のArgとポジション2のArgの間が切断され、阻害効果が減弱することが懸念された。実際、PVF-tet(分子量5572)を1 μg/mlのトリプシン存在下で37℃、24時間処理した後、質量分析器による質量測定を行なったところ、ポジション1のArgとポジション2のArgの間が切断されたもの(分子量4138)が生成することが示された(図10)。
MDCK細胞に各濃度の阻害薬(PVF-tet、(D)PVF-tet、RVH-tet)あるいはフェツインを添加し、30分後にA/PR/8/34インフルエンザウイルスを低力価(MOI=0.001)あるいは高力価(MOI=10)で感染させ、それぞれ48、24時間培養後の細胞の生存率をWST法にて測定した。フェツインは高密度でシアル酸を含有し、効率よくHAの受容体結合部に結合することが知られている。図13A、Bは、低力価感染(MOI=0.001)の結果を示しており、図13B)は、高力価感染(MOI=10)の結果を示している。
インフルエンザウイルス感染によるマウス個体毒性活性に対するペプチド性HA阻害薬の阻害効果を検討した。
Claims (3)
- 3つのリジン(Lys)が結合して形成された分子核構造の端部に位置する4つのアミノ基の各々に、配列番号1のペプチドモチーフが、直接またはスペーサーを介して結合している4価ペプチドであることを特徴とするヘマグルチニン結合ペプチド。
- 配列番号1のペプチドモチーフのN末端側に位置するアルギニン(Arg)が、非天然異性体(D-Arg)に置換されていることを特徴とする請求項1のヘマグルチニン結合ペプチド。
- 請求項1または2のヘマグルチニン結合ペプチドを含有することを特徴とするインフルエンザウイルス感染症の予防・治療薬。
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WO2000059932A1 (fr) * | 1999-03-31 | 2000-10-12 | Otsuka Pharmaceutical Co., Ltd. | Peptides se liant a l'hemagglutinine du virus de la grippe |
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JP2006101709A (ja) * | 2004-09-30 | 2006-04-20 | Glycomedics Inc | ヘマグルチニン結合ペプチド、インフルエンザウイルス感染阻害剤、リポソーム、インフルエンザ治療薬、インフルエンザ予防薬 |
JP5635779B2 (ja) * | 2009-09-14 | 2014-12-03 | 学校法人同志社 | Stx毒性阻害ペプチドおよびStxに起因する疾患の治療薬 |
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-
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- 2017-08-23 WO PCT/JP2017/030158 patent/WO2018038168A1/ja active Application Filing
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Patent Citations (7)
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WO2000059932A1 (fr) * | 1999-03-31 | 2000-10-12 | Otsuka Pharmaceutical Co., Ltd. | Peptides se liant a l'hemagglutinine du virus de la grippe |
JP2002284798A (ja) * | 2001-03-27 | 2002-10-03 | Keio Gijuku | インフルエンザウイルス・ヘマグルチニン結合性ペプチド |
JP2006101709A (ja) * | 2004-09-30 | 2006-04-20 | Glycomedics Inc | ヘマグルチニン結合ペプチド、インフルエンザウイルス感染阻害剤、リポソーム、インフルエンザ治療薬、インフルエンザ予防薬 |
JP5635779B2 (ja) * | 2009-09-14 | 2014-12-03 | 学校法人同志社 | Stx毒性阻害ペプチドおよびStxに起因する疾患の治療薬 |
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CN113490526A (zh) * | 2019-02-18 | 2021-10-08 | 肽梦想株式会社 | 血球凝集素结合肽 |
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