JP2646013B2 - Antiviral agent - Google Patents
Antiviral agentInfo
- Publication number
- JP2646013B2 JP2646013B2 JP63228843A JP22884388A JP2646013B2 JP 2646013 B2 JP2646013 B2 JP 2646013B2 JP 63228843 A JP63228843 A JP 63228843A JP 22884388 A JP22884388 A JP 22884388A JP 2646013 B2 JP2646013 B2 JP 2646013B2
- Authority
- JP
- Japan
- Prior art keywords
- gly
- peptide
- arg
- asp
- dna
- 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.)
- Expired - Fee Related
Links
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Peptides Or Proteins (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
【発明の詳細な説明】 [産業上の利用分野] 本発明は、末端にタンパク質を持つ核酸(DNA又はRN
A)を有するウイルスの増殖に対し阻害作用を有する生
理活性ペプチドに関する。DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a nucleic acid (DNA or RN) having a protein at a terminal.
The present invention relates to a bioactive peptide having an inhibitory effect on the growth of a virus having A).
[従来の技術] 5′末端に結合タンパク質を持つ核酸を有するウイル
スといて、枯草菌ファージ、アデノウイルス、ポリオウ
イルス、肝炎ウイルス等が知られている。これらのウイ
ルスの殆どは、人に対して各種の感染症を引き起こすた
め、種々の抗ウイルス剤の開発が行われている。[Prior Art] Bacillus subtilis phage, adenovirus, poliovirus, hepatitis virus and the like are known as viruses having a nucleic acid having a binding protein at the 5 'end. Since most of these viruses cause various infectious diseases to humans, various antiviral agents are being developed.
ところで、Arg−Gly−Asp、Arg−Gly−Asp−Ser、Arg
−Gly−Asp−Val、Gly−Arg−Gly−Asp、Gly−Arg−Gly
−Asp−Ser、Gly−Arg−Gly−Glu−Ser、Gly−Arg−Gly
−Asp−Ser−Pro、Gly−Arg−Gly−Glu−Ser−Pro等の
簡単なアミノ酸配列からなるペプチドが、フィブロネク
チンの接着阻害を起させ、癌細胞の転移抑制作用を有す
ることが知られている(例えば、Humphries,M.J.et a
l.,Science,233,p467−470、Humphries,M.J.et al.,J.C
ell Biol.,103,p2637−2647、Humphries,M.J.et al.,J.
Clin Invest.,81,p782−790等参照)。しかし、上記の
ペプチドが、ウイルスの増殖を抑制する作用を有するこ
とは知られていない。By the way, Arg-Gly-Asp, Arg-Gly-Asp-Ser, Arg
-Gly-Asp-Val, Gly-Arg-Gly-Asp, Gly-Arg-Gly
-Asp-Ser, Gly-Arg-Gly-Glu-Ser, Gly-Arg-Gly
-Asp-Ser-Pro, peptides consisting of a simple amino acid sequence such as Gly-Arg-Gly-Glu-Ser-Pro, are known to have an inhibitory effect on metastasis of cancer cells by causing the inhibition of fibronectin adhesion. (Eg, Humphries, MJet a
l., Science, 233 , p467-470; Humphries, MJ et al., JC
ell Biol., 103 , p2637-2647; Humphries, MJ et al., J.
Clin Invest., 81 , p782-790 etc.). However, it is not known that the above-mentioned peptide has an action of suppressing virus growth.
[発明が解決しようとする課題] 本発明は、かかる現状に鑑み、合成の容易な簡単なア
ミノ酸配列のペプチドからなる新規な抗ウイルス剤を提
供することを課題とするものである。[Problems to be Solved by the Invention] In view of the present situation, an object of the present invention is to provide a novel antiviral agent comprising a peptide having a simple amino acid sequence which is easy to synthesize.
[課題を解決するための手段] 本発明者は、上述した5′末端に結合タンパク質を持
つ核酸、すなわち、DNA或いはRNAの結合タンパク質中
に、所定のアミノ酸配列を含むヘプチドをレセプトする
部位が存在し、当該部位にペプチドがレセプトされるこ
とにより、DNAの複製が阻害され、ウイルスの増殖が抑
制されることを見出した。本発明は、かかる知見に基づ
きなされたものである。[Means for Solving the Problems] The present inventor has proposed that a nucleic acid having a binding protein at the 5 ′ end, that is, a DNA or RNA binding protein has a site for recepting a peptide containing a predetermined amino acid sequence. However, it was found that, by recepting the peptide at the site, DNA replication was inhibited, and virus growth was suppressed. The present invention has been made based on such findings.
すなわち、本発明は、末端にタンパク質を持つ核酸を
有するウイルスに対する抗ウイルス剤として、次式の X1−X2−X3 (X1は塩基性アミノ酸を、X2はアラニン、グリシン又は
サルコシンを、X3は酸性アミノ酸を表わす)のアミノ酸
配列を含むペプチドからなるものである。That is, the present invention is, as antiviral agents against the virus with a nucleic acid having a protein-terminated and X 1 -X 2 -X 3 (X 1 is a basic amino acid of the formula, X 2 is alanine, glycine or sarcosine , X 3 is made of a peptide comprising the amino acid sequence of the representative of the acidic amino acids).
上記塩基性アミノ酸としては、ヒスチジン、リジン、
アルギニンを、また酸性アミノ酸は、アスパラギン酸、
グルタミン酸を挙げることが出来る。The basic amino acids include histidine, lysine,
Arginine and acidic amino acids are aspartic acid,
Glutamic acid can be mentioned.
本発明のペプチドは、上記アミノ酸配列をその一部に
含んでいるものであれば良く、上記アミノ酸配列の両端
に、さらに他のアミノ酸を結合させても良い。The peptide of the present invention only needs to include the above-mentioned amino acid sequence in a part thereof, and other amino acids may be further bound to both ends of the above-mentioned amino acid sequence.
本発明の、特に好ましいペプチドを例示すると次の通
りである。Examples of particularly preferred peptides of the present invention are as follows.
Arg−Gly−Asp、Arg−Gly−Asp−Ser、Arg−Gly−Asp
−Val、Gly−Arg−Gly−Asp、Gly−Arg−Gly−Asp−Se
r、Gly−Arg−Gly−Glu−Ser、Gly−Arg−Gly−Asp−Se
r−Pro、Gly−Arg−Gly−Glu−Ser−Pro、Arg−Gly−Gl
u、Arg−Sar−Asp。Arg-Gly-Asp, Arg-Gly-Asp-Ser, Arg-Gly-Asp
-Val, Gly-Arg-Gly-Asp, Gly-Arg-Gly-Asp-Se
r, Gly-Arg-Gly-Glu-Ser, Gly-Arg-Gly-Asp-Se
r-Pro, Gly-Arg-Gly-Glu-Ser-Pro, Arg-Gly-Gl
u, Arg-Sar-Asp.
これらのペプチドは、固相法、液相法等、通常用いら
れるペプチド合成手法により得ることができる。また、
精製にあたっては、ゲル過、イオン交換ゲルクロマト
グラフィー、逆相高速液体クロマトグラフィー等のペプ
チド精製に通常用いられる手法を用いることができる。These peptides can be obtained by a commonly used peptide synthesis technique such as a solid phase method and a liquid phase method. Also,
In the purification, a method usually used for peptide purification such as gel permeation, ion exchange gel chromatography, reverse phase high performance liquid chromatography and the like can be used.
尚、本発明のペプチドは、末端にタンパク質を持つ核
酸、すなわち、DNA或いRNAを有するウイルスであれば、
特に区別することなく増殖阻害作用を有する。これは、
末端タンパク質に存在する上記ペプチドのレセプターが
ウイルス間で差がなく、また、この種のDNA又はRNAの複
製が、先ず、一方の鎖だけが鋳型になり、末端まで複製
されたあと、次いでも、もう一方の鎖の合成が行われる
プロテインプライミング−置換型複製機構であり、末端
タンパク質に上記ペプチドがレセプトされることによ
り、前記複製機構が働かなくなるためである。Incidentally, the peptide of the present invention is a nucleic acid having a protein at the end, that is, a virus having DNA or RNA,
It has a growth inhibitory effect without distinction. this is,
The receptor of the peptide present in the terminal protein does not differ between viruses, and this type of DNA or RNA replication, first, only one strand becomes a template, and after replication to the end, This is a protein priming-substitution type replication mechanism in which synthesis of the other chain is performed. This is because the above-mentioned replication mechanism does not work when the above peptide is receptive to a terminal protein.
尚、これらのウイルスとしては、枯草菌ファージφ2
9、枯草ファージM2、アデノウイルス、ポリオウイル
ス、肝炎ウイルス等を例示できる。These viruses include Bacillus subtilis phage φ2
9. Bacillus phage M2, adenovirus, poliovirus, hepatitis virus and the like can be exemplified.
尚、上記ペプチドは、ウイルス1μgに対して、0.01
〜1000mg程度用いると良い。The peptide was used in an amount of 0.01 to 1 μg of the virus.
It is good to use about 1000mg.
次に、実施例を挙げて本発明を具体的に説明するが、
本発明はこの実施例により制限されるものではない。Next, the present invention will be described specifically with reference to examples.
The present invention is not limited by this embodiment.
[実施例] (ペプチドH−Arg−Gly−Asp−OHの合成) t−ブトキシカルボニル−L−アスパラギン酸−β−
シクロヘキシルエステル2gを水・メタノール(1:3)20m
lに溶解し、10重量%濃度の酸セシウム水溶液を加えてP
H7にした。これを減圧濃縮してメタノールを除去した
後、凍結乾燥して、2.4gのt−ブトキシカルボニル−L
−アスパラギン酸−β−シクロヘキシルエステル−α−
セシウム塩の結晶を得た。[Example] (Synthesis of peptide H-Arg-Gly-Asp-OH) t-butoxycarbonyl-L-aspartic acid-β-
Cyclohexyl ester 2g water / methanol (1: 3) 20m
l, and add a 10% by weight aqueous solution of cesium acid
H7. This was concentrated under reduced pressure to remove methanol, and then freeze-dried to obtain 2.4 g of t-butoxycarbonyl-L.
-Aspartic acid-β-cyclohexyl ester-α-
Cesium salt crystals were obtained.
次に、上記で得られたt−ブトキシカルボニル−L−
アスパラギン酸−β−シクロヘキシルエステル−α−セ
シウム塩の1.12gをジメチルホルムアミド60mlに溶解
し、クロロメチル樹脂(ペプチド研究所製、ジビニルベ
ンゼン1%含有、200〜400メッシュ、クロル含量0.65me
q/g)10gを加え、50℃、24時間反応した。反応後のアス
パラギン酸含量は、0.25mmol/g−樹脂であった。その
後、グラスフィルター上で過することにより、ジメチ
ルホルムアミドを除き、ジメチルホルムアミド、90%ジ
メチルホルムアミド−水、ジメチルホルムアミド、エタ
ノールの順で洗浄し、乾燥した。Next, the t-butoxycarbonyl-L-
1.12 g of aspartic acid-β-cyclohexyl ester-α-cesium salt was dissolved in 60 ml of dimethylformamide, and chloromethyl resin (manufactured by Peptide Research Institute, containing 1% of divinylbenzene, 200 to 400 mesh, chlor content of 0.65me)
q / g) 10 g was added and reacted at 50 ° C. for 24 hours. The aspartic acid content after the reaction was 0.25 mmol / g-resin. Thereafter, the mixture was passed through a glass filter to remove dimethylformamide, and washed with dimethylformamide, 90% dimethylformamide-water, dimethylformamide, and ethanol in that order, and dried.
このようにして得られたt−ブトキシカルボニル−L
−アスパラギン酸−樹脂5g(1.25mmol)を塩化メチレン
中、50%濃度のトリフルオロ酢酸水溶液で処理して、t
−ブトキシカルボニル基をはずし、t−ブトキシカルボ
ニル−グリシン(ペプチド研究所製)3.125mmolをジ7
シクロヘキシルカルボジイミドを用いて結合させた。The thus obtained t-butoxycarbonyl-L
5 g (1.25 mmol) of aspartic acid-resin treated with 50% strength aqueous trifluoroacetic acid in methylene chloride to give t
-Butoxycarbonyl group was removed, and 3.125 mmol of t-butoxycarbonyl-glycine (manufactured by Peptide Research Laboratories) was added to di7.
The coupling was carried out using cyclohexylcarbodiimide.
これを塩化メチレン中、50%濃度のトリフルオロ酢酸
水溶液で処理して、t−ブトキシカルボニル基をはず
し、t−ブトキシカルボニル−Nw−パラトルエンスルホ
ニル−L−アルギニン(ペプチド研究所製)3.125mmol
をジシクロヘキシルカルボジイミドを用いて結合させ
た。This was treated with a 50% aqueous solution of trifluoroacetic acid in methylene chloride to remove the t-butoxycarbonyl group, and 3.125 mmol of t-butoxycarbonyl-Nw-paratoluenesulfonyl-L-arginine (manufactured by Peptide Research Institute)
Was coupled using dicyclohexylcarbodiimide.
尚、以上の反応は、ベックマン社製のペプチドシンセ
サイザーモデル990Eを用いて行った。The above reaction was performed using a peptide synthesizer model 990E manufactured by Beckman.
上述した方法で得たペプチド樹脂全量を、アニソール
の存在下に、フッ化水素で、0℃、1時間反応させ、脱
保護及びクロロメチル樹脂の脱離を行い、1規定の酢酸
に溶解して乾燥凍結した後、逆相高速液体クロマトグラ
フィーにより精製し、白色の粉末であるペプチドH−Ar
g−Gly−Asp−OH189mgを得た。The whole amount of the peptide resin obtained by the above method was reacted with hydrogen fluoride at 0 ° C. for 1 hour in the presence of anisole, deprotected and desorbed from the chloromethyl resin, and dissolved in 1N acetic acid. After freeze-drying, purification by reversed-phase high-performance liquid chromatography yielded a white powder of peptide H-Ar.
189 mg of g-Gly-Asp-OH were obtained.
(ファージDNAの精製) 枯草菌(Bacillus subtilis 222)をトリプトン−酵
母エキス培地(TY培地)で培養し、対数増殖期にバクテ
リオファージM2を感染させ、37℃で、1.5時間保持して
完全に溶菌させた。得られたファージM2を、CsClグラジ
エントによる遠心分離で精製した。次いで、これをSSC
バッファー溶液に懸濁し、1012PFU(plaque forming un
its)/mlになるまで希釈し、ラウロイル サルコシン
ナトリウム〔Sodium Lauroyl Sarcosinate(SLS)〕を
2%になるように加え、室温で5〜10分放置した。これ
をSSCバッファー溶液で飽和させたフェノールを当量加
え、室温で10分間振盪し、7000rpmで、5分間遠心分離
し、フェノールを除去した。これを再度SSCバッファー
飽和フェノールで抽出し、DNA層を4℃で、SSCバッファ
ー溶液に対して透析した。この場合のA260/A280nmは1.8
〜2.0とした。(Purification of phage DNA) Bacillus subtilis 222 was cultured in a tryptone-yeast extract medium (TY medium), infected with bacteriophage M2 during the logarithmic growth phase, and maintained at 37 ° C for 1.5 hours to completely lyse the bacterium. I let it. The resulting phage M2 was purified by centrifugation with a CsCl gradient. Then this is SSC
Suspend in a buffer solution and add 10 12 PFU (plaque forming un
its) / ml and dilute to lauroyl sarcosine
Sodium [Sodium Lauroyl Sarcosinate (SLS)] was added to 2% and left at room temperature for 5 to 10 minutes. This was added with an equivalent amount of phenol saturated with an SSC buffer solution, shaken at room temperature for 10 minutes, and centrifuged at 7,000 rpm for 5 minutes to remove phenol. This was extracted again with phenol saturated with SSC buffer, and the DNA layer was dialyzed at 4 ° C against the SSC buffer solution. A260 / A280nm in this case is 1.8
It was 2.0.
尚、上記と同様の方法で、末端にペプチドを有しない
DNAをもつファージであるSP50についても、DNAを調製
し、これをコントロールとして用いた。In addition, in the same manner as described above, there is no peptide at the terminal.
DNA was also prepared for SP50, a phage having DNA, and used as a control.
(コンピテントセルの調製) 枯草菌(Bacillus subtilis 222)をTBAB(Try−ptos
e Blood Agar Base)培地により、30〜35℃で一晩増殖
させ、これをCI培地にOD660で0.08となるように植種し
た。これを35〜36℃で、4時間振盪培養した。次に、こ
れを遠心分離して、菌を集め、2倍容のC II培地に懸濁
し、35〜36℃で、1時間振盪培養し、コンピテントセル
溶液を得た。(Preparation of competent cells) Bacillus subtilis 222 was converted to TBAB (Try-ptos
The e Blood Agar Base) medium, grown overnight at 30 to 35 ° C., which was Ueshu to 0.08 at OD 660 in CI medium. This was cultured with shaking at 35 to 36 ° C for 4 hours. Next, this was centrifuged to collect the bacteria, suspended in a double volume CII medium, and cultured with shaking at 35 to 36 ° C for 1 hour to obtain a competent cell solution.
(抗ウイルス作用試験) 前記のファージDNAの調製に記載した方法で得た1μg
/ml濃度のファージDNAのSSCバッファー溶液100μlと上
記で合成した3mg/ml濃度のArg−Gly−Aspペプチド水溶
液の所定量とを混合し、37℃で、10分間インキュベート
し、DNA−Arg−Gly−Aspインキュベート液を得た。(Antiviral action test) 1 μg obtained by the method described in the above-mentioned preparation of phage DNA
/ ml concentration of the phage DNA SSC buffer solution 100 μl and the above-prepared 3 mg / ml concentration Arg-Gly-Asp peptide aqueous solution was mixed with a predetermined amount, incubated at 37 ° C. for 10 minutes, and DNA-Arg-Gly -An Asp incubation solution was obtained.
次に、上記コンピテントセル溶液500μlとこのDNA−
Arg−Gly−Aspインキュベート液を混合し、30℃で、30
分間インキュベートした。Next, 500 μl of the above competent cell solution and this DNA-
Mix the Arg-Gly-Asp incubator and at 30 ° C.
Incubated for minutes.
LTTプレートにトリプトン−酵母エキス培地を入れ、
これに枯草菌(Bacillus subtilis SR22)をまき、上記
のインキュベート液をスプレッダーでプレーティングし
た。これを、37℃で一晩培養した後、プラークの数を数
え、コントロールに対するプラークの割合としてトラン
スフェクション効率を求めた。この結果を図に、Arg−G
ly−Aspの濃度との関係で示した。Put tryptone-yeast extract medium in LTT plate,
This was inoculated with Bacillus subtilis SR22, and the above-mentioned incubation solution was plated with a spreader. After culturing this overnight at 37 ° C., the number of plaques was counted, and the transfection efficiency was calculated as the ratio of plaque to control. The results show that Arg-G
The results are shown in relation to the concentration of ly-Asp.
この結果から明らかなように、本発明のペプチドが抗
ウイルス作用を有することが分かる。As is clear from these results, it is found that the peptide of the present invention has an antiviral effect.
発明の効果 以上のように本発明は、合成が極めて容易なペプチド
で、新たな抗ウイルス剤として有効なものである。Effect of the Invention As described above, the present invention is a peptide that is extremely easy to synthesize and is effective as a new antiviral agent.
図面は、抗ウイルス作用試験の結果を示したもので、Ar
g−Gly−Aspの濃度を変えた場合のプラークの数の変化
を表わしたものである。The drawing shows the results of the antiviral action test,
This figure shows the change in the number of plaques when the concentration of g-Gly-Asp was changed.
───────────────────────────────────────────────────── フロントページの続き (56)参考文献 特開 平1−110700(JP,A) 特開 昭62−187489(JP,A) 特開 昭54−98719(JP,A) 国際公開88/10267(WO,A1) J.Virol.,Vol.48,N o.3,P.604−615(1983) Chemical Abstract s Vol.111,No.2977(1988) ──────────────────────────────────────────────────続 き Continuation of the front page (56) References JP-A-1-110700 (JP, A) JP-A-62-187489 (JP, A) JP-A-54-98719 (JP, A) International Publication No. 88/10267 (WO, A1) Virol. , Vol. 48, No. 3, p. 604-615 (1983) Chemical Abstracts Vol. 111, no. 2977 (1988)
Claims (1)
サルコシンを、X3は酸性アミノ酸を表わす)のアミノ酸
配列を含むペプチドからなる末端にタンパク質を持つ核
酸を有するウイルスに対する抗ウイルス剤。1. A peptide comprising an amino acid sequence of the following formula X 1 -X 2 -X 3 (X 1 represents a basic amino acid, X 2 represents alanine, glycine or sarcosine, and X 3 represents an acidic amino acid). An antiviral agent for a virus having a nucleic acid having a protein at the end.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP63228843A JP2646013B2 (en) | 1988-09-14 | 1988-09-14 | Antiviral agent |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP63228843A JP2646013B2 (en) | 1988-09-14 | 1988-09-14 | Antiviral agent |
Publications (2)
Publication Number | Publication Date |
---|---|
JPH0278631A JPH0278631A (en) | 1990-03-19 |
JP2646013B2 true JP2646013B2 (en) | 1997-08-25 |
Family
ID=16882735
Family Applications (1)
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JP63228843A Expired - Fee Related JP2646013B2 (en) | 1988-09-14 | 1988-09-14 | Antiviral agent |
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JP (1) | JP2646013B2 (en) |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
HU201964B (en) * | 1989-01-13 | 1991-01-28 | Richter Gedeon Vegyeszet | Process for producing peptides inhibiting maturation of t-lymphocytes and activity of macrophages, as well as pharmaceutical compositions comprising same |
US5686567A (en) * | 1989-06-16 | 1997-11-11 | Cor Therapeutics, Inc. | Platelet aggregation inhibitors |
US5807828A (en) * | 1989-06-16 | 1998-09-15 | Cor Therapeutics, Inc. | Platelet aggregation inhibitors |
US6465253B1 (en) | 1994-09-08 | 2002-10-15 | Genvec, Inc. | Vectors and methods for gene transfer to cells |
US5846782A (en) | 1995-11-28 | 1998-12-08 | Genvec, Inc. | Targeting adenovirus with use of constrained peptide motifs |
US6127525A (en) * | 1995-02-21 | 2000-10-03 | Cornell Research Foundation, Inc. | Chimeric adenoviral coat protein and methods of using same |
JP2002525065A (en) | 1998-09-11 | 2002-08-13 | ジェンベク、インコーポレイティッド | Adenoviruses selectively targeted |
-
1988
- 1988-09-14 JP JP63228843A patent/JP2646013B2/en not_active Expired - Fee Related
Non-Patent Citations (2)
Title |
---|
Chemical Abstracts Vol.111,No.2977(1988) |
J.Virol.,Vol.48,No.3,P.604−615(1983) |
Also Published As
Publication number | Publication date |
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JPH0278631A (en) | 1990-03-19 |
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