JPH0259526A - Azidothymidine-protein complex and production thereof - Google Patents
Azidothymidine-protein complex and production thereofInfo
- Publication number
- JPH0259526A JPH0259526A JP63210588A JP21058888A JPH0259526A JP H0259526 A JPH0259526 A JP H0259526A JP 63210588 A JP63210588 A JP 63210588A JP 21058888 A JP21058888 A JP 21058888A JP H0259526 A JPH0259526 A JP H0259526A
- Authority
- JP
- Japan
- Prior art keywords
- protein
- azt
- azidothymidine
- complex
- protein complex
- 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.)
- Pending
Links
- 238000004519 manufacturing process Methods 0.000 title description 3
- 102000004169 proteins and genes Human genes 0.000 claims abstract description 21
- 108090000623 proteins and genes Proteins 0.000 claims abstract description 21
- HBOMLICNUCNMMY-XLPZGREQSA-N zidovudine Chemical group O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-XLPZGREQSA-N 0.000 claims abstract description 21
- 125000003277 amino group Chemical group 0.000 claims abstract description 4
- 239000002262 Schiff base Substances 0.000 claims abstract 2
- 150000004753 Schiff bases Chemical class 0.000 claims abstract 2
- 239000000126 substance Substances 0.000 claims 2
- 229960002555 zidovudine Drugs 0.000 abstract description 10
- 230000000840 anti-viral effect Effects 0.000 abstract description 6
- 230000000694 effects Effects 0.000 abstract description 6
- 238000002560 therapeutic procedure Methods 0.000 abstract description 3
- 102000009123 Fibrin Human genes 0.000 abstract description 2
- 108010073385 Fibrin Proteins 0.000 abstract description 2
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 abstract description 2
- 241001465754 Metazoa Species 0.000 abstract description 2
- 102000016943 Muramidase Human genes 0.000 abstract description 2
- 108010014251 Muramidase Proteins 0.000 abstract description 2
- 108010062010 N-Acetylmuramoyl-L-alanine Amidase Proteins 0.000 abstract description 2
- 102000007562 Serum Albumin Human genes 0.000 abstract description 2
- 108010071390 Serum Albumin Proteins 0.000 abstract description 2
- 239000003638 chemical reducing agent Substances 0.000 abstract description 2
- 229950003499 fibrin Drugs 0.000 abstract description 2
- 239000004325 lysozyme Substances 0.000 abstract description 2
- 229960000274 lysozyme Drugs 0.000 abstract description 2
- 235000010335 lysozyme Nutrition 0.000 abstract description 2
- 238000000034 method Methods 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- WGLPBDUCMAPZCE-UHFFFAOYSA-N Trioxochromium Chemical compound O=[Cr](=O)=O WGLPBDUCMAPZCE-UHFFFAOYSA-N 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 102000008100 Human Serum Albumin Human genes 0.000 description 2
- 108091006905 Human Serum Albumin Proteins 0.000 description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 125000003172 aldehyde group Chemical group 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 125000002485 formyl group Chemical group [H]C(*)=O 0.000 description 2
- 125000006850 spacer group Chemical group 0.000 description 2
- FNEHAOQZWPHONV-UHFFFAOYSA-N 9h-carbazole;sulfuric acid Chemical compound OS(O)(=O)=O.C1=CC=C2C3=CC=CC=C3NC2=C1 FNEHAOQZWPHONV-UHFFFAOYSA-N 0.000 description 1
- 102000007469 Actins Human genes 0.000 description 1
- 108010085238 Actins Proteins 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 102000003505 Myosin Human genes 0.000 description 1
- 108060008487 Myosin Proteins 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 102000004338 Transferrin Human genes 0.000 description 1
- 108090000901 Transferrin Proteins 0.000 description 1
- 150000003973 alkyl amines Chemical class 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 239000002259 anti human immunodeficiency virus agent Substances 0.000 description 1
- 230000002155 anti-virotic effect Effects 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 210000002798 bone marrow cell Anatomy 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 229910000423 chromium oxide Inorganic materials 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- MQYQOVYIJOLTNX-UHFFFAOYSA-N dichloromethane;n,n-dimethylformamide Chemical compound ClCCl.CN(C)C=O MQYQOVYIJOLTNX-UHFFFAOYSA-N 0.000 description 1
- 102000013361 fetuin Human genes 0.000 description 1
- 108060002885 fetuin Proteins 0.000 description 1
- 238000002523 gelfiltration Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 208000004235 neutropenia Diseases 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229920000729 poly(L-lysine) polymer Polymers 0.000 description 1
- 229920002643 polyglutamic acid Polymers 0.000 description 1
- 150000003138 primary alcohols Chemical class 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000012581 transferrin Substances 0.000 description 1
- 241001430294 unidentified retrovirus Species 0.000 description 1
Landscapes
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Peptides Or Proteins (AREA)
Abstract
Description
【発明の詳細な説明】
［産業上の利用分野］
３′−デオキシ−３′−アジドチミジン（以下、ＡＺＴ
）は、近年、抗エイズ１乍用を含め広範なレトロウィル
スに対する有効性か知られれてきた薬物である。[Detailed description of the invention] [Industrial application field] 3'-deoxy-3'-azidothymidine (hereinafter referred to as AZT)
) is a drug that has recently become known for its effectiveness against a wide range of retroviruses, including anti-AIDS drugs.
本発明は、ＡＺＴの５′位と蛋白質とを結合させた複合
体に関する。The present invention relates to a complex in which the 5' position of AZT and a protein are bound.
［従来の技術］
ＡＺＴは、それ自体、抗ウィルス剤として、実用化され
ているが、重篤な骨髄細胞抑制や好中球減少などの副作
用があり、問題点が多い。そのため蛋白質にＡＺＴを担
持させたものが研究されている０例えば、抗ウイルス抗
体を蛋白質として用いると抗ウィルス作用を持ったミサ
イル療法薬としての効果が期待できる。また、直接、抗
ウイルス抗体に結合すると、抗体の活性を損ねることも
考えられるが、その場合ある蛋白質をスペーサーとして
用いることが考えられ、適当な蛋白質を結合した複合体
も研究されている。[Prior Art] AZT itself has been put into practical use as an antiviral agent, but it has many problems, including side effects such as severe bone marrow cell suppression and neutropenia. Therefore, research is being carried out on proteins carrying AZT.For example, if an anti-viral antibody is used as a protein, it can be expected to be effective as a missile therapy drug with anti-viral effects. Additionally, direct binding to an antiviral antibody may impair the activity of the antibody, but in that case, it is possible to use a certain protein as a spacer, and complexes with appropriate proteins bound are also being studied.
［発明が解決しようとする課題］
上述のように蛋白質にＡＺＴを担持させたものは種々研
究されているが、本発明は新たな結合部位により結合さ
れなＡＺＴ−蛋白質複合体及びその製法を提供すること
を目的とするものである。[Problems to be Solved by the Invention] As mentioned above, various studies have been conducted on proteins carrying AZT, but the present invention provides an AZT-protein complex that is not bound by a new binding site and a method for producing the same. The purpose is to
［課題を解決するための手段及び作用〕本発明者らは上
記課題に関し鋭意検討した結果、本発明に到達した。[Means and effects for solving the problems] The present inventors have made intensive studies regarding the above problems, and as a result, have arrived at the present invention.
即ち本発明は、
（１）下記一般式（１）の閘造をもつ３′−デオキシ−
３′−アジドチミジン−蛋白質複合体。That is, the present invention provides (1) a 3'-deoxy-
3'-azidothymidine-protein complex.
（ｎは正の整数）
（２）３′−デオキシ−３′−アジドチミジン誘導体（
ＩＩ）
の５′位のＣＨＯと蛋白質のアミノ基との間でシック塩
基を形成させた後、還元することを特徴とする請求項１
記載の複合体の製法である。(n is a positive integer) (2) 3'-deoxy-3'-azidothymidine derivative (
Claim 1, characterized in that a thick base is formed between the 5'-position CHO of II) and the amino group of the protein, and then reduced.
A method for producing the described complex.
ＡＺＴ−蛋白質複合体＜Ｉンは例えはＡＺＴ誘導体（ｎ
）と蛋白質とを結合させればよ１）。AZT-protein complex <In is an example of an AZT derivative (n
) and a protein 1).
ＡＺＴ誘導体（Ｉ）はＡ Ｚ Ｔの５′位の第１級アル
コールをアルデヒドへ変換することにより得ることがで
きる。この方法は、公知の酸化方法を用いて行なうこと
ができる。例えは、酸化りＸコノ角（ｖｌ）−・ピリジ
ン錯体による酸化方法（コーレイとサムエルソン；ジャ
ーナル・オブ・オーガニフク・ケミストリー第４９巻、
、４７３５頁。AZT derivative (I) can be obtained by converting the primary alcohol at the 5' position of AZT to an aldehyde. This method can be performed using a known oxidation method. For example, the oxidation method using oxidation
, 4735 pages.
１９８４年）に準じて行なうことができる。(1984).
このようにして合成したＡ Ｚ Ｔ誘導体（ｆｆ＞と、
蛋白質を結合させ、ＡＺＴ−蛋白質複合体（Ｉ）を得る
が、この蛋白質については、特に限定しない。具体的に
は、種々のマウス、ヒト、ラットなどのモノクロナール
抗体、ポリクロナール抗体、各種動物の血清アルブミン
、トランスフェリン。The A Z T derivative (ff> and
The proteins are combined to obtain the AZT-protein complex (I), but this protein is not particularly limited. Specifically, monoclonal antibodies and polyclonal antibodies from various mice, humans, rats, etc., serum albumin from various animals, and transferrin.
リゾチーム、フィブリン、フェツイン、アクチン。Lysozyme, fibrin, fetuin, actin.
ミオシン、ポリーＬ−リジン、ポリ−Ｌ−グルタミン酸
などを例示することかできる。種々の用途により、適当
な蛋白質を選択することが可能である。また、アルキル
アミン等を用いることらできる。Examples include myosin, poly-L-lysine, and poly-L-glutamic acid. Appropriate proteins can be selected depending on various uses. Alternatively, an alkylamine or the like can be used.
上記したＡＺＴ誘導体（Ｉｔ）と蛋白質との結合は、例
えば蛋白質分子中の遊離アミノ基と、ＡＺＴ誘導体（Ｉ
Ｉ）の５′位のアルデヒド基とを反応させシップ塩基を
形成させた後、温和な還元剤で処理し、アルキルアミノ
誘導体へと誘導することにより行なうことができる。こ
の反応は、公知の方法を用いれば良く、具体例をあげれ
ば１０ｍＭ炭酸緩衝液（ｐＨ９，５）中で両者を一昼夜
４℃で反応した後１．Ｎ ａ Ｂ Ｈｔ、を用い、４℃
で還元すれば良い。なお反応後、ゲル濾過、透析等の方
法を用いて、未反応のＡＺＴ誘導体（ＩＩ）を除去し、
反応生成物として、本発明のＡＺＴ−蛋白質複合体（Ｉ
）を得ることができる。The above-mentioned bond between the AZT derivative (It) and the protein is, for example, a bond between a free amino group in the protein molecule and the AZT derivative (It).
This can be carried out by reacting I) with the aldehyde group at the 5' position to form a ship base, and then treating with a mild reducing agent to derive an alkylamino derivative. This reaction may be carried out using a known method; for example, after reacting the two in a 10 mM carbonate buffer (pH 9,5) at 4°C overnight, 1. Using N a B Ht, 4°C
You should get it back. After the reaction, unreacted AZT derivative (II) is removed using a method such as gel filtration or dialysis.
As a reaction product, the AZT-protein complex (I
) can be obtained.
蛋白質１分子あたりに担持されるＡＺＴの分子数ｎは用
いられる蛋白質により異なるが、−例をあげるとヒト血
清アルブミン１分子に対し、ＡＺＴ１１分子が担持され
る。Although the number n of AZT molecules supported per protein molecule varies depending on the protein used, for example, 11 molecules of AZT are supported per molecule of human serum albumin.
［発明の効果］
本発明のＡＺＴ−蛋白質複合体（Ｉ）は、蛋白質として
゛抗ウィルス抗体を用いれは、抗ウィルス作用をもった
ミサイル療法薬としての効果が期待できる。また、ＡＺ
Ｔに直接抗体を結合すると、抗体の活性を損ねることも
あり、その場合に、本発明によってスペーサーとなる蛋
白質を導入することができる。[Effects of the Invention] When the AZT-protein complex (I) of the present invention uses an anti-virus antibody as the protein, it can be expected to be effective as a missile therapy drug with anti-viral action. Also, AZ
Direct binding of an antibody to T may impair the activity of the antibody; in this case, the present invention allows the introduction of a protein that serves as a spacer.
本発明のＡＺＴ−蛋白質複合体＜Ｉ＞は本発明方法によ
って作製することかできる。The AZT-protein complex <I> of the present invention can be produced by the method of the present invention.
（実施例）
以下、本発明を実施例にてさらに詳細に説明するが、本
発明はこれら実施例にのみ限定されるものではない。(Examples) Hereinafter, the present invention will be explained in more detail with reference to Examples, but the present invention is not limited only to these Examples.
（１）酸化クロム（ｖＩ）（ＣｒＯ３）２０■、ピリジ
ン３２．３μρをジクロロメタン−Ｎ、Ｎ−ジメチルホ
ルムアミド（以下、ＣＨ２（１２−ＤＭＦとする＞（４
：１ｖ／ｖ）２５０μβ中に懸濁し、１５分間室温で撹
拌した。これに、ＡＺＴ１３．４■をＣＨ２Ｃ、ｆ’
２ Ｄ Ｍ Ｆ （４： １ ｖ ／ ｖ ）２０
０μρに溶解したものと、無水酢酸１８゜９μβを転化
し、５分間室温で撹拌。(1) Chromium oxide (vI) (CrO3) 20μ and pyridine 32.3μρ were mixed with dichloromethane-N,N-dimethylformamide (hereinafter referred to as CH2(12-DMF)>(4
:1v/v) and stirred at room temperature for 15 minutes. To this, AZT13.4■ is CH2C, f'
2 DMF (4: 1 v/v) 20
0 μρ and acetic anhydride were converted to 18°9 μβ and stirred at room temperature for 5 minutes.
反応させた。反応後、エタノール２５μβを添加した後
、酢酸エチル２，５ｍｌ中へ反応物を注ぎ、濾過を行な
った。炉液について、ＴＳＫ−ｇｅ（ｌ ５ｉｌｉｃ
ａ６０ （東ソー■製）を用いて、酢酸エチルを展開溶
媒として高速液体クロマトグラフィーを行ない、５′位
をアルデヒド基に酸化したＡＺＴ誘導（ＩＩ）を分離し
た。Made it react. After the reaction, 25 μβ of ethanol was added, and the reaction product was poured into 2.5 ml of ethyl acetate and filtered. Regarding the furnace liquid, TSK-ge (l 5ilic
High performance liquid chromatography was performed using a60 (manufactured by Tosoh ■) and ethyl acetate as a developing solvent to separate the AZT derivative (II) in which the 5' position was oxidized to an aldehyde group.
（２）上記ＡＺＴ誘導体（ＩＩ）２．７■とヒト血清ア
ルブミン（以下、Ｈ３Ａという）６．６■を１０ｍＭ炭
酸＃炭酸液（ｐＨ９，５）中で、室温で６時間インキュ
ベーションを行なった後、１０μｍｏｎのＮ ａ Ｂ
Ｈ４を添加し、４°Ｃで一昼夜反応させた。これを、Ｔ
ＳＫ−ｇｅｆｌＧ−３０００３Ｗ（東ソー■製）（２，
１５Ｘ６０■）を用いて、Ｏ，１Ｍリン酸緩衝液（ｐＨ
６，０）を展開溶液として、ゲルと過を行ない、ＡＺＴ
誘導体（ｎ）とＨ８Ａとの複合体（Ｉ＞を分離精製しな
。収率は９７％であった。(2) After incubating 2.7■ of the above AZT derivative (II) and 6.6■ of human serum albumin (hereinafter referred to as H3A) in a 10mM carbonate solution (pH 9.5) at room temperature for 6 hours. , 10 μmon N a B
H4 was added and reacted at 4°C overnight. This is T
SK-geflG-30003W (manufactured by Tosoh) (2,
15×60■) using O.1M phosphate buffer (pH
6,0) as a developing solution, gel and filter were applied.
The complex (I>) of derivative (n) and H8A was separated and purified. The yield was 97%.
また、カルバゾール−硫酸法によると
Ｈ３ＡＩ分子あたり１１分子のＡＺＴか担持されていた
。Furthermore, according to the carbazole-sulfuric acid method, 11 molecules of AZT were supported per molecule of H3AI.
Claims (2)
−３′−アジドチミジン−蛋白質複合体。 ▲数式、化学式、表等があります▼（ I ） （ｎは正の整数）(1) A 3'-deoxy-3'-azidothymidine-protein complex having the structure of the following general formula (I). ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (n is a positive integer)
II） ▲数式、化学式、表等があります▼（II） の５′位のＣＨＯと蛋白質のアミノ基との間でシッフ塩
基を形成させた後、還元することを特徴とする請求項１
記載の複合体の製法。(2) 3'-deoxy-3'-azidothymidine derivative (
II) ▲There are mathematical formulas, chemical formulas, tables, etc.▼Claim 1, characterized in that a Schiff base is formed between CHO at the 5' position of (II) and an amino group of a protein, and then reduced.
Preparation of the described complexes.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63210588A JPH0259526A (en) | 1988-08-26 | 1988-08-26 | Azidothymidine-protein complex and production thereof |
| US07/396,984 US4977882A (en) | 1988-08-26 | 1989-08-22 | Distributor type fuel injection pump |
| DE3928219A DE3928219A1 (en) | 1988-08-26 | 1989-08-25 | FUEL INJECTION PUMP WITH DISTRIBUTION FUNCTION |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63210588A JPH0259526A (en) | 1988-08-26 | 1988-08-26 | Azidothymidine-protein complex and production thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH0259526A true JPH0259526A (en) | 1990-02-28 |
Family
ID=16591805
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP63210588A Pending JPH0259526A (en) | 1988-08-26 | 1988-08-26 | Azidothymidine-protein complex and production thereof |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0259526A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0503741A1 (en) * | 1991-03-12 | 1992-09-16 | LABORATORI BALDACCI Spa | Conjugate of azidothymidine and human albumin, process for its preparation and pharmaceutical compositions containing it |
-
1988
- 1988-08-26 JP JP63210588A patent/JPH0259526A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0503741A1 (en) * | 1991-03-12 | 1992-09-16 | LABORATORI BALDACCI Spa | Conjugate of azidothymidine and human albumin, process for its preparation and pharmaceutical compositions containing it |
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