RU97101169A - NEW PEPTIDES - Google Patents

NEW PEPTIDES

Info

Publication number
RU97101169A
RU97101169A RU97101169/04A RU97101169A RU97101169A RU 97101169 A RU97101169 A RU 97101169A RU 97101169/04 A RU97101169/04 A RU 97101169/04A RU 97101169 A RU97101169 A RU 97101169A RU 97101169 A RU97101169 A RU 97101169A
Authority
RU
Russia
Prior art keywords
seq
amide
oligopeptide
alaasnlysilesertyrgln
amino acid
Prior art date
Application number
RU97101169/04A
Other languages
Russian (ru)
Other versions
RU2162855C2 (en
Inventor
ДеФео-Джонс Дебора
Фенг Донг-Мей
М.Гарски Виктор
Е.Джонс Раймонд
И.Олифф Аллен
Original Assignee
Мерк Энд Ко., Инк.
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority claimed from US08/267,092 external-priority patent/US5599686A/en
Application filed by Мерк Энд Ко., Инк. filed Critical Мерк Энд Ко., Инк.
Publication of RU97101169A publication Critical patent/RU97101169A/en
Application granted granted Critical
Publication of RU2162855C2 publication Critical patent/RU2162855C2/en

Links

Claims (19)

1. Олигопептид, который имеет аминокислотную последовательность, распознаваемую и селективно протеолитически расщепляемую свободным простатическим антигеном.1. Oligopeptide, which has an amino acid sequence recognized and selectively proteolytically cleaved by a free prostatic antigen. 2. Олигопептид по п.1, имеющий следующую аминокислотную последовательность:
а) AsnLysIleSerTyrGln|Ser (SEQ ID No 13),
b) LysIleSerTyrGln|Ser (SEQ ID No 14),
c) GlyGluAsnGlyValGlnLysAspValSerGlnXaaSerIleTyr|SerGlnThrGlu (SEQ ID No 15),
d) GlyLysGlyIleSerSerGlnTyrlSerAsnThrGluGluArqLeu (SEQ ID No 2),
e) AsnLysIleSerTyrTyrlSer (SEQ ID No 127),
f) AsnLysAlaSerTyrGln|Ser (SEQ ID No 128),
g) SerTyrGlnlSerSer (SEQ ID No 129),
h) LysTyrGlnlSerSer (SEQ ID No 140),
i) hArgTyrGln|SerSer (SEQ ID No 141);
где hArq представляет собой гомоаргинин, а Xaa представляет собой натуральную аминокислоту.2. Oligopeptide according to claim 1, having the following amino acid sequence:
a) AsnLysIleSerTyrGln | Ser (SEQ ID No 13),
b) LysIleSerTyrGln | Ser (SEQ ID No 14),
c) GlyGluAsnGlyValGlnLysAspValSerGlnXaaSerIleTyr | SerGlnThrGlu (SEQ ID No 15),
d) GlyLysGlyIleSerSerGlnTyrlSerAsnThrGluGluArqLeu (SEQ ID No 2),
e) AsnLysIleSerTyrTyrlSer (SEQ ID No 127),
f) AsnLysAlaSerTyrGln | Ser (SEQ ID No 128),
g) SerTyrGlnlSerSer (SEQ ID No 129),
h) LysTyrGlnlSerSer (SEQ ID No 140),
i) hArgTyrGln | SerSer (SEQ ID No 141);
where hArq is homoarginine, and Xaa is a natural amino acid. 3. Олигопептид по п.2, имеющий следующую аминокислотную последовательность:
а) AsnLysIleSerTyrGln|SerSer (SEQ ID No 16),
b) AsnLysIleSerTyrGln|SerAla (SEQ ID No 130),
c) AsnLysIleSerTyrGln|SerSerSer (SEQ ID No 17),
d) AlaAsnLysIleSerTyrGln|SerSerSer (SEQ ID No 18),
e) LysIleSerTyrGln|SerSerSerThrGlu (SEQ ID No 19),
f) GlyGluAsnGlyValGlnLysAspValSerGlnArgSerIleTyr| SerGlnGlu (SEQ ID No 4),
g) GlyGluAsnGlyValGlnLysAspValSerGlnSerSerIleTyr|SerGlnThrGlu (SEQ ID No 5),
h) AlaAsnTysIleSerTyrTyrlSer (SEQ ID No 131),
i) AlaAsnLysAlaSerTyrGlnlSer (SEQ ID No 132),
j) SerTyrGlnlSerSerThr (SEQ ID No 133),
k) SerTyrGln|SerSerSer (SEQ ID No 134),
l) LysTyrGlnlSerSerSer (SEQ ID No 142),
m) hArqTyrGln|SerSerSer (SEQ ID No 143), или
n) SerTyrGlnlSerSerLeu (SEQ ID No 135).3. Oligopeptide according to claim 2, having the following amino acid sequence:
a) AsnLysIleSerTyrGln | SerSer (SEQ ID No 16),
b) AsnLysIleSerTyrGln | SerAla (SEQ ID No 130),
c) AsnLysIleSerTyrGln | SerSerSer (SEQ ID No 17),
d) AlaAsnLysIleSerTyrGln | SerSerSer (SEQ ID No 18),
e) LysIleSerTyrGln | SerSerSerThrGlu (SEQ ID No 19),
f) GlyGluAsnGlyValGlnLysAspValSerGlnArgSerIleTyr | SerGlnGlu (SEQ ID No 4),
g) GlyGluAsnGlyValGlnLysAspValSerGlnSerSerIleTyr | SerGlnThrGlu (SEQ ID No 5),
h) AlaAsnTysIleSerTyrTyrlSer (SEQ ID No 131),
i) AlaAsnLysAlaSerTyrGlnlSer (SEQ ID No 132),
j) SerTyrGlnlSerSerThr (SEQ ID No 133),
k) SerTyrGln | SerSerSer (SEQ ID No 134),
l) LysTyrGlnlSerSerSer (SEQ ID No 142),
m) hArqTyrGln | SerSerSer (SEQ ID No 143), or
n) SerTyrGlnlSerSerLeu (SEQ ID No 135). 4. Олигопептид по п.2, имеющий следующую аминокислотную последовательность:
а) AsnLysIleSerTyrGln|SerSerSerThr (SEQ ID No 10),
b) AlaAsnLysIleSerTyrGln|SerAla (SEQ ID No 136),
c) AsnLysIleSerTyrGln|SerSerSerThrGlu (SEQ ID No 3),
d) AlaAsnLysIleSerTyrGln|SerSerSerThrGlu (SEQ ID No 11),
e) GlyGluAsnGlyValGlnLysAspValSerGlnArgSerIleTyr|SerGlnThrGlu (SEQ ID No 4),
f) AlaAsnLysIleSerTyrTyr|SerSer (SEQ ID No 137),
g) AlaAsnLysIleSerTyrTyr|SerAla (SEQ ID No 138),
h) AlaAsnLysAlaSerTyrGln|SerAla (SEQ ID No 139), или
i) AlaSerTyrGln|SerSerLeu (SEQ ID No 94).4. Oligopeptide according to claim 2, having the following amino acid sequence:
a) AsnLysIleSerTyrGln | SerSerSerThr (SEQ ID No 10),
b) AlaAsnLysIleSerTyrGln | SerAla (SEQ ID No 136),
c) AsnLysIleSerTyrGln | SerSerSerThrGlu (SEQ ID No 3),
d) AlaAsnLysIleSerTyrGln | SerSerSerThrGlu (SEQ ID No 11),
e) GlyGluAsnGlyValGlnLysAspValSerGlnArgSerIleTyr | SerGlnThrGlu (SEQ ID No 4),
f) AlaAsnLysIleSerTyrTyr | SerSer (SEQ ID No 137),
g) AlaAsnLysIleSerTyrTyr | SerAla (SEQ ID No 138),
h) AlaAsnLysAlaSerTyrGln | SerAla (SEQ ID No 139), or
i) AlaSerTyrGln | SerSerLeu (SEQ ID No 94). 5. Олигопептид по п.2, имеющий следующую аминокислотную последовательность:
а) GlyArgLysAlaAsnLysIleSerTyrGln|SerSerSerThrGluGluArgArgLeuHisTyrGlyGluAsnGly (SEQ ID No 6).5. Oligopeptide according to claim 2, having the following amino acid sequence:
a) GlyArgLysAlaAsnLysIleSerTyrGln | SerSerSerThrGluGluArgArgLeuHisTyrGlyGluAsnGly (SEQ ID No 6). 6. Олигопептид по п.1, который выбирают из:
AsnArqIleSerTyrGln|Ser (SEQ ID No 21),
AsnLysValSerTyrGln|Ser (SEQ ID No 22),
AsnLysMetSerTyrGln|SerSer (SEQ ID No 23)
AsnLysLeuSerTyrGln|SerSer (SEQ ID No 24)
AsnLysIleThrTyrGln|SerSerSer (SEQ ID No 25)
AsnLysIleSerPheGln|SerSerSer (SEQ ID No 26)
AsnLysIleSerTrpGln|SerSerSerThr (SEQ ID No 27)
AsnLysIleSerTyrAsn|SerSerSerThr (SEQ ID No 28)
AsnLysIleSerTrpGln|ThrSerSerThr (SEQ ID No 29)
AsnLysIleSerTyrGln|Ser (SEQ ID No 30)
GlnLysIleSerTyrGln|SerSer (SEQ ID No 31)
AsnArgIleThrTyrGln|SerSerSer (SEQ ID No 32)
AsnArqIleSerPheGln|SerSerSerSerThr (SEQ ID No 33)
AsnArqIleSerThrGln|SerSerSerThr (SEQ ID No 35)
AsnArqIleSerTyrGln|ThrSerSerThr (SEQ ID No 36)
AsnLysIleThrTyrGln|ThrSerSerThr (SEQ ID No 37)
AsnLysLeuSerTyrGln|ThrSerSerThr (SEQ ID No 38)
GlnLysLeuSerTyrGln|SerSerSerThr (SEQ ID No 39)
AsnArqLeuSerTyrGln|ThrSerSerThr (SEQ ID No 40)
AsnLysValSerPheGln|SerSerSerThr (SEQ ID No 41)
AsnArqValSerGln|SerSerSerThr (SEQ ID No 42)
GlnLysValSerTyrGln|SerSerSerThr (SEQ ID No 43)
GlnLysIleSerTyrGln|ThrSerSerThr (SEQ ID No 34)
AsnLysIleSerTyrGln|SerSerSerThr (SEQ ID No 44).6. Oligopeptide according to claim 1, which is chosen from:
AsnArqIleSerTyrGln | Ser (SEQ ID No 21),
AsnLysValSerTyrGln | Ser (SEQ ID No 22),
AsnLysMetSerTyrGln | SerSer (SEQ ID No 23)
AsnLysLeuSerTyrGln | SerSer (SEQ ID No 24)
AsnLysIleThrTyrGln | SerSerSer (SEQ ID No 25)
AsnLysIleSerPheGln | SerSerSer (SEQ ID No 26)
AsnLysIleSerTrpGln | SerSerSerThr (SEQ ID No 27)
AsnLysIleSerTyrAsn | SerSerSerThr (SEQ ID No 28)
AsnLysIleSerTrpGln | ThrSerSerThr (SEQ ID No 29)
AsnLysIleSerTyrGln | Ser (SEQ ID No 30)
GlnLysIleSerTyrGln | SerSer (SEQ ID No 31)
AsnArgIleThrTyrGln | SerSerSer (SEQ ID No 32)
AsnArqIleSerPheGln | SerSerSerSerThr (SEQ ID No 33)
AsnArqIleSerThrGln | SerSerSerThr (SEQ ID No 35)
AsnArqIleSerTyrGln | ThrSerSerThr (SEQ ID No 36)
AsnLysIleThrTyrGln | ThrSerSerThr (SEQ ID No 37)
AsnLysLeuSerTyrGln | ThrSerSerThr (SEQ ID No 38)
GlnLysLeuSerTyrGln | SerSerSerThr (SEQ ID No 39)
AsnArqLeuSerTyrGln | ThrSerSerThr (SEQ ID No 40)
AsnLysValSerPheGln | SerSerSerThr (SEQ ID No 41)
AsnArqValSerGln | SerSerSerThr (SEQ ID No 42)
GlnLysValSerTyrGln | SerSerSerThr (SEQ ID No 43)
GlnLysIleSerTyrGln | ThrSerSerThr (SEQ ID No 34)
AsnLysIleSerTyrGln | SerSerSerThr (SEQ ID No 44). 7. Олигопептид по п.1, который представляет собой:
AlaAsnLysIleSerTyrGln|SerSerSerThrGlu-амид (SEQ ID No 11),
Ac-AlaAsnLysIleSerTyrGln|SerSerSerThrLeu (SEQ ID No 70),
Ac-AlaAsnLysIleSerTyrGln|SerSerSerThrGlu-амид (SEQ ID No 11),
Ac-AlaAsnLysIleSerTyrGln|SerSerSerThrLeu-амид (SEQ ID No 70),
Ac-AlaAsnLysIleSerTyrGln|SerAlaSerThrGlu-амид (SEQ ID No 73),
Ac-AlaAsnLysIleSerTyrGln|SerSerLysThrGlu-амид (SEQ ID No 74),
Ac-AlaAsnLysIleSerTyrGln|SerSerThrGlu-амид (SEQ ID No 75),
Ac-AlaAsnLysIleSerTyrGln|SerSerGlnThrGlu-амид (SEQ ID No 78),
Ac-AlaAsnLysIleSerTyrGln|SerAlaLysThrGlu-амид (SEQ ID No 79),
Ac-AlaAsnLysIleSerTyrGln|SerThrGlu-амид (SEQ ID No 81),
Ac- AlaAsnLysSerTyrGln|SerSerThrGlu-амид (SEQ ID No 82),
Ac- AlaAsnLysAlaSerTyrGln|SerAlaSerTyrGlu-амид (SEQ ID No 84),
Ac-AlaAsnGluIleSerTyrGln|SerAlaSerThrGlu-амид (SEQ ID No 85),
Ac-AsnLysIleSerTyrGln|SerSer-амид (SEQ ID No 16),
Ac-LysIleSerTyrGln|SerSer-амид (SEQ ID No 86),
Ac-SerTyrGln|SerSerThrGlu-амид (SEQ ID No 87),
Ac-AlaSerTyrGln|SerSerThrGlu-амид (SEQ ID No 89),
Ac-AlaAsnLysIleSerTyrTyr|SerSerSerThrGlu-амид (SEQ ID No 92),
Ac- AlaAsnLysIleSerTyrTyr|SerAlaSerThrGlu-амид (SEQ ID No 93),
Ac-AlaSerTyrGln|SerSerLeu-амид (SEQ ID No 94),
Ac-AlaAsnSerTyrGln|SerSerSerThrGlu-амид (SEQ ID No 95),
Ac-AlaSerTyrGln|SerSerSerThrGlu-амид (SEQ ID No 96),
Ac-SerTyrGln|SerSerSerThrGlu-амид (SEQ ID No 97),
Ac-AlaAsnLysAlaSerTyrGln|SerAlaSerCys-амид (SEQ ID No 98).7. The oligopeptide according to claim 1, which is:
AlaAsnLysIleSerTyrGln | SerSerSerThrGlu-amide (SEQ ID No 11),
Ac-AlaAsnLysIleSerTyrGln | SerSerSerThrLeu (SEQ ID No 70),
Ac-AlaAsnLysIleSerTyrGln | SerSerSerThrGlu-amide (SEQ ID No 11),
Ac-AlaAsnLysIleSerTyrGln | SerSerSerThrLeu-amide (SEQ ID No 70),
Ac-AlaAsnLysIleSerTyrGln | SerAlaSerThrGlu-amide (SEQ ID No 73),
Ac-AlaAsnLysIleSerTyrGln | SerSerLysThrGlu-amide (SEQ ID No 74),
Ac-AlaAsnLysIleSerTyrGln | SerSerThrGlu-amide (SEQ ID No 75),
Ac-AlaAsnLysIleSerTyrGln | SerSerGlnThrGlu-amide (SEQ ID No 78),
Ac-AlaAsnLysIleSerTyrGln | SerAlaLysThrGlu-amide (SEQ ID No 79),
Ac-AlaAsnLysIleSerTyrGln | SerThrGlu-amide (SEQ ID No 81),
Ac- AlaAsnLysSerTyrGln | SerSerThrGlu-amide (SEQ ID No 82),
Ac- AlaAsnLysAlaSerTyrGln | SerAlaSerTyrGlu-amide (SEQ ID No 84),
Ac-AlaAsnGluIleSerTyrGln | SerAlaSerThrGlu-amide (SEQ ID No 85),
Ac-AsnLysIleSerTyrGln | SerSer-amide (SEQ ID No 16),
Ac-LysIleSerTyrGln | SerSer-amide (SEQ ID No 86),
Ac-SerTyrGln | SerSerThrGlu-amide (SEQ ID No 87),
Ac-AlaSerTyrGln | SerSerThrGlu-amide (SEQ ID No 89),
Ac-AlaAsnLysIleSerTyrTyr | SerSerSerThrGlu-amide (SEQ ID No 92),
Ac- AlaAsnLysIleSerTyrTyr | SerAlaSerThrGlu-amide (SEQ ID No 93),
Ac-AlaSerTyrGln | SerSerLeu-amide (SEQ ID No 94),
Ac-AlaAsnSerTyrGln | SerSerSerThrGlu-amide (SEQ ID No 95),
Ac-AlaSerTyrGln | SerSerSerThrGlu-amide (SEQ ID No 96),
Ac-SerTyrGln | SerSerSerThrGlu-amide (SEQ ID No 97),
Ac-AlaAsnLysAlaSerTyrGln | SerAlaSerCys-amide (SEQ ID No 98). 8. Способ определения протеолитической активности свободного простатического антигена в образце, включающий в себя следующие стадии: (а) осуществление реакции субстрата, где субстрат представляет собой олигопептид, имеющий аминокислотную последовательность, распознаваемую и селективно протеолитически расщепляемую свободным простатическим антигеном, с образцом и (b) обнаружение расщепления субстрата. 8. A method for determining the proteolytic activity of a free prostatic antigen in a sample, comprising the following steps: (a) performing a substrate reaction, where the substrate is an oligopeptide having an amino acid sequence recognized and selectively proteolytically cleaved by the free prostatic antigen, with the sample and (b) detection of substrate splitting. 9. Способ по п. 8, в котором стадия обнаружения расщепления субстрата включает в себя анализ реакционной смеси с помощью высокоразрешающей жидкостной хроматографии. 9. The method of claim 8, wherein the step of detecting the splitting of the substrate involves analyzing the reaction mixture using high-resolution liquid chromatography. 10. Способ идентификации соединений, ингибирующих протеолитическую активность простатического антигена, включающий в себя следующие стадии: (а) осуществление реакции субстрата, который имеет аминокислотную последовательность, распознаваемую и селективно протеолитически расщепляемую свободным простатическим антигеном, со свободным простатическим антигеном в присутствии испытуемого соединения и (b) обнаружение расщепления субстрата, где на способность испытуемого соединения ингибировать протеолитическую активность простатического антигена указывает снижение уровня расщепления субстрата по сравнению с уровнем расщепления субстрата в отсутствии испытуемого соединения. 10. A method for identifying compounds inhibiting the proteolytic activity of a prostate antigen, comprising the following steps: (a) performing a substrate reaction that has an amino acid sequence recognized and selectively proteolytically cleaved by a free prostatic antigen with a free prostatic antigen in the presence of the test compound and (b ) detection of substrate cleavage, where the ability of the test compound to inhibit the proteolytic activity of the prostate antigen indicates a decrease in the level of substrate cleavage compared to the level of substrate cleavage in the absence of the test compound. 11. Способ по п.10, где стадия обнаружения расщепления субстрата предусматривает анализ аналитической смеси с помощью высокоразрешающей жидкостной хроматографии. 11. The method according to claim 10, wherein the step of detecting the splitting of the substrate involves analyzing the analytical mixture using high-resolution liquid chromatography. 12. Конъюгат, который может быть использован для лечения рака предстательной железы и который включает в себя цитотоксический агент, связанный с олигопептидом, имеющим аминокислотную последовательность, распознаваемую и селективно протеолитически расщепляемую свободным простатическим антигеном; причем, указанный цитотоксический агент связан с указанным олигопептидом посредством ковалентной связи или химического линкера. 12. A conjugate that can be used to treat prostate cancer and that includes a cytotoxic agent that is associated with an oligopeptide that has an amino acid sequence that is recognized and selectively proteolytically cleaved by a free prostatic antigen; moreover, the specified cytotoxic agent is associated with the specified Oligopeptide through a covalent bond or chemical linker. 13. Конъюгат по п.12, где цитотоксический агент является членом класса цитотоксических агентов, выбранного из следующих классов: а) семейство антрациклиновых лекарственных средств; b) винкаалкалоидные лекарственные средства; с) митомицины; d) блеомицины; е) цитотоксические нуклеозиды; f) семейство птеридиновых лекарственных средств; g) диинены; h) эстрамустин; i) циклофосфамид и j) подофиллотоксины. 13. The conjugate of claim 12, wherein the cytotoxic agent is a member of the class of cytotoxic agents selected from the following classes: a) a family of anthracycline drugs; b) Vinca-alcaloid medicines; c) mitomycin; d) bleomycins; e) cytotoxic nucleosides; f) a pteridine drug family; g) diinene; h) estramustine; i) cyclophosphamide; and j) podophyllotoxins. 14. Конъюгат по п.12, где цитотоксический агент выбирают из следующих цитотоксических агентов: а) доксорубицин, b) карминомицин, с) даунорубицин, d) аминоптерин, e) метотрексат, f) метоптерин, g) дихлоро-метотрексат, h) митомицин С, i) порфиромицин, j) 5-фтороурацил, k) 6-меркаптопурин, l) цитозинарабинозид, m) подофиллотоксин, n) этопозид, о) этопозида фосфат, p) мелфалан, q) винбластин, r) винкристин, s) лейрозидин, t) виндезин, u) эстрамустин, v) цисплатин, w) циклофосфамид и х) лейрозин. 14. The conjugate of claim 12, wherein the cytotoxic agent is selected from the following cytotoxic agents: a) doxorubicin, b) carminomycin, c) daunorubicin, d) aminopterin, e) methotrexate, f) metopterin, g) dichloro-methotrexate, h) mitomycin C, i) porphyromycin, j) 5-fluorouracil, k) 6-mercaptopurine, l) cytosine arabinoside, m) podophyllotoxin, n) etoposide, o) etoposide phosphate, p) melphalan, q) vinblastine, r) vincristine, s) lerosusidin, , t) vindesine, u) estramustine, v) cisplatin, w) cyclophosphamide, and x) leyrosin. 15. Конъюгат по п.12, где цитотоксический агент выбирают из доксорубицина и винбластина или их цитотоксического производного. 15. The conjugate of claim 12, wherein the cytotoxic agent is selected from doxorubicin and vinblastine or a cytotoxic derivative thereof. 16. Конъюгат по п.12, где цитотоксическим агентом является доксорубицин или его цитотоксическое производное. 16. The conjugate of claim 12, wherein the cytotoxic agent is doxorubicin or its cytotoxic derivative. 17. Конъюгат по п.16, имеющий формулу
Figure 00000001

где олигопептид представляет собой олигопептид, специфически распознаваемый свободным простатическим антигеном (PSA) и протеолитически расщепляемый под действием ферментативной активности свободного простатического антигена;
XL отсутствует или представляет собой аминокислоту, выбранную из группы аминокислот, включающей в себя: а) фенилаланин, b) лейцин, с) валин, d) изолейцин, е) (2-нафтил)аланин, f) циклогексилаланин, g) дифенилаланин, h) норвалин и i) норлейцин;
R представляет собой водород или -(C=O)R1;
R1 представляет собой C1 - C6-алкил или арил.17. The conjugate according to clause 16, having the formula
Figure 00000001

where the oligopeptide is an oligopeptide specifically recognized by the free prostatic antigen (PSA) and proteolytically cleaved by the enzymatic activity of the free prostatic antigen;
X L is absent or is an amino acid selected from the group of amino acids that includes: a) phenylalanine, b) leucine, c) valine, d) isoleucine, e) (2-naphthyl) alanine, f) cyclohexylalanine, g) diphenylalanine, h) norvaline and i) norleucine;
R is hydrogen or - (C = O) R 1 ;
R 1 represents C 1 - C 6 -alkyl or aryl. 18. Конъюгат по п.17, где олигопептидом является олигопептид, имеющий аминокислотную последовательность, выбранную из
а) AsnLysIleSerTyrGln|Ser (SEQ ID No 13),
b) LysIleSerTyrGln|Ser (SEQ ID No 14),
с) GlyGluAsnGlyValGlnLysAspValSerGlnXaaSerIleTyr|SerGlnThrGlu (SEQ ID No 15),
d) GlyLysGlyIleSerSerGlnTyr|SerAsnThrGluGluArgLeu (SEQ ID No 2),
e) AsnLysIleSerTyrTyr|Ser (SEQ ID No 127),
f) AsnLysAlaSerTyrGln|Ser (SEQ ID No 128),
g) SerTyrGln|SerSer (SEQ ID No 129),
h) hArgTyrGln|SerSer (SEQ ID No 141),
где hArg представляет собой гомоаргинин,
Хаа представляет собой любую натуральную аминокислоту, встречающуюся в природе,
XL отсутствует или представляет собой аминокислоту, выбранную из: а) лейцина, b) изолейцина и с) валина,
R представляет собой ацетил, пивалоил или бензоил.18. The conjugate of claim 17, wherein the oligopeptide is an oligopeptide having an amino acid sequence selected from
a) AsnLysIleSerTyrGln | Ser (SEQ ID No 13),
b) LysIleSerTyrGln | Ser (SEQ ID No 14),
c) GlyGluAsnGlyValGlnLysAspValSerGlnXaaSerIleTyr | SerGlnThrGlu (SEQ ID No 15),
d) GlyLysGlyIleSerSerGlnTyr | SerAsnThrGluGluArgLeu (SEQ ID No 2),
e) AsnLysIleSerTyrTyr | Ser (SEQ ID No 127),
f) AsnLysAlaSerTyrGln | Ser (SEQ ID No 128),
g) SerTyrGln | SerSer (SEQ ID No 129),
h) hArgTyrGln | SerSer (SEQ ID No 141),
where hArg is homoarginine,
Haa is any natural amino acid found in nature,
X L is absent or is an amino acid selected from: a) leucine, b) isoleucine and c) valine,
R is acetyl, pivaloyl or benzoyl. 19. Конъюгат по п.16, который выбирают из
Figure 00000002

где Х представляет собой
Figure 00000003

Figure 00000004

Figure 00000005

Figure 00000006

Figure 00000007

Figure 00000008

Figure 00000009

Figure 00000010

Figure 00000011

Figure 00000012

Figure 00000013

Figure 00000014

Figure 00000015

Figure 00000016

Figure 00000017

Figure 00000018

20. Конъюгат по п.15, имеющий формулу
Figure 00000019

где олигопептид представляет собой олигопептид, специфически распознаваемый свободным простатическим антигеном (PSA),
и протеолитически расщепляемый под действием ферментативной активности свободного простатического антигена.19. The conjugate according to clause 16, which is chosen from
Figure 00000002

where X represents
Figure 00000003

Figure 00000004

Figure 00000005

Figure 00000006

Figure 00000007

Figure 00000008

Figure 00000009

Figure 00000010

Figure 00000011

Figure 00000012

Figure 00000013

Figure 00000014

Figure 00000015

Figure 00000016

Figure 00000017

Figure 00000018

20. Conjugate indicated in paragraph 15, having the formula
Figure 00000019

where the oligopeptide is an oligopeptide specifically recognized by the free prostatic antigen (PSA),
and proteolytically cleavable by the enzymatic activity of the free prostate antigen.
RU97101169/04A 1994-06-28 1995-06-07 Novel peptides RU2162855C2 (en)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US08/267,092 US5599686A (en) 1994-06-28 1994-06-28 Peptides
US267092 1994-06-28
US40483395A 1995-03-15 1995-03-15
US404833 1995-03-15

Publications (2)

Publication Number Publication Date
RU97101169A true RU97101169A (en) 1999-02-20
RU2162855C2 RU2162855C2 (en) 2001-02-10

Family

ID=26952210

Family Applications (1)

Application Number Title Priority Date Filing Date
RU97101169/04A RU2162855C2 (en) 1994-06-28 1995-06-07 Novel peptides

Country Status (27)

Country Link
US (1) US6143864A (en)
EP (1) EP0771209B1 (en)
JP (1) JPH10502619A (en)
KR (1) KR100379351B1 (en)
CN (1) CN1156964A (en)
AT (1) ATE223224T1 (en)
AU (1) AU689934B2 (en)
BG (1) BG63453B1 (en)
BR (1) BR9508151A (en)
CA (1) CA2192957A1 (en)
CZ (1) CZ381096A3 (en)
DE (1) DE69528064T2 (en)
DK (1) DK0771209T3 (en)
ES (1) ES2182908T3 (en)
FI (1) FI965225A (en)
HK (1) HK1009038A1 (en)
HU (1) HU220877B1 (en)
MX (1) MX9700043A (en)
NO (1) NO965592L (en)
NZ (1) NZ290239A (en)
PL (1) PL186341B1 (en)
PT (1) PT771209E (en)
RO (1) RO116198B1 (en)
RU (1) RU2162855C2 (en)
SK (1) SK164096A3 (en)
UA (1) UA55371C2 (en)
WO (1) WO1996000503A1 (en)

Families Citing this family (39)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5502037A (en) * 1993-07-09 1996-03-26 Neuromed Technologies, Inc. Pro-cytotoxic drug conjugates for anticancer therapy
US5866679A (en) * 1994-06-28 1999-02-02 Merck & Co., Inc. Peptides
DK0769967T3 (en) * 1994-08-19 2008-03-31 Wallone Region Conjugates comprising an antitumor agent and its use
WO1997014416A1 (en) * 1995-10-18 1997-04-24 Merck & Co., Inc. Conjugates useful in the treatment of benign prostatic hyperplasia
US5952294A (en) * 1996-07-31 1999-09-14 University Of Pittsburgh Of The Commonwealth System Of Higher Education Peptidyl prodrugs and methods of making and using the same
US5998362A (en) * 1996-09-12 1999-12-07 Merck & Co., Inc. Conjugates useful in the treatment of prostate cancer
US6177404B1 (en) 1996-10-15 2001-01-23 Merck & Co., Inc. Conjugates useful in the treatment of benign prostatic hyperplasia
US5948750A (en) * 1996-10-30 1999-09-07 Merck & Co., Inc. Conjugates useful in the treatment of prostate cancer
HRP970566A2 (en) * 1996-10-30 1998-08-31 Jones Deborah Defeo Conjugates useful in the treatment of prostate canser
EP0941334B1 (en) * 1996-11-06 2004-06-02 THE UNITED STATES OF AMERICA, as represented by the Secretary of the Department of Health and Human Services Protease-activatable pseudomonas exotoxin a-like proproteins
US6504014B1 (en) 1997-05-19 2003-01-07 The John Hopkins University Tissue specific prodrug
WO1998052966A1 (en) 1997-05-19 1998-11-26 The Johns Hopkins University School Of Medecine Tissue specific prodrug
US6545131B1 (en) 1997-05-19 2003-04-08 The Johns Hopkins University Tissue specific prodrug
US6391305B1 (en) * 1997-09-10 2002-05-21 Merck & Co., Inc. Conjugates useful in the treatment of prostate cancer
PL197006B1 (en) * 1997-12-02 2008-02-29 Merck & Co Inc Conjugates useful in treating prostatic carcinoma
AU749063B2 (en) * 1998-03-05 2002-06-20 Merck & Co., Inc. Conjugates useful in the treatment of prostrate cancer
US6174858B1 (en) 1998-11-17 2001-01-16 Merck & Co., Inc. Conjugates useful in the treatment of prostate cancer
US7425541B2 (en) 1998-12-11 2008-09-16 Medarex, Inc. Enzyme-cleavable prodrug compounds
US6482943B1 (en) 1999-04-30 2002-11-19 Slil Biomedical Corporation Quinones as disease therapies
US6649587B1 (en) 1999-04-30 2003-11-18 Slil Biomedical Corporation Polyamine analog conjugates and quinone conjugates as therapies for cancers and prostate diseases
CA2368801A1 (en) * 1999-04-30 2000-11-09 Slil Biomedical Corporation Conjugates as therapies for cancer and prostate diseases
JP2004500553A (en) * 1999-10-07 2004-01-08 シファーゲン　バイオシステムズ，　インコーポレイテッド Prostate cancer marker protein
GB9924759D0 (en) 1999-10-19 1999-12-22 Merck Sharp & Dohme Process for preparing peptide intermediates
JP2003526683A (en) 2000-03-15 2003-09-09 ブリストル−マイヤーズ スクイブ ファーマ カンパニー Peptidase-cleavable targeted antineoplastic drugs and their therapeutic use
JP2004510702A (en) * 2000-06-14 2004-04-08 メダレックス，インコーポレイティド Prodrug compounds having isoleucine
EP1219634A1 (en) * 2000-12-27 2002-07-03 Bayer Aktiengesellschaft Cytostatic-glycoconjugates having specifically cleavable peptidic linking units
WO2002081630A2 (en) * 2001-04-06 2002-10-17 The Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services Use of semenogelin in the diagnosis, prognosis and treatment of cancer
WO2003018611A2 (en) * 2001-08-24 2003-03-06 University Of Victoria Innovation And Development Corporation Proaerolysin containing protease activation sequences and methods of use for treatment of prostate cancer
WO2003046180A2 (en) * 2001-11-28 2003-06-05 Genset S.A. Human cdnas and proteins and uses thereof
US7108976B2 (en) * 2002-06-17 2006-09-19 Affymetrix, Inc. Complexity management of genomic DNA by locus specific amplification
AU2003286816B2 (en) * 2002-10-31 2010-08-19 Metabasis Therapeutics, Inc. Novel cytarabine monophosphate prodrugs
WO2005041981A1 (en) * 2003-10-31 2005-05-12 Kurume University Combination therapy of peptide vaccination and estramustine treatment
DK1891093T3 (en) 2005-06-14 2011-07-11 Protox Therapeutics Inc Method of treating or preventing benign prostate hyperplasia using modified pore-forming proteins
JP5278873B2 (en) * 2008-05-14 2013-09-04 国立大学法人九州工業大学 Cancer diagnostic reagents
US9046529B2 (en) 2009-04-10 2015-06-02 The Regents Of The University Of California Prostatitis-associated antigens and methods of use thereof
KR20110069618A (en) * 2009-12-17 2011-06-23 주식회사 셀앤바이오 Kit and method for diagnosis of prostate cancer
JP2017512183A (en) 2014-02-13 2017-05-18 リガンド・ファーマシューティカルズ・インコーポレイテッド Prodrug compounds and their use
EP3164136A4 (en) 2014-07-02 2018-04-04 Ligand Pharmaceuticals, Inc. Prodrug compounds and uses therof
JP2021509907A (en) 2018-01-09 2021-04-08 リガンド・ファーマシューティカルズ・インコーポレイテッド Acetal compounds and their therapeutic use

Family Cites Families (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4296105A (en) * 1978-08-03 1981-10-20 Institut International De Pathologie Cellulaire Et Moleculaire Derivatives of doxorubicine, their preparation and use
US4277466A (en) * 1978-08-29 1981-07-07 Institut International De Pathologie Cellulaire Et Moleculaire Complexes of DNA and esters derived from daunorubicine, their preparation and use
US4446122A (en) * 1979-12-28 1984-05-01 Research Corporation Purified human prostate antigen
OA06421A (en) * 1980-06-10 1981-09-30 Omnium Chimique Sa Process for the preparation of N- (vinblastinoyl-23) derivatives of amino acids and peptides.
GR81790B (en) * 1983-04-29 1984-12-12 Omnichem Sa
FR2546163B1 (en) * 1983-05-16 1987-10-09 Centre Nat Rech Scient NOVEL HYDROSOLUBLE ACYLATED DERIVATIVES OF PEPTIDES OR AMINO ACIDS, THEIR PREPARATION AND THEIR APPLICATION
EP0126344A2 (en) * 1983-05-20 1984-11-28 Abbott Laboratories Tripeptide esters of therapeutic agents
FR2583983B1 (en) * 1985-06-07 1988-05-27 Centre Nat Rech Scient NOVEL WATER-SOLUBLE MACROMOLECULAR PRODUCTS, THEIR PREPARATION AND THEIR USE AS MEDICAMENTS, ESPECIALLY ANTI-TUMOR AND PEST CONTROL
EP0232693A3 (en) * 1985-12-16 1988-04-06 La Region Wallonne Conjugates of vinblastine and its derivatives, process for their preparation and pharmaceutical compositions containing them
FR2626882B1 (en) * 1988-02-08 1991-11-08 Ire Celltarg Sa VINCA DERIVATIVE CONJUGATES COMPRISING A DETERGENT CHAIN IN POSITION C-3
US5391723A (en) * 1989-05-31 1995-02-21 Neorx Corporation Oligonucleotide conjugates
US5220001A (en) * 1989-10-25 1993-06-15 Zaidan Hojim Biseibutsu Dong-A Pharm Co. Anthracycline glycoside derivatives
US5137877B1 (en) * 1990-05-14 1996-01-30 Bristol Myers Squibb Co Bifunctional linking compounds conjugates and methods for their production
SE9002480D0 (en) * 1990-07-23 1990-07-23 Hans Lilja ASSAY OF FREE AND COMPLEXED PROSTATE-SPECIFIC ANTIGEN
FR2678274A1 (en) * 1991-06-25 1992-12-31 Medgenix Group Sa N-Leucylepirubicin, application as antitumour medicinal product and process for preparing it
US5288612A (en) * 1991-07-03 1994-02-22 The Scripps Research Institute Assay methods for detecting serum proteases, particularly activated protein C
US5622929A (en) * 1992-01-23 1997-04-22 Bristol-Myers Squibb Company Thioether conjugates
DE4233152A1 (en) * 1992-10-02 1994-04-07 Behringwerke Ag Antibody-enzyme conjugates for prodrug activation
CA2148350A1 (en) * 1992-10-29 1994-05-11 Carlo Croce Methods of detecting micrometastasis of prostate cancer
WO1994020114A1 (en) * 1993-03-12 1994-09-15 Board Of Regents, The University Of Texas System Anthracyclines with unusually high activity against cells resistant to doxorubicin and its analogs
AU699748B2 (en) * 1994-05-10 1998-12-10 Hybritech Incorporated Recombinant HK2 polypeptide
US5866679A (en) * 1994-06-28 1999-02-02 Merck & Co., Inc. Peptides
US5599686A (en) * 1994-06-28 1997-02-04 Merck & Co., Inc. Peptides
DK0769967T3 (en) * 1994-08-19 2008-03-31 Wallone Region Conjugates comprising an antitumor agent and its use
AUPM769394A0 (en) * 1994-08-25 1994-09-15 Commonwealth Scientific And Industrial Research Organisation Assay for the detection of proteases

Similar Documents

Publication Publication Date Title
RU97101169A (en) NEW PEPTIDES
KR970703780A (en) Novel Peptides
Gray et al. Conotoxin GI: disulfide bridges, synthesis, and preparation of iodinated derivatives
Metzger et al. Electrospray mass spectrometry and tandem mass spectrometry of synthetic multicomponent peptide mixtures: determination of composition and purity
EP1144011B1 (en) Prodrug compounds and process for preparation thereof
US5094848A (en) Cleavable diphosphate and amidated diphosphate linkers
Swann et al. Nonspecific protease‐catalyzed hydrolysis/synthesis of a mixture of peptides: Product diversity and ligand amplification by a molecular trap
EP1404356B1 (en) Method for designing cd10-activated prodrug compounds
AU2001266853B2 (en) Prodrug compounds with an oligopeptide having an isoleucine residue
AU2002316539A1 (en) CD10-activated prodrug compounds
CA2173990A1 (en) A library of glyco-peptides useful for identification of cell adhesion inhibitors
Camargo et al. Brain peptidases: conversion and inactivation of kinin hormones
Joys et al. o-Phthalaldehyde and the fluorogenic detection of peptides
US8669231B2 (en) Activation of peptide prodrugs by hK2
CN110023763A (en) It can be used for the glycan amino acid complex of label and preparation method thereof of LC-MS analysis
Greene et al. The structure of the bovine pancreatic secretory trypsin inhibitor—kazal's inhibitor: I. The isolation and amino acid sequences of the tryptic peptides from reduced aminoethylated inhibitor
Wower et al. Photochemical cross-linking of yeast tRNAPhe containing 8-azidoadenosine at positions 73 and 76 to the Escherichia coli ribosome
Ponomariov et al. Universal Access to Protease Chemiluminescent Probes through Solid-Phase Synthesis
Gutheil et al. N-to-C solid-phase peptide and peptide trifluoromethylketone synthesis using amino acid tert-butyl esters
US20050123911A1 (en) Method of mass spectrometry
WO1991013097A1 (en) Polyaminocarboxylic acid derivatives
NuMAo et al. Prediction of the active sites of proteins from amino acid sequences
Burzynski Sequential analysis in subnanomolar amounts of peptides. Determination of the structure of a habituation-induced brain peptide (ameletin)
Wilcox et al. Substrate binding site in bovine chymotrypsin Aγ. Crystallographic study using peptide chloromethyl ketones as site-specific inhibitors
US20020123068A1 (en) Water-soluble, fluorescent, & electrophoretically mobile peptidic substrates for enzymatic reactions and methods for their use in high-throughput screening assays