公开(公告)号：US5969096A

公开(公告)日：1999-10-19

申请号：US105715

申请日：1998-06-26

申请人： Ki-Joon Shon ,  William R. Gray ,  John Dykert ,  Doju Yoshikami ,  Maren Watkins ,  David R. Hillyard ,  Jean E. F. Rivier ,  Baldomero M. Olivera

发明人： Ki-Joon Shon ,  William R. Gray ,  John Dykert ,  Doju Yoshikami ,  Maren Watkins ,  David R. Hillyard ,  Jean E. F. Rivier ,  Baldomero M. Olivera

IPC分类号： A61K38/00 ,  C07K14/435

CPC分类号： C07K14/43504 ,  A61K38/00

摘要： Substantially pure conotoxin peptides are provided which inhibit synaptic transmissions at the neuromuscular junctions and which are useful both in vivo and in assays because they specifically target particular skeletal nAChRs to the exclusion of neuronal nAChRs. The peptides are of such length that they can be made by chemical synthesis, and the preferred peptides have formula: H-His-4Hyp-4Hyp-Cys-Cys-Leu-Tyr-Gly-Lys-Cys-Arg-Arg-Tyr-4Hyp-Gly-Cys-Ser-Ser-Ala-Ser-Cys-Cys-Gln-Xaa.sub.24 -NH.sub.2 wherein Xaa.sub.24 is Arg or Gly.

摘要翻译： 提供基本上纯的芋螺毒素肽，其在神经肌肉接头处抑制突触传递，并且其在体内和测定中都是有用的，因为它们特异性靶向特定的骨骼nAChR以排除神经元nAChR。 肽的长度可以通过化学合成制成，优选的肽具有式：H-His-4Hyp-4Hyp-Cys-Cys-Leu-Tyr-Gly-Lys-Cys-Arg-Arg-Tyr- 4Hyp-Gly-Cys-Ser-Ser-Ala-Ser-Cys-Cys-Gln-Xaa 24-NH 2，其中Xaa24是Arg或Gly。

公开(公告)号：US5739276A

公开(公告)日：1998-04-14

申请号：US624123

申请日：1996-03-29

申请人： Ki-Joon Shon ,  Michelle M. Grilley ,  Baldomero M. Olivera

发明人： Ki-Joon Shon ,  Michelle M. Grilley ,  Baldomero M. Olivera

IPC分类号： A61K38/00 ,  C07K14/435 ,  A61K38/17

CPC分类号： C07K14/43504 ,  C07K14/435 ,  A61K38/00

摘要： The present invention is directed to .delta.-conotoxin PVIA having the formula Glu-Ala-Cys-Tyr-Ala-Xaa.sub.1 -Gly-Thr-Phe-Cys-Gly-Ile-Lys-Xaa.sub.2 -Gly-Leu-Cys-Cys-Ser-Glu-Phe-Cys-Leu-Pro-Gly-Val-Cys-Pro-Gly (Xaa.sub.1 or Xaa.sub.2 is Pro or 4-trans-hydroxyproline) (SEQ ID NO:7). The C-terminus may be free or amidated. This latter conotoxin is vertebrate-specific which targets voltage-sensitive Na channels.

摘要翻译： 本发明涉及具有式Glu-Ala-Cys-Tyr-Ala-Xaa1-Gly-Thr-Phe-Cys-Gly-Ile-Lys-Xaa2-Gly-Leu-Cys-Cys-Ser的δ-毒素PVIA -Glu-Phe-Cys-Leu-Pro-Gly-Val-Cys-Pro-Gly（Xaa1或Xaa2是Pro或4-反式 - 羟基脯氨酸）（SEQ ID NO：7）。 C末端可以是免费的或酰胺化的。 后者的芋螺毒素是脊椎动物特异性的，其靶向电压敏感的Na通道。

公开(公告)号：US5672682A

公开(公告)日：1997-09-30

申请号：US619936

申请日：1996-03-18

申请人： Heinrich Terlau ,  Ki-Joon Shon ,  Michelle Grilley ,  Baldomero M. Olivera

发明人： Heinrich Terlau ,  Ki-Joon Shon ,  Michelle Grilley ,  Baldomero M. Olivera

IPC分类号： A61K38/00 ,  C07K14/435 ,  C07K14/00

CPC分类号： C07K14/43504 ,  A61K38/00

摘要： A new peptide, .kappa.-conotoxin PVIIA, is disclosed. This peptide is found naturally in the cone snail Conus purpurascens and has the amino acid sequence Cys-Arg-Ile-Xaa-Asn-Gln-Lys-Cys-Phe-Gln-His-Leu-Asp-Asp-Cys-Cys-Ser-Arg-Lys-Cys-Asn-Arg-Phe-Asn-Lys-Cys-Val (SEQ ID NO:1) where Xaa represents 4-trans-hydroxyproline hydroxyproline or proline. This peptide together with a previously disclosed peptide, .delta.-conotoxin PVIA, act synergistically to rapidly immobilize fish which are injected with the two peptides. Injection of .kappa.-conotoxin PVIIA alone results in different symptoms with an injected fish becoming hyperactive and then contracting and suddenly extending all major fins. This "fin-popping" occurs repeatedly resulting in a series of jerky movements, but injection of only .kappa.-conotoxin PVIIA does not immobilize or kill the fish.

摘要翻译： 公开了一种新的肽，κ-毒素PVIIA。 这种肽天然存在于锥螺旋锥体中，具有氨基酸序列Cys-Arg-Ile-Xaa-Asn-Gln-Lys-Cys-Phe-Gln-His-Leu-Asp-Asp-Cys-Cys-Ser -Arg-Lys-Cys-Asn-Arg-Phe-Asn-Lys-Cys-Val（SEQ ID NO：1），其中Xaa表示4-反式 - 羟脯氨酸羟脯氨酸或脯氨酸。 该肽与先前公开的肽δ-毒素PVIA一起协同作用以快速固定注射了两种肽的鱼。 单独注射κ-毒素PVIIA导致不同的症状，注射的鱼变得活跃，然后收缩并突然延伸所有主要鳍。 这种“昙花一现”反复发生，导致一连串的剧烈运动，但只注射κ-毒素PVIIA不会使鱼类不能固定或杀死。

公开(公告)号：US5670622A

公开(公告)日：1997-09-23

申请号：US599556

申请日：1996-02-15

申请人： Ki-Joon Shon ,  Doju Yoshikami ,  Maren Marsh ,  Lourdes J. Cruz ,  David R. Hillyard ,  Baldomero M. Olivera

发明人： Ki-Joon Shon ,  Doju Yoshikami ,  Maren Marsh ,  Lourdes J. Cruz ,  David R. Hillyard ,  Baldomero M. Olivera

IPC分类号： A61K38/00 ,  C07K14/435 ,  C07K14/00

CPC分类号： C07K14/435 ,  A61K38/00 ,  Y10S530/855

摘要： The invention is directed to a new .mu.-conotoxin named GIIIA. .mu.-Conotoxin PIIIA consists of 22 amino residues and is found in the Eastern Pacific fish-hunting species Conus purpurascens. This conotoxin is a new Na.sup.+ channel blocker and can be used to resolve tetrodotoxin-sensitive sodium channels into three categories: 1) sensitive to .mu.-PIIIA and .mu.-conotoxin GIIIA; 2) sensitive to .mu.-PIIIA but not to .mu.-GIIIA; and 3) sensitive to neither of these two .mu.-conotoxins. In rat brain, binding competition studies between the two .mu.-conotoxins and saxitoxin suggest at least three pharmacologically distinguishable binding sites. Thus, .mu.-conotoxin PIIIA should be a key tool for distinguishing among different sodium channel subtypes.

摘要翻译： 本发明涉及一种名为GIIIA的新型mu -conotoxin。 mu-毒素PIIIA由22个氨基酸残基组成，在东太平洋狩猎物种Conus purpurascens中发现。 这种芋螺毒素是一种新的Na +通道阻断剂，可用于将河豚毒素敏感的钠通道分解为三类：1）对mu -PIIIA和mu -conotoxin GIIIA敏感; 2）对mu -PIIIA敏感但不对mu-GIIIA敏感; 和3）对这两种mu -conotoxins都不敏感。 在大鼠脑中，两种mu-毒素和saxitoxin之间的结合竞争研究表明至少有三个药理学上可区分的结合位点。 因此，mu -conotoxin PIIIA应该是区分不同钠通道亚型的关键工具。

公开(公告)号：US5990295A

公开(公告)日：1999-11-23

申请号：US6156

申请日：1998-01-13

申请人： Ki-Joon Shon ,  Baldomero M. Olivera ,  J. Michael McIntosh

发明人： Ki-Joon Shon ,  Baldomero M. Olivera ,  J. Michael McIntosh

IPC分类号： C07K14/435 ,  C12N15/12

CPC分类号： C07K14/43504

摘要： The present invention is directed to conotoxin peptides having 25-35 amino acids, six cysteines which form three disulfide bonds between the first and fourth, second and fifth, and third and sixth cysteines, respectively. The invention is directed to .delta.-conotoxin GmVIA having the formula Val-Lys-Pro-Cys-Arg-Lys-Glu-Gly-Gln-Leu-Cys-Asp-Pro-Ile-Phe-Gln-Asn-Cys-Cys-Arg-Gly-Trp-Asn-Cys-Val-Leu-Phe-Cys-Val (SEQ ID NO:1). This peptide activates sodium channels. The invention is further directed to .mu.O-conotoxin peptides of the generic formula Ala-Cys-Xaa.sub.1 -Lys-Lys-Trp-Glu-Tyr-Cys-Ile-Val-Pro-Ile-Xaa.sub.2 -Gly-Phe-Xaa.sub.3 -Tyr-Cys-Cys-Pro-Gly-Leu-Ile-Cys-Gly-Pro-Phe-Val-Cys-Val, wherein Xaa.sub.1 is Arg or Ser, Xaa.sub.2 is Ile or Leu and Xaa.sub.3 is Ile or Val (SEQ ID NO:2). These peptides block sodium channels. Examples of .mu.O-conotoxin peptides of the present invention are MrVIA, having the formula Ala-Cys-Arg-Lys-Lys-Trp-Glu-Tyr-Cys-Ile-Val-Pro-Ile-Ile-Gly-Phe-Ile-Tyr-Cys-Cys-Pro-Gly-Leu-Ile-Cys-Gly-Pro-Phe-Val-Cys-Val (SEQ ID NO:3), and MrVIB, having the formula Ala-Cys-Ser-Lys-Lys-Trp-Glu-Tyr-Cys-Ile-Val-Pro-Ile-Leu-Gly-Phe-Val-Tyr-Cys-Cys-Pro-Gly-Leu-Ile-Cys-Gly-Pro-Phe-Val-Cys-Val (SEQ ID NO:4).

摘要翻译： 本发明涉及分别在第一和第四，第二和第五以及第三和第六半胱氨酸之间形成25-35个氨基酸的唾液毒素肽，六个半胱氨酸形成三个二硫键。 本发明涉及具有式Val-Lys-Pro-Cys-Arg-Lys-Glu-Gly-Gln-Leu-Cys-Asp-Pro-Ile-Phe-Gln-Asn-Cys-Cys- Arg-Gly-Trp-Asn-Cys-Val-Leu-Phe-Cys-Val（SEQ ID NO：1）。 该肽激活钠通道。 本发明进一步涉及通式为Ala-Cys-Xaa1-Lys-Lys-Trp-Glu-Tyr-Cys-Ile-Val-Pro-Ile-Xaa2-Gly-Phe-Xaa3-Tyr的mu O-芋螺毒素肽 -Cys-Cys-Pro-Gly-Leu-Ile-Cys-Gly-Pro-Phe-Val-Cys-Val，其中Xaa1是Arg或Ser，Xaa2是Ile或Leu，Xaa3是Ile或Val（SEQ ID NO： 2）。 这些肽阻断钠通道。 本发明的mu O-芋螺毒素肽的实例​​是具有式Ala-Cys-Arg-Lys-Lys-Trp-Glu-Tyr-Cys-Ile-Val-Pro-Ile-Gly-Phe-Ile的MrVIA -Tyr-Cys-Cys-Pro-Gly-Leu-Ile-Cys-Gly-Pro-Phe-Val-Cys-Val（SEQ ID NO：3）和具有式Ala-Cys-Ser-Lys- Lys-Trp-Glu-Tyr-Cys-Ile-Val-Pro-Ile-Leu-Gly-Phe-Val-Tyr-Cys-Cys-Pro-Gly-Leu-Ile-Cys-Gly-Pro-Phe-Val- Cys-Val（SEQ ID NO：4）。

公开(公告)号：US5719264A

公开(公告)日：1998-02-17

申请号：US319554

申请日：1994-10-07

申请人： Ki-Joon Shon ,  Baldomero M. Olivera ,  J. Michael McIntosh ,  Arik Hasson ,  Micha E. Spira

发明人： Ki-Joon Shon ,  Baldomero M. Olivera ,  J. Michael McIntosh ,  Arik Hasson ,  Micha E. Spira

IPC分类号： C07K14/435 ,  A61K38/00 ,  C07K5/00 ,  C07K7/00 ,  C07K16/00

CPC分类号： C07K14/43504

摘要： The present invention is directed to conotoxin peptides having 25-35 amino acids, six cysteines which form three disulfide bonds between the first and fourth, second and fifth, and third and sixth cysteines, respectively. The invention is directed to .delta.-conotoxin GmVIA having the formula Val-Lys-Pro-Cys-Arg-Lys-Glu-Gly-Gln-Leu-Cys-Asp-Pro-Ile-Phe-Gln-Asn-Cys-Cys-Arg-Gly-Trp-Asn-Cys-Val-Leu-Phe-Cys-Val (SEQ ID NO:1). This peptide activates sodium channels. The invention is further directed to .mu.O-conotoxin peptides of the generic formula Ala-Cys-Xaa.sub.1 -Lys-Lys-Trp-Glu-Tyr-Cys-Ile-Val-Pro-Ile-Xaa.sub.2 -Gly-Phe-Xaa.sub.3 -Tyr-Cys-Cys-Pro-Gly-Leu-Ile-Cys-Gly-Pro-Phe-Val-Cys-Val, wherein Xaa.sub.1 is Arg or Ser, Xaa.sub.2 is Ile or Leu and Xaa.sub.3 is Ile or Val (SEQ ID NO:2). These peptides block sodium charmels. Examples of .mu.O-conotoxin peptides of the present invention are MrVIA, having the formula Ala-Cys-Arg-Lys-Lys-Trp-Glu-Tyr-Cys-Ile-Val-Pro-Ile-Ile-Gly-Phe-Ile-Tyr-Cys-Cys-Pro-Gly-Leu-Ile-Cys-Gly-Pro-Phe-Val-Cys-Val (SEQ ID NO:3), and MrVIB, having the formula Ala-Cys-Ser-Lys-Lys-Trp-Glu-Tyr-Cys-Ile-Val-Pro-Ile-Leu-Gly-Phe-Val-Tyr-Cys-Cys-Pro-Gly-Leu-Ile-Cys-Gly-Pro-Phe-Val-Cys-Val (SEQ ID NO:4).

摘要翻译： 本发明涉及分别在第一和第四，第二和第五以及第三和第六半胱氨酸之间形成25-35个氨基酸的唾液毒素肽，六个半胱氨酸形成三个二硫键。 本发明涉及具有式Val-Lys-Pro-Cys-Arg-Lys-Glu-Gly-Gln-Leu-Cys-Asp-Pro-Ile-Phe-Gln-Asn-Cys-Cys- Arg-Gly-Trp-Asn-Cys-Val-Leu-Phe-Cys-Val（SEQ ID NO：1）。 该肽激活钠通道。 本发明进一步涉及通式为Ala-Cys-Xaa1-Lys-Lys-Trp-Glu-Tyr-Cys-Ile-Val-Pro-Ile-Xaa2-Gly-Phe-Xaa3-Tyr的mu O-芋螺毒素肽 -Cys-Cys-Pro-Gly-Leu-Ile-Cys-Gly-Pro-Phe-Val-Cys-Val，其中Xaa1是Arg或Ser，Xaa2是Ile或Leu，Xaa3是Ile或Val（SEQ ID NO： 2）。 这些肽阻断钠的魅力。 本发明的mu O-芋螺毒素肽的实例​​是具有式Ala-Cys-Arg-Lys-Lys-Trp-Glu-Tyr-Cys-Ile-Val-Pro-Ile-Gly-Phe-Ile的MrVIA -Tyr-Cys-Cys-Pro-Gly-Leu-Ile-Cys-Gly-Pro-Phe-Val-Cys-Val（SEQ ID NO：3）和具有式Ala-Cys-Ser-Lys- Lys-Trp-Glu-Tyr-Cys-Ile-Val-Pro-Ile-Leu-Gly-Phe-Val-Tyr-Cys-Cys-Pro-Gly-Leu-Ile-Cys-Gly-Pro-Phe-Val- Cys-Val（SEQ ID NO：4）。