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公开(公告)号：US07579433B2
公开(公告)日：2009-08-25
申请号：US11414719
申请日：2006-04-28
摘要： The present invention provides a new 18-residue homodimerized peptide, designated PIP [59-67] dimer (SEQ ID NO: 1), which is a mutant of the optimized anti-inflammatory peptide P-NT.II, the patent for which has recently been filed [1]. P-NT.II has the potential to modulate both the inflammatory and bone damaging components of rheumatoid arthritis, and was originally designed on the basis of the primary structure of the anti-inflammatory protein termed ‘Phospholipase Inhibitor from Python (PIP)’ [2]. Using solid phase chemistry, variants of P-NT.II were designed and examined for inhibitory activity against secretory phospholipase A2 (sPLA2), a key enzyme involved in the inflammatory pathway, and matrix metalloproteinases (MMPs) that are involved in the remodeling and degradation of the extracellular matrix in rheumatoid arthritis (RA) and cancer. Among the family of mutants tested, the dimerized peptide was found to be the most potent inhibitor against sPLA2 as well as the human recombinant MMP-1. This invention provides the utility of the peptide analogue PIP [59-67] dimer as a potential therapeutic agent for modulation of inflammatory diseases such as rheumatoid arthritis, and cancer. This invention relates to all the polypeptide analogues (SEQ ID NO: 1 to 3) and polynucleotides (SEQ ID NO: 4), and to the use of those polypeptides and polynucleotides, their synthetic chemical analogues or variants that inhibit activity and synthesis of sPLA2 and MMPs, in the diagnosis, study, prevention and treatment of rheumatoid arthritis and/or cancer.
摘要翻译： 本发明提供了一种称为PIP [59-67]二聚体（SEQ ID NO：1）的新的18残基同源二聚体肽，其是优化的抗炎肽P-NT.II的突变体，其专利具有 最近被提交[1]。 P-NT.II具有调节类风湿性关节炎的炎性和骨损伤成分的潜力，并且最初是基于称为“来自Python（PIP）的磷脂酶抑制剂”的抗炎蛋白质的一级结构设计的[2 ]。 使用固相化学，设计了P-NT.II的变体，并检测了与分泌性磷脂酶A2（sPLA2）（参与炎症途径的关键酶）和参与重塑和降解的基质金属蛋白酶（MMP）的抑制活性 的类风湿关节炎（RA）和癌症中的细胞外基质。 在测试的突变体家族中，发现二聚化肽是针对sPLA2以及人重组MMP-1的最有效的抑制剂。 本发明提供了肽类似物PIP [59-67]二聚体作为调节炎性疾病如类风湿性关节炎和癌症的潜在治疗剂的用途。 本发明涉及所有多肽类似物（SEQ ID NO：1至3）和多核苷酸（SEQ ID NO：4），以及这些多肽和多核苷酸的合成化学类似物或变体，其抑制sPLA2的活性和合成 和MMPs在类风湿性关节炎和/或癌症的诊断，研究，预防和治疗中的应用。
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2.发明授权Phospholipase A2-inhibitory peptide with anti-arthritic and neuroprotective activities 有权具有抗关节炎和神经保护活性的磷脂酶A2抑制肽公开(公告)号：US07176281B2
公开(公告)日：2007-02-13
申请号：US10836825
申请日：2004-04-30
摘要： Peptides that have potent PLA2-inhibitory activity are disclosed. Homology searches of known PLA inhibitory molecules were used to identify and subsequently design potent peptide molecules that can induce neuroprotective as well as anti-inflammatory effect. These peptides were shown to protect against degeneration of joints in transgenic mouse model prone to arthritis. Protection from kainate-induced excitotoxic neuronal injury was also observed using these peptides. These peptides, their analogs and derivatives have potential as neuroprotective and/or anti-inflammatory agents in a clinical setting.
摘要翻译： 公开了具有有效的PLA 2 - 抑制活性的肽。 已知PLA抑制分子的同源性检索用于鉴定并随后设计可诱导神经保护作用以及抗炎作用的有效肽分子。 显示这些肽可以防止易于发生关节炎的转基因小鼠模型中关节的变性。 使用这些肽也观察到保护免受红藻氨酸诱发的兴奋性毒性神经元损伤。 这些肽，其类似物和衍生物在临床环境中具有作为神经保护和/或抗炎剂的潜力。
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公开(公告)号：US20070037253A1
公开(公告)日：2007-02-15
申请号：US11414719
申请日：2006-04-28
摘要： The present invention provides a new 18-residue homodimerized peptide, designated PIP [59-67] dimer (SEQ ID NO: 1), which is a mutant of the optimized anti-inflammatory peptide P-NT.II, the patent for which has recently been filed [1]. P-NT.II has the potential to modulate both the inflammatory and bone damaging components of rheumatoid arthritis, and was originally designed on the basis of the primary structure of the anti-inflammatory protein termed ‘Phospholipase Inhibitor from Python (PIP)’ [2]. Using solid phase chemistry, variants of P-NT.II were designed and examined for inhibitory activity against secretory phospholipase A2 (sPLA2), a key enzyme involved in the inflammatory pathway, and matrix metalloproteinases (MMPS) that are involved in the remodeling and degradation of the extracellular matrix in rheumatoid arthritis (RA) and cancer. Among the family of mutants tested, the dimerized peptide was found to be the most potent inhibitor against sPLA2 as well as the human recombinant MMP-1. This invention provides the utility of the peptide analogue PIP [59-67] dimer as a potential therapeutic agent for modulation of inflammatory diseases such as rheumatoid arthritis, and cancer. This invention relates to all the polypeptide analogues (SEQ ID NO: 1 to 3) and polynucleotides (SEQ ID NO: 4), and to the use of those polypeptides and polynucleotides, their synthetic chemical analogues or variants that inhibit activity and synthesis of sPLA2 and MMPs, in the diagnosis, study, prevention and treatment of rheumatoid arthritis and/or cancer.
摘要翻译： 本发明提供了一种称为PIP [59-67]二聚体（SEQ ID NO：1）的新的18残基同源二聚体肽，其是优化的抗炎肽P-NT.II的突变体，其专利具有 最近被提交[1]。 P-NT.II具有调节类风湿性关节炎的炎性和骨损伤成分的潜力，并且最初是基于称为“来自Python（PIP）的磷脂酶抑制剂”的抗炎蛋白质的一级结构设计的[2 ]。 使用固相化学，设计了P-NT.II的变体，并检测了与分泌性磷脂酶A2（sPLA2）（参与炎症途径的关键酶）和参与重塑和降解的基质金属蛋白酶（MMPS）的抑制活性 的类风湿性关节炎（RA）和癌症中的细胞外基质。 在测试的突变体家族中，发现二聚化肽是针对sPLA2以及人重组MMP-1的最有效的抑制剂。 本发明提供了肽类似物PIP [59-67]二聚体作为调节炎性疾病如类风湿性关节炎和癌症的潜在治疗剂的用途。 本发明涉及所有多肽类似物（SEQ ID NO：1至3）和多核苷酸（SEQ ID NO：4），以及这些多肽和多核苷酸的合成化学类似物或变体，其抑制sPLA2的活性和合成 和MMPs在类风湿性关节炎和/或癌症的诊断，研究，预防和治疗中的应用。
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4.发明申请Phospholipase A2-inhibitory peptide with anti-arthritic and neuroprotective activities 有权具有抗关节炎和神经保护活性的磷脂酶A2抑制肽公开(公告)号：US20050069530A1
公开(公告)日：2005-03-31
申请号：US10836825
申请日：2004-04-30
摘要： Peptides that have potent PLA2-inhibitory activity are disclosed. Homology searches of known PLA inhibitory molecules were used to identify and subsequently design potent peptide molecules that can induce neuroprotective as well as anti-inflammatory effect. These peptides were shown to protect against degeneration of joints in transgenic mouse model prone to arthritis. Protection from kainate-induced excitotoxic neuronal injury was also observed using these peptides. These peptides, their analogs and derivatives have potential as neuroprotective and/or anti-inflammatory agents in a clinical setting.
摘要翻译： 公开了具有强的PLA2抑制活性的肽。 已知PLA抑制分子的同源性检索用于鉴定并随后设计可诱导神经保护作用以及抗炎作用的有效肽分子。 显示这些肽可以防止易于发生关节炎的转基因小鼠模型中关节的变性。 使用这些肽也观察到保护免受红藻氨酸诱发的兴奋性毒性神经元损伤。 这些肽，其类似物和衍生物在临床环境中具有作为神经保护和/或抗炎剂的潜力。
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公开(公告)号：US07094575B2
公开(公告)日：2006-08-22
申请号：US10163499
申请日：2002-06-07
申请人： Ponnampalam Gopalakrishnakone , Maung-Maung Thwin , Kandiah Jeyaseelan , Arunmozhiarasi Armugam
发明人： Ponnampalam Gopalakrishnakone , Maung-Maung Thwin , Kandiah Jeyaseelan , Arunmozhiarasi Armugam
IPC分类号： C12N15/09
CPC分类号： C07K14/46 , A61K38/00 , C12Q1/34 , G01N33/6893 , G01N2333/4609 , G01N2333/914 , G01N2800/42
摘要： A phospholipase A2 inhibitor protein designated “Phospholipase Inhibitor from Python” (PIP)—formerly designated “Python Antitoxic Factor” (PAF)—is given by SEQ ID NO:2. The partial amino acid sequence for PIP was initially determined from the native protein purified from the blood serum of a non-venomous snake, Python reticulatus. The complete PIP polynucleotide sequence was obtained from a cDNA clone encoding PIP, given by SEQ ID NO:1, along with the full amino acid sequence deduced from it. Also disclosed is a recombinant protein PIP, which shows strong lethal toxin neutralizing activity similar to the native PIP, and has potent anti-inflammatory activity. Both the native and the functionally equivalent recombinant PIP are useful for the prevention or treatment of conditions such as snakebites, insect stings, and inflammatory diseases. Also, phospholipase A2 (PLA2) inhibitory polypeptides designated P-0029, P-0009, and P-0006, the sequences of which are given as SEQ ID NO:10, SEQ ID NO:11, and SEQ ID NO:12, respectively, are disclosed. Those polypeptides, and their synthetic chemical analogues and polypeptide variants that inhibit PLA2 activity and alleviate inflammation, may also be used in the diagnosis, study, prevention, and treatment of PLA2-related human inflammatory diseases.
摘要翻译： 由SEQ ID NO：2给出的称为“Python抗氧化因子”（PAF）的称为“来自Python的磷脂酶抑制剂”（PIP）的磷脂酶A 2 N抑制剂蛋白质。 PIP的部分氨基酸序列最初是从从非毒蛇蛇纹状体的血清中纯化的天然蛋白质来确定的。 从编码PIP的cDNA克隆获得完整的PIP多核苷酸序列，由SEQ ID NO：1给出，以及从其推导出的完整氨基酸序列。 还公开了重组蛋白PIP，其显示出与天然PIP类似的强致死毒素中和活性，并且具有有效的抗炎活性。 天然和功能等同的重组PIP都可用于预防或治疗诸如蛇咬伤，昆虫叮咬和炎性疾病的病症。 另外，称为P-0029，P-0009和P-0006的磷脂酶A 2（PLA 2 H 2）抑制性多肽，其序列如SEQ ID NO： 10，SEQ ID NO：11和SEQ ID NO：12。 抑制PLA 2活性和减轻炎症的那些多肽及其合成的化学类似物和多肽变体也可以用于诊断，研究，预防和治疗PLA2 相关人类炎症性疾病。
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公开(公告)号：US20060078551A1
公开(公告)日：2006-04-13
申请号：US11289494
申请日：2005-11-30
申请人： Ponnampalam Gopalakrishnakone , Maung-Maung Thwin , Kandiah Jey Aseelan , Arunmozhiarasi Armugam
发明人： Ponnampalam Gopalakrishnakone , Maung-Maung Thwin , Kandiah Jey Aseelan , Arunmozhiarasi Armugam
CPC分类号： C07K14/46 , A61K38/00 , C12Q1/34 , G01N33/6893 , G01N2333/4609 , G01N2333/914 , G01N2800/42
摘要： A phospholipase A2 inhibitor protein designated “Phospholipase Inhibitor from Python” (PIP)—formerly designated “Python Antitoxic Factor” (PAF)—is given by SEQ ID NO:2. The partial amino acid sequence for PIP was initially determined from the native protein purified from the blood serum of a non-venomous snake, Python reticulatus. The complete PIP polynucleotide sequence was obtained from a cDNA clone encoding PIP, given by SEQ ID NO:1, along with the full amino acid sequence deduced from it. Also disclosed is a recombinant protein PIP, which shows strong lethal toxin neutralizing activity similar to the native PIP, and has potent anti-inflammatory activity. Both the native and the functionally equivalent recombinant PIP are useful for the prevention or treatment of conditions such as snakebites, insect stings, and inflammatory diseases. Also, phospholipase A2 (PLA2) inhibitory polypeptides designated P-0029, P-0009, and P-0006, the sequences of which are given as SEQ ID NO:10, SEQ ID NO:11, and SEQ ID NO:12, respectively, are disclosed. Those polypeptides, and their synthetic chemical analogues and polypeptide variants that inhibit PLA2 activity and alleviate inflammation, may also be used in the diagnosis, study, prevention, and treatment of PLA2-related human inflammatory diseases.
摘要翻译： 由SEQ ID NO：2给出的称为“Python抗氧化因子”（PAF）的称为“来自Python的磷脂酶抑制剂”（PIP）的磷脂酶A 2 N抑制剂蛋白质。 PIP的部分氨基酸序列最初是从从非毒蛇蛇纹状体的血清中纯化的天然蛋白质来确定的。 从编码PIP的cDNA克隆获得完整的PIP多核苷酸序列，由SEQ ID NO：1给出，以及从其推导出的完整氨基酸序列。 还公开了重组蛋白PIP，其显示出与天然PIP类似的强致死毒素中和活性，并且具有有效的抗炎活性。 天然和功能等同的重组PIP都可用于预防或治疗诸如蛇咬伤，昆虫叮咬和炎性疾病的病症。 另外，称为P-0029，P-0009和P-0006的磷脂酶A 2（PLA 2 H 2）抑制性多肽，其序列如SEQ ID NO： 10，SEQ ID NO：11和SEQ ID NO：12。 抑制PLA 2活性和减轻炎症的那些多肽及其合成的化学类似物和多肽变体也可以用于诊断，研究，预防和治疗PLA2 相关人类炎症性疾病。
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公开(公告)号：US07422890B2
公开(公告)日：2008-09-09
申请号：US11289494
申请日：2005-11-30
申请人： Ponnampalam Gopalakrishnakone , Maung-Maung Thwin , Kandiah Jeyaseelan , Arunmozhiarasi Armugam
发明人： Ponnampalam Gopalakrishnakone , Maung-Maung Thwin , Kandiah Jeyaseelan , Arunmozhiarasi Armugam
CPC分类号： C07K14/46 , A61K38/00 , C12Q1/34 , G01N33/6893 , G01N2333/4609 , G01N2333/914 , G01N2800/42
摘要： A phospholipase A2 inhibitor protein designated “Phospholipase Inhibitor from Python” (PIP)—formerly designated “Python Antitoxic Factor” (PAF)—is given by SEQ ID NO:2. The partial amino acid sequence for PIP was initially determined from the native protein purified from the blood serum of a non-venomous snake, Python reticulatus. The complete PIP polynucleotide sequence was obtained from a cDNA clone encoding PIP, given by SEQ ID NO:1, along with the full amino acid sequence deduced from it. Also disclosed is a recombinant protein PIP, which shows strong lethal toxin neutralizing activity similar to the native PIP, and has potent anti-inflammatory activity. Both the native and the functionally equivalent recombinant PIP are useful for the prevention or treatment of conditions such as snakebites, insect stings, and inflammatory diseases. Also, phospholipase A2 (PLA2) inhibitory polypeptides designated P-0029, P-0009, and P-0006, the sequences of which are given as SEQ ID NO:10, SEQ ID NO:11, and SEQ ID NO:12, respectively, are disclosed. Those polypeptides, and their synthetic chemical analogues and polypeptide variants that inhibit PLA2 activity and alleviate inflammation, may also be used in the diagnosis, study, prevention, and treatment of PLA2-related human inflammatory diseases.
摘要翻译： 由SEQ ID NO：2给出的称为“Python抗氧化因子”（PAF）的称为“来自Python的磷脂酶抑制剂”（PIP）的磷脂酶A 2 N抑制剂蛋白质。 PIP的部分氨基酸序列最初是从从非毒蛇蛇纹状体的血清中纯化的天然蛋白质来确定的。 从编码PIP的cDNA克隆获得完整的PIP多核苷酸序列，由SEQ ID NO：1给出，以及从其推导出的完整氨基酸序列。 还公开了重组蛋白PIP，其显示出与天然PIP类似的强致死毒素中和活性，并且具有有效的抗炎活性。 天然和功能等同的重组PIP都可用于预防或治疗诸如蛇咬伤，昆虫叮咬和炎性疾病的病症。 另外，称为P-0029，P-0009和P-0006的磷脂酶A 2（PLA 2 H 2）抑制性多肽，其序列如SEQ ID NO： 10，SEQ ID NO：11和SEQ ID NO：12。 抑制PLA 2活性和减轻炎症的那些多肽及其合成的化学类似物和多肽变体也可以用于诊断，研究，预防和治疗PLA2 相关人类炎症性疾病。
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