长效LHRH拮抗剂类似物的设计、合成及生物活性研究
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摘要
通过调研LHRH拮抗剂类似物研究进展及酶学研究结果，提出假设：如果在多肽合适的位置上连接一些强的质子给体、受体或两者兼有的基团，使之能够在水解反应中与酶的活性中心以氢键的形式形成过渡态类似物，有可能会抑制蛋白酶对肽键的水解，从而延长多肽的作用时间。
基于此假设，以LHRH拮抗剂LXT-101为先导化合物，对其进行合理氨基酸修饰或替换，设计并合成了33个新的十肽化合物。经大鼠体内抑制睾酮作用实验的初步筛选，有31个类似物显示出拮抗活性，其中10个类似物活性强于阳性对照LXT-101，5个类似物活性与LXT-101相当。此外，对6个合成的LHRH拮抗剂类似物进行了胰混合酶体系中的降解实验，有5个类似物的半衰期长于阳性对照LXT-101。
根据体内活性及体外代谢评价，本文得到以下初步结论：(1)体内活性评价：N端进行乙酰化、氨甲酰基化修饰的系列类似物活性较N端未修饰的系列类似物活性强；对Phe苯环引入氨基、脲基、羟基等基团，选择侧链上带有胍基、酰胺、羧基等脂肪族氨基酸，并将这些氨基酸引入多肽序列5位，所得类似物拮抗活性明显强于修饰前结构(5位为Phe、Leu的系列类似物)。(2)胰混合酶体系代谢评价：N端氨甲酰基化修饰可以提高多肽的抗酶解能力，且作用强于乙酰化修饰；5位为Aph、Phe(NAM)的系列类似物代谢时间明显长于5位为Phe的系列类似物。(3)以上初步结论与课题提出假设相符。
According to the development of LHRH antagonists and proteolytic mechanism, we hypothesize that adequate proteolytic stability could be obtained with peptides which have proton-donor and proton-receptor groups in the suitable sites of the side chains, probably induced by forming hydrogen bonds and a transition state between the peptide side chains and active site of a proteinase.Based on this hypothesis, 33 new decapeptides were designed and synthesized by using LXT-101, an effective LHRH antagonist, as a leading compound. There are 31 of analogs showing inhibiting testosterone-activity. 10 of them are more potent than LXT-101, and 5 are the same as LXT-101. A proteolysis test of 6 new analogs was studied in pancreas proteinase mixture. Half-lives of 5 new analogs are longer than that of LXT-101.It found that the inhibiting activity of the analogs with N-terminal modification with acetyl and aminoformyl is stronger than that of unmodified analogs. When the functional groups such as amino, ureido, hydroxyl, carboxyl, amide, guanidine were introduced on the side chains of Phe or Leu at positions 5, the inhibiting activity of the produced analogs is obviously stronger than that of unmodified analogs. The proteolytic stability of the analogs with aminoformyl functional group on N-terminal could be increased, and their half-lives are longer than that of the analogs with acetyl. The proteolytic stability of the analogs with Aph, Phe(NAM) on position 5 is higher than that of analogs with Phe on position 5. The results are consistent with the hypothesis we proposed.
基于此假设，以LHRH拮抗剂LXT-101为先导化合物，对其进行合理氨基酸修饰或替换，设计并合成了33个新的十肽化合物。经大鼠体内抑制睾酮作用实验的初步筛选，有31个类似物显示出拮抗活性，其中10个类似物活性强于阳性对照LXT-101，5个类似物活性与LXT-101相当。此外，对6个合成的LHRH拮抗剂类似物进行了胰混合酶体系中的降解实验，有5个类似物的半衰期长于阳性对照LXT-101。
根据体内活性及体外代谢评价，本文得到以下初步结论：(1)体内活性评价：N端进行乙酰化、氨甲酰基化修饰的系列类似物活性较N端未修饰的系列类似物活性强；对Phe苯环引入氨基、脲基、羟基等基团，选择侧链上带有胍基、酰胺、羧基等脂肪族氨基酸，并将这些氨基酸引入多肽序列5位，所得类似物拮抗活性明显强于修饰前结构(5位为Phe、Leu的系列类似物)。(2)胰混合酶体系代谢评价：N端氨甲酰基化修饰可以提高多肽的抗酶解能力，且作用强于乙酰化修饰；5位为Aph、Phe(NAM)的系列类似物代谢时间明显长于5位为Phe的系列类似物。(3)以上初步结论与课题提出假设相符。
According to the development of LHRH antagonists and proteolytic mechanism, we hypothesize that adequate proteolytic stability could be obtained with peptides which have proton-donor and proton-receptor groups in the suitable sites of the side chains, probably induced by forming hydrogen bonds and a transition state between the peptide side chains and active site of a proteinase.Based on this hypothesis, 33 new decapeptides were designed and synthesized by using LXT-101, an effective LHRH antagonist, as a leading compound. There are 31 of analogs showing inhibiting testosterone-activity. 10 of them are more potent than LXT-101, and 5 are the same as LXT-101. A proteolysis test of 6 new analogs was studied in pancreas proteinase mixture. Half-lives of 5 new analogs are longer than that of LXT-101.It found that the inhibiting activity of the analogs with N-terminal modification with acetyl and aminoformyl is stronger than that of unmodified analogs. When the functional groups such as amino, ureido, hydroxyl, carboxyl, amide, guanidine were introduced on the side chains of Phe or Leu at positions 5, the inhibiting activity of the produced analogs is obviously stronger than that of unmodified analogs. The proteolytic stability of the analogs with aminoformyl functional group on N-terminal could be increased, and their half-lives are longer than that of the analogs with acetyl. The proteolytic stability of the analogs with Aph, Phe(NAM) on position 5 is higher than that of analogs with Phe on position 5. The results are consistent with the hypothesis we proposed.
引文
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