A Molecular Clamp that Inhibits CRF Amidation

抑制 CRF 酰胺化的分子钳

• 批准号: 7011222
• 负责人: MARK L MCLAUGHLIN
• 金额: $ 15.58万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-02-01 至 2007-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7011222
• 关键词: amidation /deamidation; animal tissue; chemical substitution; corticotropin releasing factor; drug screening /evaluation; enzyme activity; enzyme inhibitors; gene expression; high performance liquid chromatography; hormone regulation /control mechanism; mental disorder chemotherapy; oxygenases; peptide hormone biosynthesis; peptides; point mutation; posttranslational modifications; protein structure function; tissue /cell culture

DESCRIPTION (provided by applicant): Approximately 50% of all mammalian bioactive peptides require a C-terminal a-amide moiety for full biological activity. The C-terminal amide is produced by oxidative cleavage of a C-terminal glycine-extended pro-hormone to yield the a-amidated peptide and glyoxylate. The enzyme catalyzing this post-translational modification reaction is peptidylglycine a-amidating monooxygenase (PAM). PAM has potential as a novel therapeutic target as a consequence of the role-played by numerous alpha-amidated peptides in disease, examples being luteinizing hormone-releasing hormone (LHRH) and vasoactive intestinal peptide (VIP) in cancer, substance P in rheumatoid arthritis, and corticotropin-releasing factor (CRF) in anxiety and depression. Inhibition of PAM would generate the glycine-extended precursor that is generally >1000-fold less potent than the mature alpha-amidated peptide. However, the large number of known mammalian alpha-amidated peptides (approximately 50-100 are known) means that a drug specifically targeted against PAM is likely to be highly toxic. Disruption or elimination of the PAM gene in mice and Drosophila is lethal. As a consequence, the potential for PAM as a therapeutic target remains untapped. We propose to solve this problem in a completely new way - with the design of molecular clamp to specifically block the amidation of a single glycine-extend pro-hormone. Such an anti-amidation molecular clamp (AM-CLAMP) would not broadly inhibit PAM and, thus, would side step the serious toxicity problems associated with a general inhibition of peptide amidation.

描述（由申请人提供）：大约 50% 的哺乳动物生物活性肽需要 C 端 α-酰胺部分才能发挥全部生物活性。 C 端酰胺是通过 C 端甘氨酸延伸的激素原氧化裂解产生 α-酰胺化肽和乙醛酸。催化这种翻译后修饰反应的酶是肽酰甘氨酸α-酰胺化单加氧酶(PAM)。由于多种 α-酰胺化肽在疾病中发挥的作用，PAM 具有作为新型治疗靶点的潜力，例如癌症中的黄体生成素释放激素 (LHRH) 和血管活性肠肽 (VIP)、类风湿性关节炎中的 P 物质，以及促肾上腺皮质激素释放因子（CRF）在焦虑和抑郁中的作用。 PAM 的抑制会产生甘氨酸延伸的前体，其效力通常比成熟的 α-酰胺化肽低 1000 倍以上。然而，大量已知的哺乳动物α-酰胺化肽（已知大约50-100种）意味着专门针对PAM的药物可能具有剧毒。小鼠和果蝇中 PAM 基因的破坏或消除是致命的。因此，PAM 作为治疗靶点的潜力尚未开发。我们建议以一种全新的方式解决这个问题——设计分子钳来特异性阻断单个甘氨酸延伸激素原的酰胺化。这种抗酰胺化分子夹（AM-CLAMP）不会广泛抑制PAM，因此可以避免与肽酰胺化的一般抑制相关的严重毒性问题。

项目成果

Synthesis of N-Boc protected hydrazine diacids as key structural units for the formation of alpha-helix mimics.

N-Boc 保护的肼二酸的合成作为形成 α-螺旋模拟物的关键结构单元。

• 发表时间: 2009
• 作者: Anderson, Laura;Topper, Melissa;Jain, Priyesh;McIntosh, Emily;McLaughlin, Mark L
• 通讯作者: McLaughlin, Mark L

Cysteine based PNA (CPNA): design and synthesis of novel CPNA monomers.

基于半胱氨​​酸的 PNA (CPNA)：新型 CPNA 单体的设计和合成。

• 发表时间: 2009
• 作者: Yi, Sung Wook;Jain, Priyesh;Ajmera, Mehul;Kaulagari, Sridhar Reddi;Topper, Melissa;Anderson, Laura;McLaughlin, Mark L
• 通讯作者: McLaughlin, Mark L