STRUCTURAL BASIS OF RELAXIN ACTION

放松作用的结构基础

• 批准号: 2857176
• 负责人: christian none schwabe
• 金额: $ 22.75万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-01-01 至 2000-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2857176
• 关键词: antineoplastics; diabetes mellitus; drug design /synthesis /production; hormone receptor; hormone regulation /control mechanism; immunoconjugates; insulin; laboratory mouse; laboratory rabbit; neoplasm /cancer immunotherapy; peptide hormone analog; protein structure function; relaxin; tissue /cell culture; vasodilators

While relaxin remains our main target, the goals have been extended to include the structure-function relations of other relaxin-like factors that generally consist of two small disulfide-linked chains. The enigma of relatively low activity of exogenous human relaxin in contrast to the noticeable activity of endogenous relaxin during pregnancy may find an explanation in the fact that RLF, until recently unknown (see progress report), is a relaxin-enhancing factor. We have now established a rigorous synthesis that allows us to synthesize all of these factors and their variants and in the next grant period we will examine in detail the physiological importance of these factors and their functional relation to relaxin. Surprising was the discovery that RLF receptors are particularly numerous on the human ovarian cancer cell line 2008 (ovarian cystadeno carcinoma) and we are therefore planing to synthesize an RLF-ricin-A-chain complex which could serve to specifically poison certain ovarian cancer cells in vivo. A similar relaxin-ricin-A complex has been successful at killing tumor cells in vitro and will be used to rapidly identify relaxin receptor- bearing cells. This in turn will be very useful for the identification of relaxin receptor-bearing tumors for receptor isolation which is also a major goal of this research. Relaxin and insulin are likely complementary in their action against diabetes, in particular the disastrous vascular consequences of the disease. Purportedly relaxin causes increased peripheral blood flow and thereby healing of trophic ulcerations and reversal of incipient gangrene in the extremities. We will synthesize relaxin, RLF, and derivatives of greater potency and biostability if possible. In light of the increasing population of diabetics and the aging of our population in general such compounds would be of consequence for a large number of patients.

虽然松弛素仍然是我们的主要目标，但目标已扩展到 包括其他松弛素样因子的结构-功能关系 一般由两条二硫键连接的小链组成。的谜团 外源性人松弛素活性相对较低 怀孕期间内源性松弛素显著活动可能会发现 直到最近还不为人所知的RLF的解释(见进展 报告)，是一种促进松弛的因素。我们现在已经建立了一个严格的 使我们能够合成所有这些因子和它们的 在下一个授权期内，我们将详细研究 这些因子在生理上的重要性及其功能关系 放松药。 令人惊讶的是，发现RLF受体特别多 人卵巢癌细胞系2008(卵巢囊腺癌)的研究 因此，我们计划合成一种RLF-蓖麻毒素-A链复合体 它可以特异性地毒化某些卵巢癌细胞 活着。 一种类似的松弛毒素-蓖麻毒素-A复合体已经成功地杀死了肿瘤 细胞，并将用于快速鉴定松弛素受体- 承载细胞。这反过来又将非常有用地识别 松弛素受体肿瘤用于受体分离，这也是一种 本研究的主要目的。 松弛素和胰岛素可能是相辅相成的 糖尿病，特别是糖尿病的灾难性血管后果 疾病。据称松弛素会导致外周血流量增加和 从而治愈萎缩性溃疡和逆转早期坏疽 在四肢上。我们将合成松弛素、RLF和其衍生物 如果可能的话，更强的效力和生物稳定性。鉴于不断增加的 糖尿病患者的人口和人口老龄化的总体情况 化合物将对大量患者产生影响。