STRUCTURAL BASIS OF RELAXIN ACTION

放松作用的结构基础

• 批准号: 2022699
• 负责人: christian none schwabe
• 金额: $ 21.76万
• 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/2022699
• 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，但目标已经扩展到 包括其他松弛素样因子的结构-功能关系， 通常由两个小的二硫键连接的链组成。之谜 相对较低的外源性人松弛素活性， 在怀孕期间，内源性松弛素的显著活性可能会发现 解释的事实，RLF，直到最近未知（见进展 报告），是一个放松增强因子。我们现在已经建立了一个严格的 综合，使我们能够综合所有这些因素及其 在下一个资助期内，我们将详细研究 这些因素的生理重要性及其与 松弛素 令人惊讶的是发现RLF受体特别多 对人卵巢癌细胞系2008（卵巢囊腺癌） 因此我们计划合成一种RLF-蓖麻毒素-A链复合物 它可以特异性地毒害某些卵巢癌细胞， vivo. 一种类似的松弛素-蓖麻毒素-A复合物已经成功地杀死了肿瘤 细胞在体外，并将用于快速识别松弛素受体- 产生细胞。这反过来将非常有助于确定 松弛素受体携带肿瘤的受体分离，这也是一个 这项研究的主要目标。 松弛素和胰岛素在对抗胰岛素抵抗的作用中可能是互补的。 糖尿病，特别是糖尿病的灾难性血管后果， 疾病据称松弛素引起外周血流量增加， 从而治愈营养性溃疡并逆转初期坏疽 在四肢。我们将合成松弛素、RLF及其衍生物， 如果可能的话，更高的效力和生物稳定性。鉴于越来越多的 糖尿病患者的人口和我们的人口老龄化， 化合物对大量患者是重要的。