Design, Synthesis, and Biological Evaluation of Allosteric Effectors That Enhance CO Release from Carboxyhemoglobin,ACS Medicinal Chemistry Letters

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Design, Synthesis, and Biological Evaluation of Allosteric Effectors That Enhance CO Release from Carboxyhemoglobin
ACS Medicinal Chemistry Letters ( IF 3.5 ) Pub Date : 2018-05-11 00:00:00 , DOI: 10.1021/acsmedchemlett.8b00166
Sara R Goldstein ₁ , Chen Liu ₂ , Martin K Safo ₃ , Akito Nakagawa ₂ , Warren M Zapol ₂ , Jeffrey D Winkler ₁

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Carbon monoxide (CO) poisoning causes between 5,000−6,000 deaths per year in the US alone. The development of small molecule allosteric effectors of CO binding to hemoglobin (Hb) represents an important step toward making effective therapies for CO poisoning. To that end, we have found that the synthetic peptide IRL 2500 enhances CO release from COHb in air, but with concomitant hemolytic activity. We describe herein the design, synthesis, and biological evaluation of analogs of IRL 2500 that enhance the release of CO from COHb without hemolysis. These novel structures show improved aqueous solubility and reduced hemolytic activity and could lead the way to the development of small molecule therapeutics for the treatment of CO poisoning.

中文翻译：

增强碳氧血红蛋白 CO 释放的变构效应器的设计、合成和生物学评价

仅在美国，一氧化碳 (CO) 中毒每年就会导致 5,000-6,000 人死亡。 CO 与血红蛋白 (Hb) 结合的小分子变构效应器的开发代表着朝着有效治疗 CO 中毒的方向迈出了重要一步。为此，我们发现合成肽 IRL 2500 可以增强空气中 COHb 的 CO 释放，但同时具有溶血活性。我们在此描述了 IRL 2500 类似物的设计、合成和生物学评价，这些类似物增强了 COHb 中 CO 的释放而不发生溶血。这些新颖的结构显示出改善的水溶性和降低的溶血活性，并可能为治疗一氧化碳中毒的小分子疗法的开发开辟道路。

更新日期：2018-05-11

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