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Design, Synthesis, and Biological Evaluation of Allosteric Effectors That Enhance CO Release from Carboxyhemoglobin.

ABSTRACT: 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.

SUBMITTER: Goldstein SR

PROVIDER: S-EPMC6047046 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Design, Synthesis, and Biological Evaluation of Allosteric Effectors That Enhance CO Release from Carboxyhemoglobin.

Goldstein Sara R SR Liu Chen C Safo Martin K MK Nakagawa Akito A Zapol Warren M WM Winkler Jeffrey D JD

ACS medicinal chemistry letters 20180511 7

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 en ...[more]

PMID: 30034606

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