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

Sara R Goldstein; Chen Liu; Martin K Safo; Akito Nakagawa; Warren M Zapol; Jeffrey D Winkler

doi:10.1021/acsmedchemlett.8b00166

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

ACS Med Chem Lett. 2018 May 11;9(7):714-718. doi: 10.1021/acsmedchemlett.8b00166. eCollection 2018 Jul 12.

Authors

Sara R Goldstein¹, Chen Liu², Martin K Safo³, Akito Nakagawa², Warren M Zapol², Jeffrey D Winkler¹

Affiliations

¹ Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104, United States.
² Anesthesia Center for Critical Care Research, Department of Anesthesia, Critical Care, and Pain Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, United States.
³ Department of Medicinal Chemistry, The Institute for Structural Biology, Drug Discovery, and Development, School of Pharmacy, Virginia Commonwealth University, Richmond, Virginia 23298, United States.

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.

Abstract

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