期刊
ACS MEDICINAL CHEMISTRY LETTERS
卷 8, 期 3, 页码 321-326出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.6b00491
关键词
Sickle cell disease; sickle cell hemoglobin; allosteric modulator; aldehyde; Schiff-base formation; oxygen affinity; red blood cell partitioning
资金
- Sandler Foundation [MR-15-328599]
- National Institutes of Health [GM105404, GM073210, GM082250, GM094625]
- National Science Foundation [1330685]
- Plexxikon Inc.
- M.D. Anderson Cancer Center
- US Department of Energy, Office of Basic Energy Sciences through Integrated Diffraction Analysis Technologies program [DE-AC02-05CH11231]
- US Department of Energy Office of Biological and Environmental Research
- Div Of Molecular and Cellular Bioscience
- Direct For Biological Sciences [1330685] Funding Source: National Science Foundation
We report the discovery of a new potent allosteric effector of sickle cell hemoglobin, GBT440 (36), that increases the affinity of hemoglobin for oxygen and consequently inhibits its polymerization when subjected to hypoxic conditions. Unlike earlier allosteric activators that bind covalently to hemoglobin in a 2:1 stoichiometry, 36 binds with a 1:1 stoichiometry. Compound 36 is orally bioavailable and partitions highly and favorably into the red blood cell with a RBC/plasma ratio of similar to 150. This partitioning onto the target protein is anticipated to allow therapeutic concentrations to be achieved in the red blood cell at low plasma concentrations. GBT440 (36) is in Phase 3 clinical trials for the treatment of sickle cell disease (NCT03036813).
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