The molecular origin of sickle cell disease (SCD) has been known since 1949, but treatments remain limited. We present the first high-throughput screening (HTS) platform for discovering small molecules that directly inhibit sickle hemoglobin (HbS) oligomerization and improve blood flow, potentially overcoming a long-standing bottleneck in SCD drug discovery. We show that at concentrations far below the threshold for nucleation and rapid polymerization, deoxygenated HbS forms small assemblies of multiple α2β2tetramers. Our HTS platform leverages high-sensitivity fluorescence lifetime measurements that monitor these temporally stable prefibrillar HbS oligomers. We show that this approach is sensitive to compounds that inhibit HbS polymerization with or without modulating hemoglobin oxygen binding affinity. We also report the results of a pilot small-molecule screen in which we discovered and validated several novel inhibitors of HbS oligomerization.
Bibliographical noteFunding Information:
We thank the patients at Children’s Hospital and Clinics of Minnesota for their generous blood donations and the sickle care team, including Dr. Steve Nelson, Ashley Kinsella, Pauline Mitby, Ali Koste, Rachel Hinsch, and Emily Olson for blood sample collection. We acknowledge funding under Grants R01HL132906 (D.K.W.), R21HL152313 (J.N.S., D.K.W.), and R35GM131814 (J.N.S.). Portions of this work were conducted in the Minnesota Nano Center, which is supported by the National Science Foundation through the National Nanotechnology Coordinated Infrastructure (NNCI) under Award Number ECCS-2025124.
© 2022 American Chemical Society. All rights reserved.
- Anemia, Sickle Cell/drug therapy
- Drug Discovery
- Hemoglobin, Sickle/chemistry
PubMed: MeSH publication types
- Journal Article
- Research Support, U.S. Gov't, Non-P.H.S.
- Research Support, N.I.H., Extramural