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Modeling of Biomolecular Systems Interactions, Dynamics, and Allostery Session VI Abstracts
Sickle Cell Hemoglobin: Allostery, Aggregation Kinetics, and Search for a Drug
William Eaton
.
NIDDK, NIH, Bethesda, MD, USA
Unlike other protein aggregation diseases, the molecular pathogenesis of sickle cell anemia is
well understood. If sickle hemoglobin were at equilibrium in the tissues with respect to fiber
formation, patients would not survive once fetal hemoglobin disappears after the first few weeks
of life. The disease is survivable because of the highly unusual kinetics of fiber formation. Like
amyloid formation, there is a delay period prior to fiber formation, which allows the vast
majority of cells to escape the narrow vessels of the tissues before fibers make the red cells less
deformable and cause vaso-occlusion. However, unlike amyloid formation, there is an enormous
sensitivity of the kinetics to solution conditions, with the delay time inversely proportional to up
to the 40
th
power of the initial sickle hemoglobin concentration and a nucleation rate proportional
to up to the 80
th
power (no typos). The kinetics can be explained by a double nucleation
mechanism, in which nucleation of new fibers on the surface of pre-existing fibers results in an
autocatalytic time course that produces the delay period. In spite of our understanding of the
thermodynamics and kinetics and their relation to pathogenesis, there is still only one partially
successful drug, hydroxyurea, discovered more than 20 years ago, which replaces about 20% of
sickle hemoglobin with fetal hemoglobin in up to 80% of cells. Hydroxyurea is therapeutic
because it dilutes the sickle hemoglobin and increases the delay time. What is needed is a drug
that acts on all cells. We have developed an automated laser-photolysis/image-analysis assay to
screen for anti-sickling compounds. Our initial screen is being carried out on compounds
already approved by the FDA for other human diseases. Compounds active in this screen would
be rapidly approved for clinical trials.
