Polymerization of the mutant hemoglobin S (HbS) upon deoxygenation in the tissues results in fibers that distort (“sickle”) and stiffen the red cells of patients with sickle cell disease. Sickling occludes the small vessels of the tissues to cause acute and chronic organ damage, a shortened life span, and episodes of pain so severe they are called “sickle cell crises”. What is urgently needed now for the vast majority of patients, who live in under-resourced countries, is an inexpensive oral drug to add to hydroxyurea, the only successful anti-sickling drug approved by the FDA.  My lab has developed a high throughput screening assay using an automated microscope system where cell sickling is induced by slow deoxygenation with nitrogen. Our assay is motivated by several novel aspects of HbS polymerization, including (i) a delay period prior to the appearance of fibers that depends inversely on over the 30<sup>th</sup> power of the initial protein concentration – the highest concentration dependence ever measured for a molecular process, (ii) homogeneously nucleated fibers triggering the formation of domains of a large number of fibers via secondary nucleation on the surface of pre-existing fibers, resulting in autocatalysis responsible for the delay period; slow deoxygenation results in few homogeneous nucleation events and therefore few domains to produce easily detected distortions of the red cells; and (iii) discovery of a universal relation between the delay time and the activity supersaturation on time scales from milliseconds to a day, validating the physiological significance of the  distribution of sickling times measured on the hours time scale of our assay rather than the seconds time scale <i>in vivo</i>.  We have used this assay to screen the 12,657 compounds of the Scripps ReFrame drug repurposing library. The ReFrame library is a very important compound collection because they are either FDA-approved drugs or have been tested in clinical trials.  From dose-response measurements using singular value decomposition to analyze the data, 106 of the 12,657 compounds are anti-sickling at concentrations ranging from 30 nM to 10 mM.  Based on a comparison of anti-sickling concentrations of the compounds with free concentrations of oral drugs in the Physicians’ Desk Reference, as many as 21 of the 106 anti-sickling compounds are potential drugs. Our results should motivate others to develop one or more of these 106 compounds into drugs for treating the disease.

Using physical chemistry to discover new drugs for treating sickle cell disease

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