Sickle-cell disease (SCD) is a genetic disorder that is characterized by the presence of sickle-shaped red blood cells in the blood stream.  These sickled cells clog small capillaries, leading to severe pain and organ damage.  SCD is the result of a single point mutation in the hemoglobin (Hb) gene, leading to the incorporation of a valine surface residue in place of glutamic acid.  Under low oxygen conditions, a binding surface for the valine residue is revealed a way as to lead to the polymerization of HbS and the subsequent characteristic sickling of red blood cells (RBCs). Despite the fact that the molecular mechanism of SCD is well understood, no effective treatment has yet reached the clinic. Therefore, the development of molecules capable of preventing HbS polymerization would be highly desirable.<br/> <br/>Through the use of a phage display library screen, several putative peptide ligands for HbS were identified with the most promising containing three proline residues among the seven positions.  Keeping this in mind, a one-bead-one-compound peptide library was subsequently synthesized in which proline was kept constant at these three positions.  Following an ELISA screen and peptide sequencing, 10 proline-rich ligands have now been identified.   These peptides inhibit HbS polymerization to varying extents and represent a unique mechanism for treating this debilitating disorder.<br/>

Proline-rich peptide inhibitors of sickle cell polymerization

2019 Fall National Meeting

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