Stereospecific Inhibitors of the Gelation of Sickle Hemoglobin

Abstract

During the last decade there have been major advances in understanding the structure of the gel of deoxyhemoglobin S and the mechanism of its formation. These advances have allowed the development of a new strategy for the inhibition of gelation, i.e., stereo-specific competitive inhibitors of the polymerization process. For this purpose we have used equilibrium solubility measurements to study the effects of amino acids and peptides on deoxyhemoglobin S solubility. We have found that aromatic amino acids and short peptides containing these amino acids significantly increase solubility; longer peptides, however, decrease solubility by an excluded-volume related effect. Recently we have used computer graphics projections of the surface of the hemoglobin molecules in the crystal form to design peptide inhibitors. In addition, we have developed 13_C nuclear magnetic resonance spectroscopic methods to quantitate the gel of deoxyhemoglobin S in hemoglobin solutions and in cells. These spectroscopic methods allow us to study the mechanism of intracellular gelation and to test the effects of inhibitors on sickle cells.