The effect of phenylalanine derivatives on the solubility of deoxyhemoglobin S. A model class of gelation inhibitors.

Among the class of non-covalent inhibitors of deoxyhemoglobin S gelation, the aromatic amino acids have been shown to be the most effective. We have examined several synthetic chemical modifications of phenylalanine in order to determine the stereospecific constraints for inhibition of gelation by this class of compounds. The phenylalanine derivatives with ring modification by electron-donating groups (NH2, CH3, or OH) inhibited gelation to the same order of magnitude as phenylalanine (10-20% increase in deoxyhemoglobin S solubility at 32 mM). The phenylalanine derivative with the electron-withdrawing group NO2 in the p-position behaved similarly, but the inhibitory effect was eliminated by NO2 in the m- and possibly o-positions. Furthermore, side-chain modifications also eliminated the inhibitory effect. These studies, in conjunction with crystallographic analyses of the binding sites of gelation inhibitors, may provide a rational strategy for finding suitable compounds (whether covalent or non-covalent inhibitors) with appropriate physicochemical and biological properties to pursue as potential therapies with sickle cell disease.