A potent new dipeptide inhibitor of cell sickling and haemoglobin S gelation

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Abstract
A dipeptide L-Lys-L-Phe inhibited both cell sickling and the gelation of solutions of human sickle-cell Hb. The effect on deoxyhemoglobin solutions and gels was followed by centrifugation; a progressive inhibition of gelation was observed up to 30 mM Lys-Phe. The Hb concentration at the plateau (26 g/dl) suggested that an effect might be seen in vivo if suitable concentrations of Lys-Phe (about 20 mM) could be maintained in the blood stream. Additional studies of lag time before onset of gelation supported this. O2 dissociation curves of sickle cells showed an effect of Lys-Phe only after incubation for 3 h before measurement, the P50 [partial pressure of O2 at which Hb is half saturated with O2] decreasing from 51 mmHg (6.8 MPa [Pascals]) to 41 mmHg (5.5 MPa) for cells depleted of 2,3-bisphosphoglycerate. The effect of Lys-Phe on intact sickle cells was more rapid. A marked increase in the number of unsickled cells in the presence of Lys-Phe was observed after only 15 min incubation. This result, together with measurements of uptake both into the cell and onto the cell membrane, showed that the compound produced a membrane-mediated anti-sickling effect in addition to the effect on Hb in solution within the cell. The membrane effect was not due to a change in cell volume. The properties of this dipeptide may be of value in the treatment of impending and early sickle crisis.