467212 Interactions Between Antimalarials and Hematin Crystal Surface Sites Determine the Mode of Growth Inhibition
In situ atomic force microscopy (AFM) reveals that hematin crystallization occurs by a classical mechanism of layer-by-layer growth involving the addition of individual molecules to specific sites presented on the crystal surface. We show that hematin crystals form in a two-phase medium, which we designed to mimic the parasite’s DV comprising a complex system with a primarily acidic aqueous phase and lipid subphase.2 We quantified the rate of layer generation and the velocities of anisotropic step advancement as a function of supersaturation in the absence and presence of antimalarials.1 We identified that current antimalarials act in unique modes of inhibition. Our current studies aim to elucidate the relationship between the functional moieties present on current antimalarials and free hematin as well as the solid-liquid interface presented on predominant {100} crystal surfaces. In parallel, we studied the prominent functional groups of antimalarial compounds using a combination of in situ AFM studies and chemical force microscopy (CFM) measurements. Identifying key factors governing molecular recognition of inhibitors to specific crystal surface sites is crucial to the development of rational design platforms for screening new drug compounds.
[1] Olafson, K.N., Ketchum, M.A., Rimer, J.D., Vekilov, P.G., Mechanisms of Hematin Crystallization and Inhibition by the Antimalarial Drug Chloroquine, Proc. Natl. Acad. Sci. 16 (2015) 4946-4951
[2] Olafson, K.N., Rimer, J.D., Vekilov, P.G., Growth of Large Hematin Crystals in Biomimetic Solutions, Cryst. Growth Des. 14 (2014) 2123-2127
[3] Ketchum, M.A., Olafson, K.N., Rimer, J.D., Vekilov, P.G., Hematin Crystallization from Aqueous and Organic Solvents, J. Chem. Phys. 139 (2013) 121911(1-9)
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