DECIPHERING THE MOLECULAR INTERACTIONS BETWEEN ANTIMALARIALS AND HEMATIN CRYSTAL SURFACES

Crystallization is the central process of materials synthesis in biological, geological, and extraterrestrial systems. Nature achieves remarkable diversity of shapes, patterns, compositions, and functions of the arising crystalline structures by combining simple strategies to control the number of nucleated crystal and the sizes to which they grow. In recent years, organic and mixed inorganic-aqueous liquids have received greater attention as alternative solvents for preparation of crystalline materials and separation (or purification) by crystallization, in particular for high-value materials such as pharmaceuticals and fine chemicals. In contrast to crystallization from purely aqueous solvents, the level of understanding of the fundamental processes of crystal growth from such liquids is severely limited. Issues that have been addressed are solvent selection, control of nucleation and growth (including seeding), solubility, transport regimes, and effects of ongoing solute synthesis, among others. In most cases, the optimization of the growth processes is carried out by trial-and-error or by mimicking pathways developed for other compounds. The lack of insight into the relevant fundamental mechanisms has emerged as a major obstacle to a rational approach to optimization and control of crystallization in organic and mixed solvents. Approximately 3.2 billion people are at risk of malaria. Hematin is released as a byproduct of hemoglobin catabolism during the malaria parasite lifecycle in human erythrocytes and detoxified by sequestration as innocuous hemozoin crystals. Hematin crystallization has been the most effective target for antimalarial drugs. Previous studies have found that the formation of hematin crystals follows a classical mechanism whereby new crystal layers are nucleated on top of existing ones and spread to cover the entire face. Direct observations established two classes of quinoline inhibition mechanisms. Amodiaquine and mefloquine were found to largely only bind to kink growth sites, where molecular units add to a step. This is the least effective mechanism of heme crystal growth inhibition. In a second mechanism, known as “step-pinning,” chloroquine and quinine bind on a flat surface face, inhibited new layer growth over broad areas of the crystal surface. We employed atomic force microscopy to monitor in real time the growth of steps on the (100) surface under the influence of varied drug combinations. This molecular-level view revealed that the action of quinine and amodiaquine is additive, indicating the lack on interaction between the action of each of these two drugs. Chloroquine and mefloquine weaken each other’s action, indicting antagonism in their suppression of hematin growth. These findings may serve as a basis for a lock-and-key approach to targeted drug development that is rooted in the physical basis for hemozoin crystal growth inhibition. One of the most relevant, yet the least investigated pathological crystal is cholesterol crystal, which is a principle component of gallstones(1-5) and atherosclerosis (6, 7). Prior studies have largely focused on the effects of phospholipids and bile salts on the formation of cholesterol crystals;(8) however, few groups have examined the mechanism(s) of crystallization. To this end, we conducted preliminary studies revealing cholesterol crystal growth occurs by a combination of classical and nonclassical (9) pathways involving the addition of monomer and precursors (i.e. clusters), respectively.