Hematin is a byproduct of heme detoxification in malaria parasites. Current antimalarial compounds have been shown to inhibit the growth of hematin crystals, referred to as hemozoin (in vivo) or b-hematin (in vitro). Identification of antimalarial drug action on this phase transformation could provide a foundation for drug design to overcome parasite resistance to antimalarials. Continued resurgence of antimalarial drug resistance drives research efforts to better characterize drug-crystal interactions from a fundamental perspective. To this end, we aim to better understand the molecular mechanism(s) of hematin crystallization and antimalarial drug action within physiologically-relevant environments as the basis for elucidating growth sites on hematin crystal surfaces and design more effective growth inhibitors that selectively bind to these sites. We employ in situ atomic force microscopy (AFM) in parallel with bulk crystallization studies and molecular modeling as a platform to study the mechanisms of crystal growth and inhibitor-crystal interactions in biomimetic growth solutions. Time-resolved in situ AFM measurements reveal that hematin crystallization occurs by single molecule incorporation, specifically involving two-dimensional nucleation of layers. We have 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, from which we identified unique modes of binding for current antimalarials as inhibition pathways. Moreover, we have shown that crystal growth occurs in a complex medium comprised of organics (neutral lipids) and water. In this talk, we will show how a biomimetic growth mixture comprised of n-octanol (lipid surrogate) exhibits unique binding modes at solid interfaces, which can alter the adsorption of antimalarials. Collectively, our findings reveal fundamental principles governing the molecular recognition of antimalarial drugs to specific sites that could lead to the rational design of new compounds with improved efficiency to overcome parasite resistance to current antimalarials.

Structuring of organic solvents at biointerfaces and its ramifications for antimalarial inhibition of hematin crystallization

2019 Spring National Meeting

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