Nonclassical Mechanisms to Inhibit β-Hematin Crystallization Illuminate the Cooperative Action of Antimalarials

Malaria parasites survive within red blood cells by converting toxic heme, released during hemoglobin digestion, into inert hemozoin crystals. Because disruption of this detoxification pathway is a major route of parasite killing, understanding how these crystals form and how drugs interfere with their formation is important for both fundamental mechanism and antimalarial development. This dissertation uses β-hematin, the synthetic analogue of hemozoin, as a mechanistic model to examine crystal structure, growth, nucleation, precursor populations, and drug action under biomimetic conditions. Structural analyses show that β-hematin and hemozoin obtained from multiple parasite strains and species are crystallographically consistent, supporting the use of β -hematin as a structurally relevant model system. Under low hematin concentrations, β-hematin grows by classical layer-by-layer propagation. Kinetic analysis, molecular modeling, and high-resolution imaging further indicate that this process proceeds primarily through incorporation of monomeric hematin rather than preformed dimers. At higher hematin concentrations, however, growth is no longer described fully by classical step flow. Mesoscopic hematin-rich clusters contribute to both nucleation and crystal growth, revealing a nonclassical pathway that coexists with surface-mediated growth. On this basis, the dissertation develops a framework in which antimalarial inhibition may occur either at existing crystal surfaces or upstream through suppression of precursor populations and alteration of surface states. Application of this framework shows that tafenoquine is a weak inhibitor of classical step growth but a stronger suppressor of precursor populations and crystal nucleation, consistent with greater activity against early parasite stages. Lumefantrine acts through a distinct step-capping mechanism and promotes surface roughening, defect formation, and other nonclassical responses. In combination, the heme-dihydroartemisinin adduct and lumefantrine produces ratio-dependent cooperative effects that strongly suppress crystal growth through nonclassical surface remodeling. Finally, a descriptor-based predictive approach demonstrates that site-specific inhibition modes can be inferred from molecular structure, providing a foundation for more mechanism-guided design of hematin crystal inhibitors and antimalarial combinations.

Name thesis:degree_name

Doctor of Philosophy

Discipline thesis:degree_discipline

Chemical Engineering

Grantor

University of Houston

Year dc:date.issued

2026

Author dc:creator

• Lee, Huan-Jui 1993-

Advisors dc:contributor.advisor

• Vekilov, Peter G.
• Rimer, Jeffrey D.

Committee members dc:contributor.committeemember

• Mountziaris, Triantafillos J.
• Zerze, Gül H.
• Kolomeisky, Anatoly B.
• Chiang, Naihao

• Antimalarial mechanisms
• Surface remodeling
• Mesoscopic clusters
• Pathological crystallization
• β-Hematin
• Hemozoin
• Biomimetic systems
• Cooperative inhibition
• Precursor-mediated growth
• Nucleation
• Crystal growth inhibition
• Nonclassical crystallization

Language dc:language.iso

English

Handle dc:identifier.uri

https://hdl.handle.net/10657/21544

OAI identifier oai:identifier

oai:uh-ir.tdl.org:10657/21544