Explore the vast range of titles available.

In malaria pathophysiology, divergent hypotheses on the inhibition of hematin crystallization posit that drugs act either by the sequestration of soluble hematin or their interaction with crystal surfaces. We use physiologically relevant, time-resolved in situ surface observations and show that quinoline antimalarials inhibit β-hematin crystal surfaces by three distinct modes of action: step pinning, kink blocking, and step bunch induction. Detailed experimental evidence of kink blocking validates classical theory and demonstrates that this mechanism is not the most effective inhibition pathway. Quinolines also form various complexes with soluble hematin, but complexation is insufficient to suppress heme detoxification and is a poor indicator of drug specificity. Collectively, our findings reveal the significance of drug–crystal interactions and open avenues for rationally designing antimalarial compounds.

Hematin crystallization is the primary mechanism of heme detoxification in malaria parasites and the target of the quinoline class of antimalarials. Despite numerous studies of malaria pathophysiology, fundamental questions regarding hematin growth and inhibition remain. Among them are the identity of the crystallization medium in vivo, aqueous or organic; the mechanism of crystallization, classical or nonclassical; and whether quinoline antimalarials inhibit crystallization by sequestering hematin in the solution, or by blocking surface sites crucial for growth. Here we use time-resolved in situ atomic force microscopy (AFM) and show that the lipid subphase in the parasite may be a preferred growth medium. We provide, to our knowledge, the first evidence of the molecular mechanisms of hematin crystallization and inhibition by chloroquine, a common quinoline antimalarial drug. AFM observations demonstrate that crystallization strictly follows a classical mechanism wherein new crystal layers are generated by 2D nucleation and grow by the attachment of solute molecules. We identify four classes of surface sites available for binding of potential drugs and propose respective mechanisms of drug action. Further studies reveal that chloroquine inhibits hematin crystallization by binding to molecularly flat {100} surfaces. A 2-μM concentration of chloroquine fully arrests layer generation and step advancement, which is ∼10 ⁴× less than hematin’s physiological concentration. Our results suggest that adsorption at specific growth sites may be a general mode of hemozoin growth inhibition for the quinoline antimalarials. Because the atomic structures of the identified sites are known, this insight could advance the future design and/or optimization of new antimalarials. Significance Approximately 40% of the global population is at risk for malaria infection and 300–660 million clinical episodes of Plasmodium falciparum malaria occur annually. During the malaria parasite lifecycle in human erythrocytes, heme released during hemoglobin catabolism is detoxified by sequestration into crystals. Many of the common antimalarials are believed to suppress the parasite by inhibiting hematin crystallization. We present, to our knowledge, the first evidence of the molecular mechanisms of hematin crystallization and antimalarial drug action as crystal growth inhibitors. These findings enable the identification and optimization of functional moieties that bind to crystal surface sites, thus providing unique guidelines for the discovery of novel antimalarials to combat increased parasite resistance to current drugs.

Implantable medical devices have revolutionized modern medicine. However, immune-mediated foreign body response (FBR) to the materials of these devices can limit their function or even induce failure. Here we describe long-term controlled-release formulations for local anti-inflammatory release through the development of compact, solvent-free crystals. The compact lattice structure of these crystals allows for very slow, surface dissolution and high drug density. These formulations suppress FBR in both rodents and non-human primates for at least 1.3 years and 6 months, respectively. Formulations inhibited fibrosis across multiple implant sites—subcutaneous, intraperitoneal and intramuscular. In particular, incorporation of GW2580, a colony stimulating factor 1 receptor inhibitor, into a range of devices, including human islet microencapsulation systems, electrode-based continuous glucose-sensing monitors and muscle-stimulating devices, inhibits fibrosis, thereby allowing for extended function. We believe that local, long-term controlled release with the crystal formulations described here enhances and extends function in a range of medical devices and provides a generalized solution to the local immune response to implanted biomaterials.

Conformational changes, and the formation of densely packed ordered aggregates or crystals, are behaviors that profoundly affect the properties of a molecule. Using the example of biological macromolecules, we discuss two types of interactions between these two behaviors. First, we demonstrate that shape change may be driven by crystallization if the gain in crystallization free energy is sufficient to overcome the transition to an unfavorable molecular conformation. Hence, the crystal structures of flexible molecules may be a poor representation of their free-phase atomic arrangements. Second, molecules with conformational variability, such as proteins, may facilitate the nucleation of their crystals by forming dense liquid clusters enriched in domain-swapped or misassembled oligomers. In the clusters, the nucleation barrier is reduced due to the lower surface free energy of the crystal/dense liquid interface, and nucleation is significantly faster.