Plant-derived chelators and ionophores as potential therapeutics for metabolic diseases

Abstract

Transition metal dysregulation is associated with a host of pathologies, many of which are therapeutically targeted using chelators and ionophores. Chelators and ionophores are used as therapeutic metal-binding compounds which impart biological effects by sequestering or trafficking endogenous metal ions in an effort to restore homeostasis. Many current therapies take inspiration or derive directly from small molecules and peptides found in plants. This review focuses on plant-derived small molecule and peptide chelators and ionophores that can affect metabolic disease states. Understanding the coordination chemistry, bioavailability, and bioactivity of such molecules provides the tools to further research applications of plant-based chelators and ionophores.

Figure 1:

Chelators (purple arcs) are small molecules that can cross cell membranes, bind metal ions (represented by spheres; the different colors – blue and orange – convey the presence of different metal ions), and subsequently evacuate bound ions from the cell. Conversely, ionophores (green arcs) are small molecules that extracellularly bind metal ions and import them into the cell passing through the cell membrane.

Figure 2:

Hereditary diseases including Menkes and Wilson diseases are linked to mutations in copper-trafficking proteins. These mutations result in dysregulation of copper populations and subsequent detrimental symptoms. Chelates are clinically employed for management and treatment of these disease. Symptoms of metabolic disorders such as type 2 diabetes are alleviated by molecules known to have chelation or ionophoric properties (indicated with purple arcs), but their mechanisms of action require further investigation. While blue spheres represent copper centers and orange spheres represent iron centers in the figure, further mechanistic insight is required to determine chelator selectivity in vivo as well as the role and interaction metal-binding serum proteins (yellow blobs) may play in metal availability and ligand exchange.

Figure 3:

Phenolic plant compounds are known to affect biological function under metabolic disease states. Additionally these phenolic compounds interact with d-block metal ions with little known about the intersection between effects on metabolic disease states.

Figure 4:

Plant-derived proteins subjected to enzymatic hydrolysis generates bioactive peptides. Such peptides have been found to have metal-interacting properties with potential health benefits.