A diphenylalanine motif in peptides plays a crucial role in supramolecular systems. The current work represents a novel strategy in which a diphenylalanine motif in the central domain of neuropeptides conserves the specific Zn2+ binding site and prevents “hopping” of the Zn2+ ion between alternative metal binding sites. Alternative metal binding sites may also include carboxylic atoms in the terminal domains of a peptide. Therefore, one needs to design a peptide in which the metal will not bind the carboxylic groups in the terminal domains. Herein, we propose that engineering and designing peptides with a diphenylalanine motif in the central domain may yield excellent metal chelators.

Neurodegenerative diseases, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), are characterized by deposits of amyloid proteins. The homeostasis of metal ions is crucial for the normal biological functions in the brain. However, in AD and PD, the imbalance of metal ions leads to formation of amyloid deposits. In the past four decades, there has been extensive effort to design compound agents than can chelate metal ions with the aim of preventing the formation of the amyloid deposits. Unfortunately, the compounds to date that were designed were not successful candidates to be used in clinical trials. Neuropeptides are small molecules that are produced and released by neurons. It has been shown that neuropeptides have neuroprotective effects in the brain and reduce the formation of amyloid deposits. This Review Article is focused on the function of neuropeptides as metal chelators. Experimental and computational studies demonstrated that neuropeptides could bind metal ions, such as Cu 2+ and Zn 2+ . This Review Article provides perspectives and initiates future studies to investigate the role of neuropeptides as metal chelators in neurodegenerative diseases.

The concept of metal chelation is based on simple coordination chemistry. The development of an ideal metal chelator that completely and selectively removes toxic metals from a specific metal binding site in proteins is required to prevent and or inhibit a variety of diseases, among them neurodegenerative diseases. This work examines neuropeptide Y (NPY) as a Zn 2+ and Cu 2+ chelator agent. NPY is a natural peptide that is produced in the human body; therefore, it is not a toxic agent and the complex that it forms is not toxic as well. Our simulations reveal that NPY has an efficient Zn 2+ chelation activity but is less effective in chelating Cu 2+ . Moreover, while NPY demonstrates several conformations, the metal chelation occurs more efficiently in its native structure. Beyond the exploration of the activity of NPY as a Zn 2+ and Cu 2+ chelator agent, this work provides an insight into the molecular mechanisms of the chelation of these metals at the molecular level. The outcomes from this work may guide future experimental studies to examine NPY in metal chelation therapy for neurodegenerative diseases.

Insulin is naturally released from the β-cells in the pancreas and plays a crucial role in controlling the blood sugar levels in the body. However, it was found that when...