Will Short Peptides Revolutionize Chelation Therapy?

It will soon be twenty years since the last chelating agent was clinically approved to be used against toxic metals. Even though metal poisoning has been known to humankind for centuries, only about a dozen compounds, all of which are small molecules, compose the pharmaceutical toolbox to expel intrinsically toxic or essential but misregulated metals. These compounds widely suffer from various drawbacks, most critically, poor metal selectivity. Can medicinal inorganic chemistry offer modern solutions to these old challenges? In this perspective, the opportunities and advantages of harnessing short peptides for chelation therapy are described. While broadly aiming to address various toxic metals, achievements in targeting lead (Pb) with peptides reveal the unexplored potential hidden in this chemical space and raise the possibility that peptides may reform chelation therapy.       &nbsp

Cyclic Octapeptides Composed of Two Glutathione Units Outperform the Monomer in Lead Detoxification

A rationally-designed scaffold of cyclic octapeptides composed of two units of the natural tripeptide glutathione (GSH) was optimized to strongly and selectively capture toxic lead ions (Pb(II)). Using state-of-the-art computational tools, a list of eleven plausible peptides was shortened to five analogs based on their calculated affinity to Pb(II) ions. We then synthesized and investigated them for their abilities to recover Pb-poisoned human cells. A clear pattern was observed from the in vitro detoxification results, indicating the importance of cavity size and polar moieties to enhance metal capturing. These, together with the apparent benefit of cyclizing the peptides, improved the detoxification of the two lead peptides by approximately two folds compared to GSH and the benchmark chelating agents against Pb poisoning. Moreover, the two peptides did not show any toxicity and, therefore, were thoroughly investigated to determine their potential as next-generation remedies for Pb poisoning

Disparities in Rate, Triggers, and Management in Pediatric and Adult Cases of Suspected Drug-Induced Anaphylaxis in Canada

INTRODUCTION: Data is sparse on drug-induced anaphylaxis (DIA) and there have not been studies assessing the differences in clinical characteristics and management of DIA between adults and children. OBJECTIVE: We assessed the percentage, diagnosis, and management of DIA among all anaphylaxis visits in three pediatric and one adult emergency departments (ED) across Canada. METHODS: Children presenting to the Montreal Children\u27s Hospital (MCH), British Columbia Children\u27s Hospital (BCCH), and Children\u27s Hospital at London Health Sciences Center and adults presenting to Hôpital du Sacré-Coeur with anaphylaxis were recruited as part of the Cross-Canada Anaphylaxis Registry. A standardized data form documenting the reaction and management was completed and patients were followed annually to determine assessment by allergist and use of confirmatory tests. RESULTS: From June 2012 to May 2016, 51 children were recruited from the pediatric centers and 64 adults from the adult center with drug-induced anaphyalxis. More than half the cases were prospectively recruited. The percentage of DIA among all cases of anaphylaxis was similar in all three pediatric centers but higher in the adult center in Montreal. Most reactions in children were triggered by non-antibiotic drugs, and in adults, by antibiotics. The majority of adults and a third of children did not see an allergist after the initial reaction. In those that did see an allergist, diagnosis was established by either a skin test or an oral challenge in less than 20% of cases. CONCLUSIONS: Our results reveal disparities in rate, culprit, and management of DIA in children versus adults. Further, most cases of suspected drug allergy are not appropriately diagnosed. Guidelines to improve assessment and diagnosis of DIA are required

Enhancing Metal-binding with Noncanonical Coordinating Amino Acids

More than 50% of proteinogenic amino acid sidechains can bind metal ions, enabling proteins and peptides to bear these ions as cofactors. Nevertheless, post-translational modifications and incorporation of noncanonical amino acids bestow peptides and proteins myriads of other coordination capabilities, thanks to an enhanced metal binding. Here we summarize selected examples of natural and artificial systems that contain one or more noncanonical amino acids coordinating a metal ion and subsequently achieve a new or enhanced function. We report on a wide array of systems: from disease-related proteins that undergo sulfurylation or phosphorylation through natural metallophores that selectively capture precious essential ions to synthetic selfassembly strategies, biocatalysts, and chelating agents against toxic metals. Regardless of their (bio)synthetic routes, all possess unique metal-binding properties that could not be effectively achieved by systems composed of canonical residues

Harnessing Peptides against lead pollution and poisoning: Achievements and prospects

Among the broad applicability of peptides in numerous aspects of life and technologies, their interactions with lead (Pb), one of the most harmful substances to the environment and health, are constantly explored. So far, peptides were developed for environmental remediation of Pb-contaminations by various strategies such as hydrogelation and surface display. They were also designed for Pb detection and sensing by electrochemical and fluorescent methods and for modeling natural proteins that involve in mechanisms by which Pb is toxic. This review aims at summarizing selected examples of these applications, manifesting the enormous potential of peptides in the combat against Pb pollution. Nevertheless, the absence of new medicinal treatments against Pb poisoning that are based on peptides is noticeable. An overview of previous achievements utilizing Pb-peptide interactions towards various goals is presented and can be therefore leveraged to construct a useful toolbox for the design of smart peptides as next-generation therapeutics against Pb

Peptide Models of Cu(I) and Zn(II) Metallochaperones: The Effect of pH on Coordination and Mechanistic Implications

The first NMR structures of Cu­(I) and Zn­(II) peptide complexes as models of metallochaperones were derived with no predetermined binding mode. The cyclic peptide <u>MDC</u>SG<u>C</u>SRPG was reacted with Cu­(I) and Zn­(II) at low and moderate pH. This peptide features the conserved sequence of copper chaperones but with Asp at position 2 as appears in the zinc binding domain of ZntA. The structures were compared with those of the Cu­(I) complexes of the wild-type sequence peptide <u>MTC</u>SG<u>C</u>SRPG. All analyses were conducted first with no metal-binding constraints to ensure accurate binding ligand assignment. Several structures included metal-Met binding, raising a possible role of Met in the metal transport mechanism. Both Cu­(I) and Zn­(II) gave different complexes when reacted with the peptide of the native-like sequence under different pH conditions, raising the possibility of pH-dependent transport mechanisms. Cu­(I) bound the <u>MTC</u>SG<u>C</u>SRPG peptide through one Cys and the Met under acidic conditions and differently under basic conditions; Zn­(II) bound the <u>MDC</u>SG<u>C</u>SRPG peptide through two Cys and the Met residues under acidic conditions and through one Cys and the Met under basic conditions, while Cu­(I) bound the non-native Asp mutant peptide through the Asp and one Cys under both conditions, suggesting that Asp may inhibit pH-dependent binding for Cu­(I). NOESY and ESI-HRMS supported the presence of an aqua ligand for Zn­(II), which likely deprotonated under basic conditions to give a hydroxo group. Coordination similarities were detected among the model system and native proteins, which overall suggest that coordination flexibility is required for the function of metallochaperones

Potent Cyclic Tetrapeptide for Lead Detoxification

Lead (Pb) is a ubiquitous poisonous metal, affecting the health of vast populations worldwide. Medications to treat Pb poisoning suffer from various limitations and are often toxic owing to insufficient metal selectivity. Here, we report a cyclic tetrapeptide that selectively binds Pb and eradicates its toxic effect on the cellular level, with superior potency than state-of-the-art drugs. The Pb-peptide complex is remarkably strong and was characterized experimentally and computationally. Accompanied by the lack of toxicity and enhanced stability of this peptide, these qualities indicate its merit as a potential remedy for Pb poisoning

Elucidating the structure–activity relationship of the pentaglutamic acid sequence of minigastrin with cholecystokinin receptor subtype 2

Derivatized minigastrin analogues make up a promising class of candidates for targeting cholecystokinin receptor subtype 2 (CCK2R), which is overexpressed on cancer cells of various neuroendocrine tumors. The pentaglutamic acid sequence of minigastrin influences its biological properties. In particular, it plays a crucial role in the kidney reuptake mechanism. However, the importance of the binding affinity and interaction of this region with the receptor on a molecular level remains unclear. To elucidate its structure-activity relationship with CCK2R, we replaced this sequence with various linkers differing in their amount of anionic charge, structural characteristics, and flexibility. Specifically, a flexible aliphatic linker, a linker with only three d-Glu residues, and a structured linker with four adjacent β -glutamic acid residues were evaluated and compared to the lead compound PP-F11N (DOTA-[d-Glu ,Nle ]gastrin-13). 1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) was conjugated to the minigastrin derivatives, which allowed radiolabeling with Lutetium-177. The levels of In vitro internalization into MZ-CRC1 cells and in vivo tumor uptake as well as human blood plasma stability increased in the following order: aliphatic linker < three d-Glu < (β -Glu) < (d-Glu) . The in vitro and in vivo behavior was therefore significantly improved with anionic charges. Computational modeling of a CCK2 receptor-ligand complex revealed ionic interactions between cationic residues (Arg and His) of the receptor and anionic residues of the ligand in the linker

Thiolation and Carboxylation of Glutathione Synergistically Enhance Its Lead-Detoxification Capabilities

The natural tripeptide glutathione (GSH) is a ubiquitous compound harboring various biological tasks, among them interacting with essential and toxic metal ions. Yet, although weakly binding the poisonous metal lead (Pb), GSH poorly detoxifies it. β-Mercaptoaspartic acid is a new-to-nature novel amino acid that was found to enhance the Pb-detoxification capability of a synthetic cyclic tetrapeptide. Aiming to explore the advantages of noncanonical amino acids (ncAAs) of this nature, we studied the detoxification capabilities of GSH and three analogue peptides, each of which contains at least one ncAA that harbors both free carboxylate and thiolate groups. A thorough investigation that includes in vitro detoxification and mechanistic evaluations, metal-binding affinity, metal selectivity, and computational studies shows that these ncAAs are highly beneficial in additively enhancing Pb binding and reveals the importance of both high affinity and metal selectivity in synergistically reducing Pb toxicity in cells. Hence, such ncAAs join the chemical toolbox against Pb poisoning and pollution, enabling peptides to strongly and selectively bind the toxic metal ion