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Identification, Characterization and Development of Bioactive Peptides

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Chemical Biology".

Deadline for manuscript submissions: closed (31 December 2022) | Viewed by 3708

Special Issue Editor


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Guest Editor
School of Biological Sciences and School of Chemical Sciences, University of Auckland, Auckland 1010, New Zealand
Interests: eptide synthesis; protein and glycoprotein synthesis; unusual amino acids; peptide lipidation

Special Issue Information

Dear Colleagues,

Despite the notion that peptides do not make good drugs, they have continued to carve out a niche between small molecules and biologics (proteins and antibodies), and have had an important place in medicine since the introduction of the peptide hormone insulin in the 1920s, with its eventual use as a treatment for diabetes.  Peptides interact exquisitely with cellular targets and have advantages over other biomolecules which suffer from batch-to-batch reproductivity issues and off-target side effects. In the past 5 years, 22 peptides have been given FDA approval, and there are currently 80 peptides on the market for a range of indications including diabetes, cancer, and infectious disease. Peptides can also be used as imaging agents, thus cementing their place in modern medicine. The discovery of new bioactive peptides and the elucidation of their structure are at the forefront of discovery; once isolated/identified and characterized, chemists (and biologists) are tasked with total synthesis to confirm the purported structure, establish bioactivity and investigate structure–activity relationships (SAR). These tasks have been aided by new technologies, such as genome mining, and the refinement of synthetic peptide chemistry techniques, such as flow chemistry, to rapidly access synthetic polypeptides. The aim of this Special Issue is to showcase all aspects of bioactive peptides, including their isolation and characterization, new methods to chemically or biologically synthesize both peptides and unnatural amino acids, and aspects of developing bioactive peptides for lead drug candidates. Both original research reports and review articles are welcome.

Dr. Paul William Richard Harris
Guest Editor

Manuscript Submission Information

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • peptides
  • synthesis
  • isolation
  • bioactivity
  • pharmaceuticals
  • drug discovery

Published Papers (2 papers)

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Research

13 pages, 2598 KiB  
Article
Engineering Peptide Inhibitors of the HFE–Transferrin Receptor 1 Complex
by Daniela Goncalves Monteiro, Gautam Rishi, Declan M. Gorman, Guillaume Burnet, Randy Aliyanto, K. Johan Rosengren, David M. Frazer, V. Nathan Subramaniam and Richard J. Clark
Molecules 2022, 27(19), 6581; https://doi.org/10.3390/molecules27196581 - 4 Oct 2022
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Abstract
The protein HFE (homeostatic iron regulator) is a key regulator of iron metabolism, and mutations in HFE underlie the most frequent form of hereditary haemochromatosis (HH-type I). Studies have shown that HFE interacts with transferrin receptor 1 (TFR1), a homodimeric type II transmembrane [...] Read more.
The protein HFE (homeostatic iron regulator) is a key regulator of iron metabolism, and mutations in HFE underlie the most frequent form of hereditary haemochromatosis (HH-type I). Studies have shown that HFE interacts with transferrin receptor 1 (TFR1), a homodimeric type II transmembrane glycoprotein that is responsible for the cellular uptake of iron via iron-loaded transferrin (holo-transferrin) binding. It has been hypothesised that the HFE/TFR1 interaction serves as a sensor to the level of iron-loaded transferrin in circulation by means of a competition mechanism between HFE and iron-loaded transferrin association with TFR1. To investigate this, a series of peptides based on the helical binding interface between HFE and TFR1 were generated and shown to significantly interfere with the HFE/TFR1 interaction in an in vitro proximity ligation assay. The helical conformation of one of these peptides, corresponding to the α1 and α2 helices of HFE, was stabilised by the introduction of sidechain lactam “staples”, but this did not result in an increase in the ability of the peptide to disrupt the HFE/TFR1 interaction. These peptides inhibitors of the protein–protein interaction between HFE and TFR1 are potentially useful tools for the analysis of the functional role of HFE in the regulation of hepcidin expression. Full article
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17 pages, 1685 KiB  
Article
Synthesis and Systematic Study on the Effect of Different PEG Units on Stability of PEGylated, Integrin-αvβ6-Specific A20FMDV2 Analogues in Rat Serum and Human Plasma
by Kuo-yuan Hung, Renata Kowalczyk, Ami Desai, Margaret A. Brimble, John F. Marshall and Paul W. R. Harris
Molecules 2022, 27(14), 4331; https://doi.org/10.3390/molecules27144331 - 6 Jul 2022
Cited by 1 | Viewed by 1696
Abstract
A20FMDV2 is a 20-mer peptide that exhibits high selectivity and affinity for the tumour-related αvβ6 integrin that can compete with extracellular ligands for the crucial RGD binding site, playing a role as a promising αvβ6-specific inhibitor for anti-cancer therapies. Unfortunately, the clinical value [...] Read more.
A20FMDV2 is a 20-mer peptide that exhibits high selectivity and affinity for the tumour-related αvβ6 integrin that can compete with extracellular ligands for the crucial RGD binding site, playing a role as a promising αvβ6-specific inhibitor for anti-cancer therapies. Unfortunately, the clinical value of A20FMDV2 is limited by its poor half-life in blood caused by rapid renal excretion and its reported high susceptibility to serum proteases. The incorporation of poly (ethylene glycol) chains, coined PEGylation, is a well-established approach to improve the pharmacokinetic properties of drug molecules. Here, we report a systematic study on the incorporation of a varying number of ethylene glycol units (1–20) into the A20FMDV2 peptide to establish the effects of PEGylation size on the peptide stability in both rat serum and human plasma. In addition, the effect of acetyl and propionyl PEGylation handles on peptide stability is also described. Selected peptide analogues were assessed for integrin-αvβ6-targeted binding, showing good specificity and activity in vitro. Stability studies in rat serum established that all of the PEGylated peptides displayed good stability, and an A20FMDV2 peptide containing twenty ethylene glycol units (PEG20) was the most stable. Surprisingly, the stability testing in human plasma identified shorter PEGs (PEG2 and PEG5) as more resistant to degradation than longer PEGs, a trend which was also observed with affinity binding to integrin αvβ6. Full article
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