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Special Issue "Cyclic Peptide Analogues and Non-peptide Mimetics"

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A special issue of Molecules (ISSN 1420-3049).

Deadline for manuscript submissions: closed (31 December 2020) | Viewed by 10328

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Special Issue Editor

Dr. Theodore Tselios
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Guest Editor

Department of Chemistry, University of Patras, Patra, Greece
Interests: organic; peptide and medicinal chemistry; rational design and synthesis of linear; cyclic peptide analogues and non-peptide mimetics; conformational studies; molecular modelling of bioactive and pharmaceutical compounds; interactions of bioactive molecules (docking studies); pharmacophore analysis; homology modelling

Special Issue Information

Dear Colleagues,

It is a great pleasure and honour for me to ask for your contribution to a Special Issue related to cyclic peptides and non-peptide mimetics. This significant and timely topic inaugurates new opportunities in the design, discovery, and development of pharmaceutical products. Peptides and proteins are significant tools for drug development and are considered attractive "drug leads" for the rational design of bioactive molecules and molecules for medical use. The growing interest in peptide-based drugs in medicinal research provides many opportunities for the development of cyclic peptides and non-peptide mimetics aiming for the treatment of several diseases. Peptide cyclization and peptidomimetics restrict the conformational flexibility of their linear counterparts, and result in increased metabolic stability and receptor selectivity, therefore providing a better pharmacological profile. The knowledge of the bioactive conformation of linear peptides in combination with structure activity relations studies (SARs) are the main tools for the "structure-based design" and development of potent cyclic peptides and non-peptide mimetics.

The principal goal of this Special Issue is to provide the scientific community with novel approaches and directions in the field of rational drug design and medicinal chemistry, using cyclic peptides and non-peptide mimetics. I cordially invite researchers working in this field to join this Issue and submit original research articles, short communications, and review articles.

Assoc. Prof. Dr. Theodore Tselios
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2300 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

Cyclic peptides
Peptidomimetics and non-peptide mimetics
Rational design of bioactive molecules
Bioactive cyclic peptides

Published Papers (7 papers)

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Research

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Open AccessArticle

Controversy of Peptide Cyclization from Tripeptide

and

Molecules 2021, 26(2), 389; https://doi.org/10.3390/molecules26020389 - 13 Jan 2021

Viewed by 1136

Abstract

The present investigation reports an attempt to synthesize naturally occurring α-cyclic tripeptide cyclo(Gly-l-Pro-l-Glu) 1, [cyclo(GPE)], previously isolated from the Ruegeria strain of bacteria with marine sponge Suberites domuncula. Three linear precursors, Boc-GPE(OBn)₂, Boc-PE(OBn)G and Boc-E(OBn)GP, were synthesized using a solution phase peptide coupling protocol. Although cyclo(GPE) 1 was our original target, all precursors were dimerized and cyclized at 0 °C with high dilution to form corresponding α-cyclic hexapeptide, cyclo(GPE(OBn))₂7, which was then converted to cyclic hexapeptide cyclo(GPE)₂2. Cyclization at higher temperature induced racemization and gave cyclic tripeptide cyclo(GP_DE(OBn)) 9. Structure characteristics of the newly synthesized cyclopeptides were determined using ¹H-NMR, ¹³C-NMR and high-resolution mass spectrometry. The chemical shift values of carbonyls of 2 and 7 are larger than 170 ppm, indicating the formation of a cyclic hexapeptide. Full article

(This article belongs to the Special Issue Cyclic Peptide Analogues and Non-peptide Mimetics)

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Open AccessArticle

A Reliable Enantioselective Route to Mono-Protected N1-Cbz Piperazic Acid Building Block

Evanthia Papadaki

Dimitris Georgiadis

and

Michail Tsakos

Molecules 2020, 25(24), 5939; https://doi.org/10.3390/molecules25245939 - 15 Dec 2020

Viewed by 1388

Abstract

The chiral N1-Cbz, N2-H derivative of the piperazic acid monomer is a valuable building block in the total synthesis of natural products, comprising this nonproteinogenic amino acid. In that context, we wish to report an improved synthetic protocol for the synthesis of both (3R)- and (3S)-piperazic acids bearing the carboxybenzyl protecting group (Cbz) selectively at the N1 position. Our method builds on previously reported protocols, circumventing their potential shortcomings, and optimizing the ultimate selective deprotection at the N2 position, thus, offering an efficient and reproducible pathway to suitably modified piperazates in high optical purity. Full article

(This article belongs to the Special Issue Cyclic Peptide Analogues and Non-peptide Mimetics)

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Graphical abstract

Open AccessCommunication

Bis-Lactam Peptide [i, i+4]-Stapling with α-Methylated Thialysines

Bo Wu

and

Weiping Zheng

Molecules 2020, 25(19), 4506; https://doi.org/10.3390/molecules25194506 - 01 Oct 2020

Viewed by 1009

Abstract

Four bis-lactam [i, i+4]-stapled peptides with d- or l-α-methyl-thialysines were constructed on a model peptide sequence derived from p110α[E545K] and subjected to circular dichroism (CD) and proteolytic stability assessment, alongside the corresponding bis-lactam [i, i+4]-stapled peptide with l-thialysine. The % α-helicity values of these four stapled peptides were found to be largely comparable to each other yet greater than that of the stapled peptide with l-thialysine. An l-α-methyl-thialysine-stapled peptide built on a model peptide sequence derived from ribonuclease A (RNase A) was also found to exhibit a greater % α-helicity than its l-thialysine-stapled counterpart. Moreover, a greater proteolytic stability was demonstrated for the l-α-methyl-thialysine-stapled p110α[E545K] and RNase A peptides than that of their respective l-thialysine-stapled counterparts. Full article

(This article belongs to the Special Issue Cyclic Peptide Analogues and Non-peptide Mimetics)

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Open AccessArticle

Convergent Synthesis of Thioether Containing Peptides

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Molecules 2020, 25(1), 218; https://doi.org/10.3390/molecules25010218 - 05 Jan 2020

Cited by 3 | Viewed by 1920

Abstract

Thioether containing peptides were obtained following three synthetic routes. In route A, halo acids esterified on 2-chlorotrityl(Cltr) resin were reacted with N-fluorenylmethoxycarbonyl (Fmoc) aminothiols. These were either cleaved from the resin to the corresponding (Fmoc-aminothiol)carboxylic acids, which were used as key building blocks in solid phase peptide synthesis (SPPS), or the N-Fmoc group was deprotected and peptide chains were elongated by standard SPPS. The obtained N-Fmoc protected thioether containing peptides were then condensed either in solution, or on solid support, with the appropriate amino components of peptides. In route B, the thioether containing peptides were obtained by the reaction of N-Fmoc aminothiols with bromoacetylated peptides, which were synthesized on Cltr-resin, followed by removal of the N-Fmoc group and subsequent peptide elongation by standard SPPS. In route C, the thioether containing peptides were obtained by the condensation of a haloacylated peptide synthesized on Cltr-resin and a thiol-peptide synthesized either on 4-methoxytrityl(Mmt) or trityl(Trt) resin. Full article

(This article belongs to the Special Issue Cyclic Peptide Analogues and Non-peptide Mimetics)

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Graphical abstract

Open AccessArticle

Solid-Phase Insertion of N-mercaptoalkylglycine Residues into Peptides

Spyridon Mourtas

Dimitrios Gatos

and

Kleomenis Barlos

Molecules 2019, 24(23), 4261; https://doi.org/10.3390/molecules24234261 - 22 Nov 2019

Viewed by 1208

Abstract

N-mercaptoalkylglycine residues were inserted into peptides by reacting N-free amino groups of peptides, which were initially synthesized on 2-chlorotrityl resin (Cltr) using the Fmoc/^tBu method, with bromoacetic acid and subsequent nucleophilic replacement of the bromide by reacting with S-4-methoxytrityl- (Mmt)/S-trityl- (Trt) protected aminothiols. The synthesized thiols containing peptide–peptoid hybrids were cleaved from the resin, either protected by treatment with dichloromethane (DCM)/trifluoroethanol (TFE)/acetic acid (AcOH) (7:2:1), or deprotected (fully or partially) by treatment with trifluoroacetic acid (TFA) solution using triethylsilane (TES) as a scavenger. Full article

(This article belongs to the Special Issue Cyclic Peptide Analogues and Non-peptide Mimetics)

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Graphical abstract

Open AccessArticle

Conformation and Dynamics of the Cyclic Lipopeptide Viscosinamide at the Water-Lipid Interface

and

Molecules 2019, 24(12), 2257; https://doi.org/10.3390/molecules24122257 - 17 Jun 2019

Cited by 4 | Viewed by 1972

Abstract

Cyclic lipodepsipeptides or CLiPs from Pseudomonas are secondary metabolites that mediate a wide range of biological functions for their producers, and display antimicrobial and anticancer activities. Direct interaction of CLiPs with the cellular membranes is presumed to be essential in causing these. To understand the processes involved at the molecular level, knowledge of the conformation and dynamics of CLiPs at the water-lipid interface is required to guide the interpretation of biophysical investigations in model membrane systems. We used NMR and molecular dynamics to study the conformation, location and orientation of the Pseudomonas CLiP viscosinamide in a water/dodecylphosphocholine solution. In the process, we demonstrate the strong added value of combining uniform, isotope-enriched viscosinamide and protein NMR methods. In particular, the use of techniques to determine backbone dihedral angles and detect and identify long-lived hydrogen bonds, establishes that the solution conformation previously determined in acetonitrile is maintained in water/dodecylphosphocholine solution. Paramagnetic relaxation enhancements pinpoint viscosinamide near the water-lipid interface, with its orientation dictated by the amphipathic distribution of hydrophobic and hydrophilic residues. Finally, the experimental observations are supported by molecular dynamics simulations. Thus a firm structural basis is now available for interpreting biophysical and bioactivity data relating to this class of compounds. Full article

(This article belongs to the Special Issue Cyclic Peptide Analogues and Non-peptide Mimetics)

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Review

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Open AccessReview

Rational Design and Synthesis of AT1R Antagonists

Nikitas Georgiou

Vasileios K. Gkalpinos

Spyridon D. Katsakos

Stamatia Vassiliou

Andreas G. Tzakos

and

Thomas Mavromoustakos

Molecules 2021, 26(10), 2927; https://doi.org/10.3390/molecules26102927 - 14 May 2021

Cited by 2 | Viewed by 1186

Abstract

Hypertension is one of the most common diseases nowadays and is still the major cause of premature death despite of the continuous discovery of novel therapeutics. The discovery of the Renin Angiotensin System (RAS) unveiled a path to develop efficient drugs to fruitfully combat hypertension. Several compounds that prevent the Angiotensin II hormone from binding and activating the AT1R, named sartans, have been developed. Herein, we report a comprehensive review of the synthetic paths followed for the development of different sartans since the discovery of the first sartan, Losartan. Full article

(This article belongs to the Special Issue Cyclic Peptide Analogues and Non-peptide Mimetics)

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