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Peptides in Chemical Biology and Drug Discovery
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Peptides in Chemical Biology and Drug Discovery

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

Deadline for manuscript submissions: closed (31 May 2019) | Viewed by 27127

Special Issue Editors

Prof. Dr. Steven L. Cobb

E-Mail Website
Guest Editor
Department of Chemistry, Durham University, South Road, Durham DH1 3LE, UK
Interests: chemical biology of peptides; organic synthesis; peptide and peptoid chemistry; bio-organic fluorine chemistry; bio-conjugation; drug target validation; infectious diseases and neglected tropical diseases
Special Issues, Collections and Topics in MDPI journals
Dr. Albert Isidro-Llobet

E-Mail Website
Guest Editor
GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, UK
Interests: peptide synthesis; organic chemistry; chemical biology; drug discovery; medicinal chemistry; drug target validation; peptide therapeutics; green chemistry

Special Issue Information

Dear Colleagues,

Peptides are biological molecules with wide-ranging applications in the fields of both chemical biology and drug discovery. Peptides can provide valuable tools for the interrogation of complex biological and cellular process, and naturally occurring peptides often provide inspiration for the design and development of novel drug candidates against a wide range of diseases.

Advances in synthetic methodology (e.g., stapling and cyclisation strategies) and site-selective amino acid modification and conjugation have greatly aided in the development of peptides in many of the aforementioned areas. For example, advances in peptide bio-conjugation strategies have helped design new systems for targeted intracellular drug delivery. Similarly, new cyclisation strategies have allowed more complex peptide scaffolds to be accessed and have also helped researchers overcome the inherently poor pharmacokinetic properties associated with many peptides.

Recent advances in the application of peptides and peptide-based systems in the fields of chemical biology and drug discovery are welcomed for inclusion in this Special Issue for Molecules.

Assoc. Prof. Steven L. Cobb
Dr. Albert Isidro-Llobet
Guest Editors

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 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

  • Peptide synthesis
  • Peptide natural products
  • Peptide based drug delivery
  • Synthesis of novel amino acids
  • Site-selective peptide modification
  • Peptide bio-conjugation strategies
  • Peptide stapling and cyclisation
  • Peptide inhibitors of protein-protein interactions
  • Peptide therapeutics
  • Peptide drug conjugates
  • Peptide ligands in PROTAC design

Published Papers (6 papers)

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Research

16 pages, 2311 KiB  
Article
Cyclic Peptides Acting as Allosteric Inhibitors of Human Thymidylate Synthase and Cancer Cell Growth
by Salvatore Pacifico, Matteo Santucci, Rosaria Luciani, Puneet Saxena, Pasquale Linciano, Glauco Ponterini, Angela Lauriola, Domenico D’Arca, Gaetano Marverti, Remo Guerrini and Maria Paola Costi
Molecules 2019, 24(19), 3493; https://doi.org/10.3390/molecules24193493 - 26 Sep 2019
Cited by 4 | Viewed by 2795
Abstract
Thymidylate synthase (TS) is a prominent drug target for different cancer types. However, the prolonged use of its classical inhibitors, substrate analogs that bind at the active site, leads to TS overexpression and drug resistance in the clinic. In the effort to identify [...] Read more.
Thymidylate synthase (TS) is a prominent drug target for different cancer types. However, the prolonged use of its classical inhibitors, substrate analogs that bind at the active site, leads to TS overexpression and drug resistance in the clinic. In the effort to identify anti-TS drugs with new modes of action and able to overcome platinum drug resistance in ovarian cancer, octapeptides with a new allosteric inhibition mechanism were identified as cancer cell growth inhibitors that do not cause TS overexpression. To improve the biological properties, 10 cyclic peptides (cPs) were designed from the lead peptides and synthesized. The cPs were screened for the ability to inhibit recombinant human thymidylate synthase (hTS), and peptide 7 was found to act as an allosteric inhibitor more potent than its parent open-chain peptide [Pro3]LR. In cytotoxicity studies on three human ovarian cancer cell lines, IGROV-1, A2780, and A2780/CP, peptide 5 and two other cPs, including 7, showed IC50 values comparable with those of the reference drug 5-fluorouracil, of the open-chain peptide [d-Gln4]LR, and of another seven prolyl derivatives of the lead peptide LR. These promising results indicate cP 7 as a possible lead compound to be chemically modified with the aim of improving both allosteric TS inhibitory activity and anticancer effectiveness. Full article
(This article belongs to the Special Issue Peptides in Chemical Biology and Drug Discovery)
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12 pages, 2732 KiB  
Communication
Cyclic Peptide-Based Sirtuin Substrates
by Di Chen, Lingling Yan and Weiping Zheng
Molecules 2019, 24(3), 424; https://doi.org/10.3390/molecules24030424 - 24 Jan 2019
Viewed by 2851
Abstract
In the current study, four side chain-to-side chain cyclic peptides (three 5-mers and one 4-mer) harboring Nε-acetyl-lysine or Nε-myristoyl-lysine were found to be in vitro substrates of the human SIRT1/2/3-catalyzed deacylation with good substrate activities, as judged by the kcat/KM ratios. Full article
(This article belongs to the Special Issue Peptides in Chemical Biology and Drug Discovery)
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11 pages, 1455 KiB  
Article
Design, Synthesis, and Evaluation of Amphiphilic Cyclic and Linear Peptides Composed of Hydrophobic and Positively-Charged Amino Acids as Antibacterial Agents
by Neda Riahifard, Saghar Mozaffari, Taibah Aldakhil, Francisco Nunez, Qamar Alshammari, Saud Alshammari, Jason Yamaki, Keykavous Parang and Rakesh Kumar Tiwari
Molecules 2018, 23(10), 2722; https://doi.org/10.3390/molecules23102722 - 22 Oct 2018
Cited by 27 | Viewed by 5721
Abstract
Antimicrobial peptides (AMPs) contain amphipathic structures and are derived from natural resources. AMPs have been found to be effective in treating the infections caused by antibiotic-resistant bacteria (ARB), and thus, are potential lead compounds against ARB. AMPs’ physicochemical properties, such as cationic nature, [...] Read more.
Antimicrobial peptides (AMPs) contain amphipathic structures and are derived from natural resources. AMPs have been found to be effective in treating the infections caused by antibiotic-resistant bacteria (ARB), and thus, are potential lead compounds against ARB. AMPs’ physicochemical properties, such as cationic nature, amphiphilicity, and their size, will provide the opportunity to interact with membrane bilayers leading to damage and death of microorganisms. Herein, AMP analogs of [R4W4] were designed and synthesized by changing the hydrophobicity and cationic nature of the lead compound with other amino acids to provide insights into a structure-activity relationship against selected model Gram-negative and Gram-positive pathogens. Clinical resistant strains of methicillin-resistant Staphylococcus aureus (MRSA) and Escherichia coli (E. coli) were used in the studies. Our results provided information about the structural requirements for optimal activity of the [R4W4] template. When tryptophan was replaced with other hydrophobic amino acids, such as phenylalanine, tyrosine, alanine, leucine, and isoleucine, the antibacterial activities were significantly reduced with MIC values of >128 µg/mL. Furthermore, a change in stereochemistry caused by d-arginine, and use of N-methyltryptophan, resulted in a two-fold reduction of antibacterial activity. It was found that the presence of tryptophan is critical for antibacterial activity, and could not be substituted with other hydrophobic residues. The study also confirmed that cyclic peptides generally showed higher antibacterial activities when compared with the corresponding linear counterparts. Furthermore, by changing tryptophan numbers in the compound while maintaining a constant number of arginine, we determined the optimal number of tryptophan residues to be four, as shown when the number of tryptophan residues increased, a decrease in activity was observed. Full article
(This article belongs to the Special Issue Peptides in Chemical Biology and Drug Discovery)
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16 pages, 4214 KiB  
Article
Application of Neurokinin-1 Receptor in Targeted Strategies for Glioma Treatment. Part I: Synthesis and Evaluation of Substance P Fragments Labeled with 99mTc and 177Lu as Potential Receptor Radiopharmaceuticals
by Agnieszka Majkowska-Pilip, Przemysław Koźmiński, Anna Wawrzynowska, Tadeusz Budlewski, Bogusław Kostkiewicz and Ewa Gniazdowska
Molecules 2018, 23(10), 2542; https://doi.org/10.3390/molecules23102542 - 05 Oct 2018
Cited by 10 | Viewed by 3135
Abstract
Gliomas, particularly WHO grade IV glioblastoma multiforme, are one of the most common and aggressive primary tumors of the central nervous system. The neuropeptide, substance P (SP), is the physiological ligand of the neurokinin-1 (NK-1) receptor that is consistently overexpressed in glioblastoma cells. [...] Read more.
Gliomas, particularly WHO grade IV glioblastoma multiforme, are one of the most common and aggressive primary tumors of the central nervous system. The neuropeptide, substance P (SP), is the physiological ligand of the neurokinin-1 (NK-1) receptor that is consistently overexpressed in glioblastoma cells. The aim of this work was to study physico-chemical and biological properties of different SP analogues labeled with technetium-99m and lutetium-177 radionuclides. The synthesized compounds were characterized in vitro by partition coefficients (logP) and their stability was investigated in various physiological solutions. Biological properties (Kd, Bmax) were characterized using the U373 MG cell line. The obtained lipophilicity values of the [99mTc]NS3/CN-SP and [177Lu]DOTA-SP radiobioconjugates were in the range of −0.3 to +0.6 and −2.5 to −5.0, respectively. The studied radiobioconjugates were stable in PBS buffer and CSF, as well as in 10 mM histidine and/or cysteine solutions whereas in human serum showed enzymatic biodegradation. [177Lu]DOTA-[Thi8,Met(O2)11]SP(1–11), [177Lu]DOTA-SP(4–11) and [177Lu]DOTA-[Thi8,Met(O2)11]SP(5–11) radiobioconjugates bound specifically to NK-1 receptors expressed on glioblastoma cells with affinity in the nanomolar range. To conclude, the shorter analogues of SP can be used as vectors, nevertheless they still do not fulfil all requirements for preparations in nuclear medicine. Full article
(This article belongs to the Special Issue Peptides in Chemical Biology and Drug Discovery)
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23 pages, 6873 KiB  
Article
d-Amino Acid Pseudopeptides as Potential Amyloid-Beta Aggregation Inhibitors
by Banafsheh Mehrazma, Stanley Opare, Anahit Petoyan and Arvi Rauk
Molecules 2018, 23(9), 2387; https://doi.org/10.3390/molecules23092387 - 18 Sep 2018
Cited by 9 | Viewed by 4232
Abstract
A causative factor for neurotoxicity associated with Alzheimer’s disease is the aggregation of the amyloid-β (Aβ) peptide into soluble oligomers. Two all d-amino acid pseudo-peptides, SGB1 and SGD1, were designed to stop the aggregation. Molecular dynamics (MD) simulations have been carried out [...] Read more.
A causative factor for neurotoxicity associated with Alzheimer’s disease is the aggregation of the amyloid-β (Aβ) peptide into soluble oligomers. Two all d-amino acid pseudo-peptides, SGB1 and SGD1, were designed to stop the aggregation. Molecular dynamics (MD) simulations have been carried out to study the interaction of the pseudo-peptides with both Aβ13–23 (the core recognition site of Aβ) and full-length Aβ1–42. Umbrella sampling MD calculations have been used to estimate the free energy of binding, ∆G, of these peptides to Aβ13–23. The highest ∆Gbinding is found for SGB1. Each of the pseudo-peptides was also docked to Aβ1–42 and subjected up to seven microseconds of all atom molecular dynamics simulations. The resulting structures lend insight into how the dynamics of Aβ1–42 are altered by complexation with the pseudo-peptides and confirmed that SGB1 may be a better candidate for developing into a drug to prevent Alzheimer’s disease. Full article
(This article belongs to the Special Issue Peptides in Chemical Biology and Drug Discovery)
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13 pages, 3045 KiB  
Article
Identification of Nucleophilic Probes for Protease-Mediated Transpeptidation
by Ga-eul Eom and Seokhee Kim
Molecules 2018, 23(9), 2109; https://doi.org/10.3390/molecules23092109 - 22 Aug 2018
Cited by 1 | Viewed by 7452
Abstract
Proteases have evolved to mediate the hydrolysis of peptide bonds but may perform transpeptidation in the presence of a proper nucleophilic molecule that can effectively compete with water to react with the acyl-enzyme intermediate. There have been several examples of protease-mediated transpeptidation, but [...] Read more.
Proteases have evolved to mediate the hydrolysis of peptide bonds but may perform transpeptidation in the presence of a proper nucleophilic molecule that can effectively compete with water to react with the acyl-enzyme intermediate. There have been several examples of protease-mediated transpeptidation, but they are generally inefficient, and little effort has been made to systematically control the transpeptidation activity of other proteases with good nucleophiles. Here, we developed an on-bead screening approach to find a probe that functions efficiently as a nucleophile in the protease-mediated transpeptidation reaction, and we identified good probes for a model protease DegP. These probes were covalently linked to the C-termini of the cleaved peptides in a mild condition and made the selective enrichment of ligated peptides possible. We suggest that good nucleophilic probes can be found for many other proteases that act via acyl-enzyme intermediates, and these probes will help characterize their substrates. Full article
(This article belongs to the Special Issue Peptides in Chemical Biology and Drug Discovery)
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