Recent Trends in Cyclic Peptides as Therapeutic Agents

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Biopharmaceuticals".

Deadline for manuscript submissions: 15 April 2024 | Viewed by 12561

Special Issue Editors

Center for Translational Science, Florida International University, Miami, FL, USA
Interests: medicinal chemistry; combinatorial chemistry; peptides; bioengineering
Department of Chemistry and Pharmacy, Friedrich-Alexander-Universität (FAU), Erlangen-Nürnberg, Germany
Interests: medicinal chemistry; peptide chemistry; protein-protein interactions; antiviral peptides; structure-based design

Special Issue Information

Dear Colleagues,

For decades, peptides have been utilized as therapeutic agents. There are currently approximately 80 peptide-based drugs on the global market with over 150 peptides in clinical development. Peptides as therapeutics offer several benefits over traditional small molecules, including high specificity, good efficacy, and good safety profiles. These features are tempered by generally lower membrane permeability, shorter half-life, and lower metabolic stability compared to small molecules. However, the use of a cyclic peptide scaffold provides a proven pathway for overcoming these limitations. In recent years, the application of cyclic peptides as therapeutics and novel probes has continued to advance.

There have been several advances in recent years that have continued to broaden the application of cyclic peptides. For example, the development of combinatorial synthesis techniques as well as display (e.g., phage, DNA, mRNA) libraries has exponentially increased the number and breadth of cyclic peptides available to screen in early drug discovery campaigns. The use of novel cyclization strategies (i.e., stapling) as well as non-canonical amino acids further extends the ability to optimize cyclic peptides for clinical and non-clinical applications. In the past decade, cyclic peptides have been approved for a wide range of uses and indications such as antibiotics, obesity, hypoactive sexual desire disorder, irritable bowel syndrome, and lupus nephritis. Cyclic peptides have also shown promise in a number of preclinical studies, including protein–protein interaction inhibitors. They have also been utilized for cell imaging and as drug conjugates, highlighting their potential broad utility.

In this Special Issue, authors are invited to submit original research and review articles highlighting recent trends in cyclic peptides as novel tools and potential therapeutic agents. 

Dr. Marc A. Giulianotti
Prof. Dr. Jutta Eichler
Guest Editors

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Keywords

  • cyclic peptides
  • cyclic peptide scaffold
  • peptide-based drugs
  • combinatorial peptide libraries
  • stapled peptide
  • phage display
  • protein-protein
  • nonconical amino acids
  • natural products

Published Papers (4 papers)

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Research

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20 pages, 4294 KiB  
Article
Tryptophan Substitution in CJ-15,208 (cyclo[Phe-D-Pro-Phe-Trp]) Introduces δ-Opioid Receptor Antagonism, Preventing Antinociceptive Tolerance and Stress-Induced Reinstatement of Extinguished Cocaine-Conditioned Place Preference
by Kristen H. Scherrer, Shainnel O. Eans, Jessica M. Medina, Sanjeewa N. Senadheera, Tanvir Khaliq, Thomas F. Murray, Jay P. McLaughlin and Jane V. Aldrich
Pharmaceuticals 2023, 16(9), 1218; https://doi.org/10.3390/ph16091218 - 29 Aug 2023
Cited by 1 | Viewed by 1130
Abstract
The macrocyclic tetrapeptide CJ-15,208 (cyclo[Phe-D-Pro-Phe-Trp]) and its D-Trp isomer exhibit kappa opioid receptor (KOR) antagonism which prevents stress-induced reinstatement of extinguished cocaine-conditioned place preference. Here, we evaluated the effects of substitution of Trp and D-Trp on the peptides’ opioid activity, antinociceptive [...] Read more.
The macrocyclic tetrapeptide CJ-15,208 (cyclo[Phe-D-Pro-Phe-Trp]) and its D-Trp isomer exhibit kappa opioid receptor (KOR) antagonism which prevents stress-induced reinstatement of extinguished cocaine-conditioned place preference. Here, we evaluated the effects of substitution of Trp and D-Trp on the peptides’ opioid activity, antinociceptive tolerance, and the ability to prevent relapse to extinguished drug-CPP. Six analogs were synthesized using a combination of solid-phase peptide synthesis and cyclization in solution. The analogs were evaluated in vitro for opioid receptor affinity in radioligand competition binding assays, efficacy in the [35S]GTPγS assay, metabolic stability in mouse liver microsomes, and for opioid activity and selectivity in vivo in the mouse 55 °C warm-water tail-withdrawal assay. Potential liabilities of locomotor impairment, respiratory depression, acute tolerance, and conditioned place preference (CPP) were also assessed in vivo, and the ameliorating effect of analogs on the reinstatement of extinguished cocaine-place preference was assessed. Substitutions of other D-amino acids for D-Trp did not affect (or in one case increased) KOR affinity, while two of the three substitutions of an L-amino acid for Trp decreased KOR affinity. In contrast, all but one substitution increased mu opioid receptor (MOR) affinity in vitro. The metabolic stabilities of the analogs were similar to those of their respective parent peptides, with analogs containing a D-amino acid being much more rapidly metabolized than those containing an L-amino acid in this position. In vivo, CJ-15,208 analogs demonstrated antinociception, although potencies varied over an 80-fold range and the mediating opioid receptors differed by substitution. KOR antagonism was lost for all but the D-benzothienylalanine analog, and the 2′-naphthylalanine analog instead demonstrated significant delta opioid receptor (DOR) antagonism. Introduction of DOR antagonism coincided with reduced acute opioid antinociceptive tolerance and prevented stress-induced reinstatement of extinguished cocaine-CPP. Full article
(This article belongs to the Special Issue Recent Trends in Cyclic Peptides as Therapeutic Agents)
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26 pages, 8067 KiB  
Article
Amphiphilic Cell-Penetrating Peptides Containing Arginine and Hydrophobic Residues as Protein Delivery Agents
by Jonathan Moreno, Khalid Zoghebi, David Salehi, Lois Kim, Sorour Khayyatnejad Shoushtari, Rakesh K. Tiwari and Keykavous Parang
Pharmaceuticals 2023, 16(3), 469; https://doi.org/10.3390/ph16030469 - 22 Mar 2023
Viewed by 1937
Abstract
The entry of proteins through the cell membrane is challenging, thus limiting their use as potential therapeutics. Seven cell-penetrating peptides, designed in our laboratory, were evaluated for the delivery of proteins. Fmoc solid-phase peptide synthesis was utilized for the synthesis of seven cyclic [...] Read more.
The entry of proteins through the cell membrane is challenging, thus limiting their use as potential therapeutics. Seven cell-penetrating peptides, designed in our laboratory, were evaluated for the delivery of proteins. Fmoc solid-phase peptide synthesis was utilized for the synthesis of seven cyclic or hybrid cyclic–linear amphiphilic peptides composed of hydrophobic (tryptophan (W) or 3,3-diphenylalanine (Dip) and positively-charged arginine (R) residues, such as [WR]4, [WR]9, [WWRR]4, [WWRR]5, [(RW)5K](RW)5, [R5K]W7, and [DipR]5. Confocal microscopy was used to screen the peptides as a protein delivery system of model cargo proteins, green and red fluorescein proteins (GFP and RFP). Based on the confocal microscopy results, [WR]9 and [DipR]5 were found to be more efficient among all the peptides and were selected for further studies. [WR]9 (1–10 µM) + protein (GFP and RFP) physical mixture did not show high cytotoxicity (>90% viability) in triple-negative breast cancer cells (MDA-MB-231) after 24 h, while [DipR]5 (1–10 µM) physical mixture with GFP exhibited more than 81% cell viability. Confocal microscopy images revealed internalization of GFP and RFP in MDA-MB-231 cells using [WR]9 (2–10 μM) and [DipR]5 (1–10 µM). Fluorescence-activated cell sorting (FACS) analysis indicated that the cellular uptake of GFP was concentration-dependent in the presence of [WR]9 in MDA-MB-231 cells after 3 h of incubation at 37 °C. The concentration-dependent uptake of GFP and RFP was also observed in the presence of [DipR5] in SK-OV-3 and MDA-MB-231 cells after 3 h of incubation at 37 °C. FACS analysis indicated that the cellular uptake of GFP in the presence of [WR]9 was partially decreased by methyl-β-cyclodextrin and nystatin as endocytosis inhibitors after 3 h of incubation in MDA-MB-231 cells, whereas nystatin and chlorpromazine as endocytosis inhibitors slightly reduced the uptake of GFP in the presence of [DipR]5 after 3 h of incubation in MDA-MB-231. [WR]9 was able to deliver therapeutically relevant proteins (Histone H2A) at different concentrations. These results provide insight into the use of amphiphilic cyclic peptides in the delivery of protein-related therapeutics. Full article
(This article belongs to the Special Issue Recent Trends in Cyclic Peptides as Therapeutic Agents)
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Review

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35 pages, 2819 KiB  
Review
Cyclic Peptides in Pipeline: What Future for These Great Molecules?
by Lia Costa, Emília Sousa and Carla Fernandes
Pharmaceuticals 2023, 16(7), 996; https://doi.org/10.3390/ph16070996 - 12 Jul 2023
Cited by 10 | Viewed by 6945
Abstract
Cyclic peptides are molecules that are already used as drugs in therapies approved for various pharmacological activities, for example, as antibiotics, antifungals, anticancer, and immunosuppressants. Interest in these molecules has been growing due to the improved pharmacokinetic and pharmacodynamic properties of the cyclic [...] Read more.
Cyclic peptides are molecules that are already used as drugs in therapies approved for various pharmacological activities, for example, as antibiotics, antifungals, anticancer, and immunosuppressants. Interest in these molecules has been growing due to the improved pharmacokinetic and pharmacodynamic properties of the cyclic structure over linear peptides and by the evolution of chemical synthesis, computational, and in vitro methods. To date, 53 cyclic peptides have been approved by different regulatory authorities, and many others are in clinical trials for a wide diversity of conditions. In this review, the potential of cyclic peptides is presented, and general aspects of their synthesis and development are discussed. Furthermore, an overview of already approved cyclic peptides is also given, and the cyclic peptides in clinical trials are summarized. Full article
(This article belongs to the Special Issue Recent Trends in Cyclic Peptides as Therapeutic Agents)
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21 pages, 2590 KiB  
Review
Cyclic Peptides with Antifungal Properties Derived from Bacteria, Fungi, Plants, and Synthetic Sources
by Naiera M. Helmy and Keykavous Parang
Pharmaceuticals 2023, 16(6), 892; https://doi.org/10.3390/ph16060892 - 18 Jun 2023
Cited by 6 | Viewed by 1759
Abstract
Fungal infections remain a significant concern for human health. The emergence of microbial resistance, the improper use of antimicrobial drugs, and the need for fewer toxic antifungal treatments in immunocompromised patients have sparked substantial interest in antifungal research. Cyclic peptides, classified as antifungal [...] Read more.
Fungal infections remain a significant concern for human health. The emergence of microbial resistance, the improper use of antimicrobial drugs, and the need for fewer toxic antifungal treatments in immunocompromised patients have sparked substantial interest in antifungal research. Cyclic peptides, classified as antifungal peptides, have been in development as potential antifungal agents since 1948. In recent years, there has been growing attention from the scientific community to explore cyclic peptides as a promising strategy for combating antifungal infections caused by pathogenic fungi. The identification of antifungal cyclic peptides from various sources has been possible due to the widespread interest in peptide research in recent decades. It is increasingly important to evaluate narrow- to broad-spectrum antifungal activity and the mode of action of synthetic and natural cyclic peptides for both synthesized and extracted peptides. This short review aims to highlight some of the antifungal cyclic peptides isolated from bacteria, fungi, and plants. This brief review is not intended to present an exhaustive catalog of all known antifungal cyclic peptides but rather seeks to showcase selected cyclic peptides with antifungal properties that have been isolated from bacteria, fungi, plants, and synthetic sources. The addition of commercially available cyclic antifungal peptides serves to corroborate the notion that cyclic peptides can serve as a valuable source for the development of antifungal drugs. Additionally, this review discusses the potential future of utilizing combinations of antifungal peptides from different sources. The review underscores the need for the further exploration of the novel antifungal therapeutic applications of these abundant and diverse cyclic peptides. Full article
(This article belongs to the Special Issue Recent Trends in Cyclic Peptides as Therapeutic Agents)
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