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Making Bioactive Peptides Druggable – Challenges and Prospects

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pharmacology".

Deadline for manuscript submissions: closed (31 July 2021) | Viewed by 14838

Special Issue Editors


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Guest Editor

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Co-Guest Editor
LAQV-REQUIMTE, Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade do Porto, Porto, Portugal
Interests: antimicrobial agents; antiparasitic agents; computational chemistry; heterocycle chemistry; peptide-based biopesticides; peptide synthesis
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Special Issue Information

Dear Colleagues,

The growing relevance of peptides in many areas of industrial and academic R&D is undeniable. Peptides have been explored in the most diverse fields, from molecular biology to materials science, from synthetic chemistry to computational and structural biology, from food science to biotechnology, from early drug discovery to clinics. The huge potential of bioactive peptides, especially, but not exclusively, for therapeutic applications, has been a major driving force for the development of robust chemical methods for peptide synthesis in the second half of the 20th century, with Merrifield’s solid-phase peptide synthesis (SPPS) emerging in the 1960s as the most revolutionary achievement. At present, researchers have easy access to a panoply of building blocks, as well as chemical and synthetic biology approaches to produce the most diverse peptides and peptidomimetics. Yet, two decades have passed in the 21st century and there is still one major obstacle to be overcome if the clinical translation of bioactive peptides is to become a trivial matter: making bioactive peptides druggable. Abolishing the well-known limitations of bioactive peptides as therapeutics, mostly due to their poor pharmacokinetics, is currently a top-priority for peptide scientists worldwide. As such, we invite all those working or interested in this particular field of research to contribute to this Special Issue, which will be an up-to-date collection of works, either original or literature reviews, focused on the current challenges, approaches, and prospects towards the improvement of peptide pharmacokinetics.

Prof. Dr. Paula A. C. Gomes
Guest Editor
Dr. Cátia Teixeira
Co-Guest Editor

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Keywords

  • peptide druggability
  • peptide pharmacokinetics
  • clinical translation of peptides
  • peptide analogs
  • peptidomimetics
  • peptide nanoencapsulation approaches
  • cyclic peptides
  • stapled peptides

Published Papers (5 papers)

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Research

17 pages, 3482 KiB  
Article
Identification of a Steric Zipper Motif in the Amyloidogenic Core of Human Cystatin C and Its Use for the Design of Self-Assembling Peptides
by Emilia Iłowska, Jakub Barciszewski, Mariusz Jaskólski, Augustyn Moliński, Maciej Kozak and Aneta Szymańska
Int. J. Mol. Sci. 2022, 23(10), 5800; https://doi.org/10.3390/ijms23105800 - 22 May 2022
Cited by 1 | Viewed by 1809
Abstract
Amyloid fibrils have been known for many years. Unfortunately, their fame stems from negative aspects related to amyloid diseases. Nevertheless, due to their properties, they can be used as interesting nanomaterials. Apart from their remarkable stability, amyloid fibrils may be regarded as a [...] Read more.
Amyloid fibrils have been known for many years. Unfortunately, their fame stems from negative aspects related to amyloid diseases. Nevertheless, due to their properties, they can be used as interesting nanomaterials. Apart from their remarkable stability, amyloid fibrils may be regarded as a kind of a storage medium and as a source of active peptides. In many cases, their structure may guarantee a controlled and slow release of peptides in their active form; therefore, they can be used as a potential nanomaterial in drug delivery systems. In addition, amyloid fibrils display controllable stiffness, flexibility, and satisfactory mechanical strength. In addition, they can be modified and functionalized very easily. Understanding the structure and genesis of amyloid assemblies derived from a broad range of amyloidogenic proteins could help to better understand and use this unique material. One of the factors responsible for amyloid aggregation is the steric zipper. Here, we report the discovery of steric zipper-forming peptides in the sequence of the amyloidogenic protein, human cystatin C (HCC). The ability of short peptides derived from this fragment of HCC to form fibrillar structures with defined self-association characteristics and the factors influencing this aggregation are also presented in this paper. Full article
(This article belongs to the Special Issue Making Bioactive Peptides Druggable – Challenges and Prospects)
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20 pages, 3579 KiB  
Article
Whey-Derived Peptides at the Heart of the COVID-19 Pandemic
by Yara Chamata, Kim G. Jackson, Kimberly A. Watson and Paula Jauregi
Int. J. Mol. Sci. 2021, 22(21), 11662; https://doi.org/10.3390/ijms222111662 - 28 Oct 2021
Cited by 4 | Viewed by 3704
Abstract
The renin–angiotensin system (RAS) is a key regulator of blood pressure and hypertension. Angiotensin-converting enzyme 2 (ACE2) and angiotensin-converting enzyme I (ACE) are two main components of the RAS that play a major role in blood pressure homeostasis. The severe acute respiratory syndrome [...] Read more.
The renin–angiotensin system (RAS) is a key regulator of blood pressure and hypertension. Angiotensin-converting enzyme 2 (ACE2) and angiotensin-converting enzyme I (ACE) are two main components of the RAS that play a major role in blood pressure homeostasis. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses ACE2 as a receptor to enter cells. Despite some controversies, numerous studies have reported a significant association between the use of ACE inhibitors and reduced risk of COVID-19. In our previous studies, we produced and identified peptide sequences present in whey hydrolysates exhibiting high ACE inhibitory activity. Therefore, the aim of this work is to obtain an improved understanding of the function of these natural peptides as RAS inhibitors and investigate their potential therapeutic role in the COVID-19 pandemic. The molecular interactions between peptides IPP, LIVTQ, IIAE, LVYPFP, and human ACE2 were assessed by employing a molecular docking approach. The results show that natural whey-derived peptides have a dual inhibitory action against both ACE and ACE2. This dual activity distinguishes these ACE inhibitory peptides from synthetic drugs, such as Captopril and Lisinopril which were not shown to inhibit ACE2 activity, and may represent a potential strategy in the treatment of COVID-19. Full article
(This article belongs to the Special Issue Making Bioactive Peptides Druggable – Challenges and Prospects)
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13 pages, 1466 KiB  
Article
Improving the Utility of a Dynorphin Peptide Analogue Using Mannosylated Glycoliposomes
by Jordan D. Lewicky, Nya L. Fraleigh, Alexandrine L. Martel, Thi M.-D. Nguyen, Peter W. Schiller, Leila Mousavifar, René Roy, Anh Dzung Le, Douglas Funk and Hoang-Thanh Le
Int. J. Mol. Sci. 2021, 22(15), 7996; https://doi.org/10.3390/ijms22157996 - 27 Jul 2021
Cited by 5 | Viewed by 2347
Abstract
Peptide therapeutics offer numerous advantages in the treatment of diseases and disorders of the central nervous system (CNS). However, they are not without limitations, especially in terms of their pharmacokinetics where their metabolic lability and low blood–brain barrier penetration hinder their application. Targeted [...] Read more.
Peptide therapeutics offer numerous advantages in the treatment of diseases and disorders of the central nervous system (CNS). However, they are not without limitations, especially in terms of their pharmacokinetics where their metabolic lability and low blood–brain barrier penetration hinder their application. Targeted nanoparticle delivery systems are being tapped for their ability to improve the delivery of therapeutics into the brain non-invasively. We have developed a family of mannosylated glycoliposome delivery systems for targeted drug delivery applications. Herein, we demonstrate via in vivo distribution studies the potential of these glycoliposomes to improve the utility of CNS active therapeutics using dynantin, a potent and selective dynorphin peptide analogue antagonist of the kappa opioid receptor (KOR). Glycoliposomal entrapment protected dynantin against known rapid metabolic degradation and ultimately improved brain levels of the peptide by approximately 3–3.5-fold. Moreover, we linked this improved brain delivery with improved KOR antagonist activity by way of an approximately 30–40% positive modulation of striatal dopamine levels 20 min after intranasal administration. Overall, the results clearly highlight the potential of our glycoliposomes as a targeted delivery system for therapeutic agents of the CNS. Full article
(This article belongs to the Special Issue Making Bioactive Peptides Druggable – Challenges and Prospects)
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25 pages, 6829 KiB  
Article
Functionalized Peptide Fibrils as a Scaffold for Active Substances in Wound Healing
by Justyna Sawicka, Emilia Iłowska, Milena Deptuła, Paweł Sosnowski, Piotr Sass, Katarzyna Czerwiec, Klaudia Chmielewska, Aneta Szymańska, Zuzanna Pietralik-Molińska, Maciej Kozak, Paweł Sachadyn, Michał Pikuła and Sylwia Rodziewicz-Motowidło
Int. J. Mol. Sci. 2021, 22(8), 3818; https://doi.org/10.3390/ijms22083818 - 07 Apr 2021
Cited by 5 | Viewed by 2941
Abstract
Technological developments in the field of biologically active peptide applications in medicine have increased the need for new methods for peptide delivery. The disadvantage of peptides as drugs is their low biological stability. Recently, great attention has been paid to self-assembling peptides that [...] Read more.
Technological developments in the field of biologically active peptide applications in medicine have increased the need for new methods for peptide delivery. The disadvantage of peptides as drugs is their low biological stability. Recently, great attention has been paid to self-assembling peptides that can form fibrils. Such a formulation makes bioactive peptides more resistant to enzymatic degradation and druggable. Peptide fibrils can be carriers for peptides with interesting biological activities. These features open up prospects for using the peptide fibrils as long-acting drugs and are a valid alternative to conventional peptidic therapies. In our study, we designed new peptide scaffolds that are a hybrid of three interconnected amino acid sequences and are: pro-regenerative, cleavable by neutrophilic elastase, and fibril-forming. We intended to obtain peptides that are stable in the wound environment and that, when applied, would release a biologically active sequence. Our studies showed that the designed hybrid peptides show a high tendency toward regular fibril formation and are able to release the pro-regenerative sequence. Cytotoxicity studies showed that all the designed peptides were safe, did not cause cytotoxic effects and revealed a pro-regenerative potential in human fibroblast and keratinocyte cell lines. In vivo experiments in a dorsal skin injury model in mice indicated that two tested peptides moderately promote tissue repair in their free form. Our research proves that peptide fibrils can be a druggable form and a scaffold for active peptides. Full article
(This article belongs to the Special Issue Making Bioactive Peptides Druggable – Challenges and Prospects)
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21 pages, 9015 KiB  
Article
Urea-Peptide Hybrids as VEGF-A165/NRP-1 Complex Inhibitors with Improved Receptor Affinity and Biological Properties
by Anna K. Puszko, Piotr Sosnowski, Rachel Rignault-Bricard, Olivier Hermine, Gérard Hopfgartner, Karolina Pułka-Ziach, Yves Lepelletier and Aleksandra Misicka
Int. J. Mol. Sci. 2021, 22(1), 72; https://doi.org/10.3390/ijms22010072 - 23 Dec 2020
Cited by 9 | Viewed by 3029
Abstract
Neuropilin-1 (NRP-1), the major co-receptor of vascular endothelial growth factor receptor-2 (VEGFR-2), may also independently act with VEGF-A165 to stimulate tumour growth and metastasis. Therefore, there is great interest in compounds that can block VEGF-A165/NRP-1 interaction. Peptidomimetic type inhibitors represent a promising [...] Read more.
Neuropilin-1 (NRP-1), the major co-receptor of vascular endothelial growth factor receptor-2 (VEGFR-2), may also independently act with VEGF-A165 to stimulate tumour growth and metastasis. Therefore, there is great interest in compounds that can block VEGF-A165/NRP-1 interaction. Peptidomimetic type inhibitors represent a promising strategy in the treatment of NRP-1-related disorders. Here, we present the synthesis, affinity, enzymatic stability, molecular modeling and in vitro binding evaluation of the branched urea–peptide hybrids, based on our previously reported Lys(hArg)-Dab-Oic-Arg active sequence, where the Lys(hArg) branching has been modified by introducing urea units to replace the peptide bond at various positions. One of the resulting hybrids increased the affinity of the compound for NRP-1 more than 10-fold, while simultaneously improving resistance for proteolytic stability in serum. In addition, ligand binding to NRP-1 induced rapid protein stock exocytotic trafficking to the plasma membrane in breast cancer cells. Examined properties characterize this compound as a good candidate for further development of VEGF165/NRP-1 inhibitors. Full article
(This article belongs to the Special Issue Making Bioactive Peptides Druggable – Challenges and Prospects)
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