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New Insights into Bioactive Peptides: Design, Synthesis, Structure-Activity Relationship (2nd Edition)

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

Deadline for manuscript submissions: 25 August 2025 | Viewed by 7177

Special Issue Editors

Dr. Marilisa Leone

E-Mail Website
Guest Editor
Institute of Biostructures and Bioimaging (IBB), National Research Council of Italy (CNR), Via Mezzocannone 16, 80134 Naples, Italy
Interests: structural biology; NMR; drug discovery; conformational analysis of proteins and peptides; protein–protein interactions (PPIs); design and evaluation of PPI inhibitors; structure-based drug design; molecular modeling; docking; cancer
Special Issues, Collections and Topics in MDPI journals
Dr. Flavia Anna Mercurio

E-Mail Website
Guest Editor
CNR-IBB (National Research Council-Institute of Biostructures and Bioimaging), Via Tommaso De Amicis 95, Naples, Italy
Interests: structural biology; NMR; drug discovery; conformational analysis of proteins and peptides; protein–protein interactions (PPIs); design and evaluation of PPI inhibitors; structure-based drug design; molecular modeling; docking
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Peptides consist of amino acids linked by covalent bonds similarly to proteins but with a shorter chain. Synthetic and natural peptides may hold interesting biological functions and consequently they have aroused increasing attention in drug design/drug discovery research fields. Peptide sequences may reflect proteins spots responsible for molecular recognition and biological activities, thus can act as enzyme inhibitors or protein-protein interaction modulators and interfere with signaling pathways. Peptides may possess therapeutic potential and be employed to set-up original therapies in alternative to small molecules and protein drugs due to their unique features of potency, specificity, and low toxicity profile. Since the discovery of Insulin for diabetes treatment, peptide drugs have been implemented to treat a wide range of diseases, including cancer, osteoporosis, multiple sclerosis, HIV infection and chronic pain. Moreover, peptides can play a supporting role in disease diagnosis and drug delivery. As peptides may be affected by high protease sensitivity and defective pharmacokinetics, different chemical strategies have been proposed for overcoming these issues, such as peptide stapling and cyclization and peptidomimetics design. Several computational tools have been also devoted to peptide ligand design and screening against biological macromolecular targets, and peptide structure manipulation.

The present Special Issue aims to cover the above-described topics by means of contributions (communication, full papers and reviews) particularly focused on innovative experimental and computational approaches towards the development of bioactive peptides.

Dr. Marilisa Leone
Dr. Flavia Anna Mercurio
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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

  • peptides
  • protein-peptide interactions
  • PPI inhibition and modulation
  • peptide drugs
  • peptidomimetics
  • cyclic peptides
  • stapled peptides
  • diagnostic peptides
  • peptides for drug delivery
  • multidisciplinary approaches
 

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Related Special Issue

Published Papers (6 papers)

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Research

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23 pages, 18738 KiB  
Article
Interaction Between Glucagon-like Peptide 1 and Its Analogs with Amyloid-β Peptide Affects Its Fibrillation and Cytotoxicity
by Ekaterina A. Litus, Marina P. Shevelyova, Alisa A. Vologzhannikova, Evgenia I. Deryusheva, Alina V. Chaplygina, Victoria A. Rastrygina, Andrey V. Machulin, Valeria D. Alikova, Aliya A. Nazipova, Maria E. Permyakova, Victor V. Dotsenko, Sergei E. Permyakov and Ekaterina L. Nemashkalova
Int. J. Mol. Sci. 2025, 26(9), 4095; https://doi.org/10.3390/ijms26094095 - 25 Apr 2025
Viewed by 139
Abstract
Clinical data as well as animal and cell studies indicate that certain antidiabetic drugs, including glucagon-like peptide 1 receptor agonists (GLP-1RAs), exert therapeutic effects in Alzheimer’s disease (AD) by modulating amyloid-β peptide (Aβ) metabolism. Meanwhile, the direct interactions between GLP-1RAs and Aβ and [...] Read more.
Clinical data as well as animal and cell studies indicate that certain antidiabetic drugs, including glucagon-like peptide 1 receptor agonists (GLP-1RAs), exert therapeutic effects in Alzheimer’s disease (AD) by modulating amyloid-β peptide (Aβ) metabolism. Meanwhile, the direct interactions between GLP-1RAs and Aβ and their functional consequences remain unexplored. In this study, the interactions between monomeric Aβ40/Aβ42 of GLP-1(7-37) and its several analogs (semaglutide (Sema), liraglutide (Lira), exenatide (Exen)) were studied using biolayer interferometry and surface plasmon resonance spectroscopy. The quaternary structure of GLP-1RAs was investigated using dynamic light scattering. The effects of GLP-1RAs on Aβ fibrillation were assessed using the thioflavin T assay and electron microscopy. The impact of GLP-1RAs on Aβ cytotoxicity was evaluated via the MTT assay. Monomeric Aβ40 and Aβ42 directly bind to GLP-1(7-37), Sema, Lira, and Exen, with the highest affinity for Lira (the lowest estimates of equilibrium dissociation constants were 42–60 nM). GLP-1RAs are prone to oligomerization, which may affect their binding to Aβ. GLP-1(7-37) and Exen inhibit Aβ40 fibrillation, whereas Sema promotes it. GLP-1 analogs decrease Aβ cytotoxicity toward SH-SY5Y cells, while GLP-1(7-37) enhances Aβ40 cytotoxicity without affecting the cytotoxic effect of Aβ42. Overall, GLP-1RAs interact with Aβ and differentially modulate its fibrillation and cytotoxicity, suggesting the need for further studies of our observed effects in vivo. Full article
(This article belongs to the Special Issue New Insights into Bioactive Peptides: Design, Synthesis, Structure-Activity Relationship (2nd Edition))
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16 pages, 2198 KiB  
Article
Inhibitory Effects of Gliadin Hydrolysates on BACE1 Expression and APP Processing to Prevent Aβ Aggregation
by Chin-Yu Lin, Cheng-Hong Hsieh, Pei-Yu Lai, Ching-Wei Huang, Yung-Hui Chung, Shang-Ming Huang and Kuo-Chiang Hsu
Int. J. Mol. Sci. 2024, 25(23), 13212; https://doi.org/10.3390/ijms252313212 - 9 Dec 2024
Cited by 1 | Viewed by 1067
Abstract
Alzheimer’s disease (AD), a leading neurodegenerative disorder, is closely associated with the accumulation of amyloid-beta (Aβ) peptides in the brain. The enzyme β-secretase (BACE1), pivotal in Aβ production, represents a promising therapeutic target for AD. While bioactive peptides derived from food protein hydrolysates [...] Read more.
Alzheimer’s disease (AD), a leading neurodegenerative disorder, is closely associated with the accumulation of amyloid-beta (Aβ) peptides in the brain. The enzyme β-secretase (BACE1), pivotal in Aβ production, represents a promising therapeutic target for AD. While bioactive peptides derived from food protein hydrolysates have neuroprotective properties, their inhibitory effects on BACE1 remain largely unexplored. In this study, we evaluated the inhibitory potential of protein hydrolysates from gliadin, whey, and casein proteins prepared using bromelain, papain, and thermolysin. Through in vitro and cellular assays, bromelain-hydrolyzed gliadin (G-Bro) emerged as the most potent BACE1 inhibitor, with an IC50 of 0.408 mg/mL. G-Bro significantly reduced BACE1 expression and amyloid precursor protein (APP) processing in N2a/PS/APP cell cultures, suggesting its potential to attenuate Aβ aggregation. The unique peptide profile of G-Bro likely contributes to its inhibitory effect, with proline residues disrupting β-sheets, lysine residues introducing positive charges that hinder aggregation, hydrophobic residues stabilizing binding interactions, and glutamine residues enhancing solubility and stability. These findings highlight gliadin hydrolysates, particularly G-Bro, as potential natural BACE1 inhibitors with applications in dietary interventions for AD prevention. However, further studies are warranted to elucidate specific peptide interactions and their bioactivity in neural pathways to better understand their therapeutic potential. Full article
(This article belongs to the Special Issue New Insights into Bioactive Peptides: Design, Synthesis, Structure-Activity Relationship (2nd Edition))
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15 pages, 3797 KiB  
Article
In Silico Hydrolysis of Lupin (Lupinus angustifolius L.) Conglutins with Plant Proteases Releases Antihypertensive and Antidiabetic Peptides That Are Bioavailable, Non-Toxic, and Gastrointestinal Digestion Stable
by Jesús Gilberto Arámburo-Gálvez, Raúl Tinoco-Narez-Gil, José Antonio Mora-Melgem, Cesar Antonio Sánchez-Cárdenas, Martina Hilda Gracia-Valenzuela, Lilian Karem Flores-Mendoza, Oscar Gerardo Figueroa-Salcido and Noé Ontiveros
Int. J. Mol. Sci. 2024, 25(23), 12866; https://doi.org/10.3390/ijms252312866 - 29 Nov 2024
Viewed by 966
Abstract
Lupin (Lupinus angustifolius L.) proteins are potential sources of bioactive peptides (LBPs) that can inhibit dipeptidyl peptidase IV (DPP-IV) and angiotensin I-converting enzyme (ACE-I) activity. However, the capacity of different enzymes to release LBPs, the pharmacokinetic and bioactivities of the peptides released, [...] Read more.
Lupin (Lupinus angustifolius L.) proteins are potential sources of bioactive peptides (LBPs) that can inhibit dipeptidyl peptidase IV (DPP-IV) and angiotensin I-converting enzyme (ACE-I) activity. However, the capacity of different enzymes to release LBPs, the pharmacokinetic and bioactivities of the peptides released, and their binding affinities with the active sites of DPP-IV and ECA-I are topics scarcely addressed. Therefore, we used in silico hydrolysis (BIOPEP-UWM platform) with various enzymes to predict the release of LBPs. Among the bioactive peptides identified in lupin proteins (n = 4813), 2062 and 1558 had DPP-IV and ACE-I inhibitory activity, respectively. Ficin, bromelain, and papain released the highest proportion of ACE-I (n = 433, 411, and 379, respectively) and DPP-IV (n = 556, 544, and 596, respectively) inhibitory peptides. LBPs with favorable pharmacokinetics and gastrointestinal stability tightly interacted with the active sites of ACE-I (–5.6 to –8.9 kcal/mol) and DPP-IV (–5.4 to –7.6 kcal/mol). Papain generated the most bioavailable LBPs (n = 459) with ACE-I (n = 223) and DPP-IV (n = 412) inhibitory activity. These peptides were non-toxic and gastrointestinal digestion stable. Notably, papain-based hydrolysis released some LBPs (n = 270) that inhibited both ACE-I and DPP-IV. Plant protease-based hydrolysis is a promising approach for producing lupin hydrolysates with ACE-I and DPP-IV inhibitory activities. Full article
(This article belongs to the Special Issue New Insights into Bioactive Peptides: Design, Synthesis, Structure-Activity Relationship (2nd Edition))
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23 pages, 3476 KiB  
Article
Exploring a Potential Optimization Route for Peptide Ligands of the Sam Domain from the Lipid Phosphatase Ship2
by Marian Vincenzi, Flavia Anna Mercurio, Sara La Manna, Rosanna Palumbo, Luciano Pirone, Daniela Marasco, Emilia Maria Pedone and Marilisa Leone
Int. J. Mol. Sci. 2024, 25(19), 10616; https://doi.org/10.3390/ijms251910616 - 2 Oct 2024
Viewed by 1051
Abstract
The Sam (Sterile alpha motif) domain of the lipid phosphatase Ship2 (Ship2-Sam) is engaged by the Sam domain of the receptor tyrosine kinase EphA2 (EphA2-Sam) and, this interaction is principally linked to procancer effects. Peptides able to hinder the formation of the EphA2-Sam/Ship2-Sam [...] Read more.
The Sam (Sterile alpha motif) domain of the lipid phosphatase Ship2 (Ship2-Sam) is engaged by the Sam domain of the receptor tyrosine kinase EphA2 (EphA2-Sam) and, this interaction is principally linked to procancer effects. Peptides able to hinder the formation of the EphA2-Sam/Ship2-Sam complex could possess therapeutic potential. Herein, by employing the FoldX software suite, we set up an in silico approach to improve the peptide targeting of the so-called Mid Loop interface of Ship2-Sam, representing the EphA2-Sam binding site. Starting from a formerly identified peptide antagonist of the EphA2-Sam/Ship2-Sam association, first, the most stabilizing mutations that could be inserted in each peptide position were predicted. Then, they were combined, producing a list of potentially enhanced Ship2-Sam ligands. A few of the in silico generated peptides were experimentally evaluated. Interaction assays with Ship2-Sam were performed using NMR and BLI (BioLayer Interferometry). In vitro assays were conducted as well to check for cytotoxic effects against both cancerous and healthy cells, and also to assess the capacity to regulate EphA2 degradation. This study undoubtedly enlarges our knowledge on how to properly target EphA2-Sam/Ship2-Sam associations with peptide-based tools and provides a promising strategy that can be used to target any protein–protein interaction. Full article
(This article belongs to the Special Issue New Insights into Bioactive Peptides: Design, Synthesis, Structure-Activity Relationship (2nd Edition))
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10 pages, 12079 KiB  
Communication
Subtle Structural Differences Affect the Inhibitory Potency of RGD-Containing Cyclic Peptide Inhibitors Targeting SPSB Proteins
by Kefa Li, Yanhong Luo, Weiwei Hu, Jinjin Yang, Danting Zhang, Huan Wei, Tingting You, Hai-Shu Lin and Zhihe Kuang
Int. J. Mol. Sci. 2024, 25(12), 6764; https://doi.org/10.3390/ijms25126764 - 20 Jun 2024
Cited by 1 | Viewed by 1312
Abstract
The SPRY domain-containing SOCS box proteins SPSB1, SPSB2, and SPSB4 utilize their SPRY/B30.2 domain to interact with a short region in the N-terminus of inducible nitric oxide synthase (iNOS), and recruit an E3 ubiquitin ligase complex to polyubiquitinate iNOS, resulting in the proteasomal [...] Read more.
The SPRY domain-containing SOCS box proteins SPSB1, SPSB2, and SPSB4 utilize their SPRY/B30.2 domain to interact with a short region in the N-terminus of inducible nitric oxide synthase (iNOS), and recruit an E3 ubiquitin ligase complex to polyubiquitinate iNOS, resulting in the proteasomal degradation of iNOS. Inhibitors that can disrupt the endogenous SPSB-iNOS interactions could be used to augment cellular NO production, and may have antimicrobial and anticancer activities. We previously reported the rational design of a cyclic peptide inhibitor, cR8, cyclo(RGDINNNV), which bound to SPSB2 with moderate affinity. We, therefore, sought to develop SPSB inhibitors with higher affinity. Here, we show that cyclic peptides cR7, cyclo(RGDINNN), and cR9, cyclo(RGDINNNVE), have ~6.5-fold and ~2-fold, respectively, higher SPSB2-bindng affinities than cR8. We determined high-resolution crystal structures of the SPSB2-cR7 and SPSB2-cR9 complexes, which enabled a good understanding of the structure–activity relationships for these cyclic peptide inhibitors. Moreover, we show that these cyclic peptides displace full-length iNOS from SPSB2, SPSB1, and SPSB4, and that their inhibitory potencies correlate well with their SPSB2-binding affinities. The strongest inhibition was observed for cR7 against all three iNOS-binding SPSB proteins. Full article
(This article belongs to the Special Issue New Insights into Bioactive Peptides: Design, Synthesis, Structure-Activity Relationship (2nd Edition))
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Review

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22 pages, 6773 KiB  
Review
Structure, Function and Engineering of the Nonribosomal Peptide Synthetase Condensation Domain
by Zhenkuai Huang, Zijing Peng, Mengli Zhang, Xinhai Li and Xiaoting Qiu
Int. J. Mol. Sci. 2024, 25(21), 11774; https://doi.org/10.3390/ijms252111774 - 1 Nov 2024
Cited by 2 | Viewed by 1816
Abstract
The nonribosomal peptide synthetase (NRPS) is a highly precise molecular assembly machinery for synthesizing structurally diverse peptides, which have broad medicinal applications. Withinthe NRPS, the condensation (C) domain is a core catalytic domain responsible for the formation of amide bonds between individual monomer [...] Read more.
The nonribosomal peptide synthetase (NRPS) is a highly precise molecular assembly machinery for synthesizing structurally diverse peptides, which have broad medicinal applications. Withinthe NRPS, the condensation (C) domain is a core catalytic domain responsible for the formation of amide bonds between individual monomer residues during peptide elongation. This review summarizes various aspects of the C domain, including its structural characteristics, catalytic mechanisms, substrate specificity, substrate gating function, and auxiliary functions. Moreover, through case analyses of the NRPS engineering targeting the C domains, the vast potential of the C domain in the combinatorial biosynthesis of peptide natural product derivatives is demonstrated. Full article
(This article belongs to the Special Issue New Insights into Bioactive Peptides: Design, Synthesis, Structure-Activity Relationship (2nd Edition))
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