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

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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 7992

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Dr. Marilisa Leone

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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
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Dr. Flavia Anna Mercurio

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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

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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

New Insights into Bioactive Peptides: Design, Synthesis, Structure-Activity Relationship in International Journal of Molecular Sciences (13 articles)

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13 pages, 1115 KiB

Open AccessArticle

Application of Lipophilic Prodrug Charge Masking Strategy to Obtain Novel, Potential Oxytocin Prodrugs

by Agata Gitlin-Domagalska, Anna Olejnik, Jarosław Ruczyński, Dominika Starego, Natalia Ptaszyńska, Anna Łęgowska, Dawid Dębowski, Chaim Gilon and Krzysztof Rolka

Int. J. Mol. Sci. 2025, 26(10), 4772; https://doi.org/10.3390/ijms26104772 - 16 May 2025

Viewed by 88

Abstract

A Lipophilic Prodrug Charge Masking (LPCM) strategy involves masking of hydrophilic peptide charges with alkoxycarbonyl groups, which are cleaved by esterases after intestinal absorption. This study investigates the LPCM strategy’s applicability to oxytocin (OT), a peptide with well-defined biological activity. A series of OT prodrugs with varying alkoxycarbonyl chain lengths (2 to 12 carbon atoms) were synthesized, and their permeability was assessed using parallel artificial membrane permeability assay (PAMPA) and Caco-2 cell culture models. The PAMPA results indicated that OT demonstrated poor permeability (P_app = 2.2 × 10⁻⁶ cm/s), while its prodrugs Hoc-OT, Oct-OT, and Dec-OT were characterized by significantly better permeability, with Dec-OT achieving a four-fold increase over OT. The prodrug with a 12-carbon chain (Dod-OT) exhibited poor permeability; however, its high mass retention suggests strong membrane affinity. Further evaluation, using the Caco-2 cell model, revealed a 1.8-fold higher P_app of Oct-OT compared to OT, indicating possible higher oral availability. Conversely, Hoc-OT exhibited lower permeability than OT. Our findings indicate that the LPCM strategy can effectively boost the oral bioavailability of certain peptides, paving the way for their transformation into bioavailable drugs. 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, 18738 KiB

Open AccessArticle

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 317

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 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

Open AccessArticle

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 1102

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 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

Open AccessArticle

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 1052

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, 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

Open AccessArticle

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

Cited by 1 | Viewed by 1105

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 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

Open AccessCommunication

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 1355

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 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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19 pages, 758 KiB

Open AccessReview

Advances and Challenges in Structural Studies of Bioactive Peptide-Anthracycline Conjugates: A Mass Spectrometric Insight

by Eszter Fehérvári, Katalin Uray and Gitta Schlosser

Int. J. Mol. Sci. 2025, 26(10), 4896; https://doi.org/10.3390/ijms26104896 - 20 May 2025

Viewed by 137

Abstract

Drug conjugates, in which chemotherapeutic or cytotoxic agents are coupled to targeting or delivering macromolecules like peptides or proteins via a linker, revolutionize cancer treatment. While protein-drug and antibody-drug conjugates have already secured a role in clinical oncology, peptide–drug conjugates (PDCs) are emerging as a promising alternative, offering enhanced efficacy and fewer side effects compared to the free drug molecules. Comprehensive chemical and biological investigation of PDCs is crucial during drug development and optimization, paving the way for the next generation of targeted therapies. Anthracycline-containing peptide conjugates have emerged as promising candidates in targeted cancer therapies due to their ability to deliver cytotoxic agents directly to tumor cells. However, their structural complexity poses significant analytical challenges, particularly in mass spectrometric characterization. Accurate identification and quantification of these conjugates are critical for assessing their stability, efficacy, and mechanism of action. This article explores the major difficulties encountered during mass spectrometry (MS) analysis of anthracycline-peptide conjugates, focusing on ionization issues, fragmentation behavior, and challenges of detection from biological matrix. 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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22 pages, 6773 KiB

Open AccessReview

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 1962

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 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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