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Pharmaceuticals
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Peptide Synthesis and Drug Development: Exploring Progress and Potential
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Peptide Synthesis and Drug Development: Exploring Progress and Potential

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

Deadline for manuscript submissions: closed (25 November 2025) | Viewed by 22258

Special Issue Editors

Dr. Othman Al Musaimi

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Guest Editor
1. School of Pharmacy, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE1 7RU, UK
2. Department of Chemical Engineering, Imperial College London, London SW7 AZ, UK
3. Orthogonal Peptides Limited, London SW7 2AZ, UK
Interests: peptide synthesis; separation; purification and greening; drug development
Special Issues, Collections and Topics in MDPI journals
Dr. Da’san M.M. Jaradat

E-Mail Website
Guest Editor
1. Department of Chemistry, Faculty of Science, Al-Balqa Applied University, P.O. Box 206, Al-Salt 19117, Jordan
2. Helmholtz-Zentrum Berlin für Materialien und Energie (HZB), Berlin, Germany
Interests: solid-phase peptide synthesis; drug development
Dr. Vera D'Aloisio

E-Mail Website
Guest Editor
Bachem AG, Hauptstrasse 144, 4416 Bubendorf, Switzerland
Interests: peptides; TIDES; drug discovery; medicinal chemistry; CMC; DMPK; marketed peptides
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Peptides are becoming increasingly important in a variety of fields such as drug development, immunology, sensing, and biomaterials. Because of their significant binding footprint with therapeutic targets, peptides are regarded as superior to their small-molecule counterparts. On the other hand, they encounter stability challenges due to enzymatic degradation. Ongoing efforts to harmonise interdisciplinary fields have been instrumental in improving the pharmacokinetic and pharmacodynamic profiles of peptides.

Out of roughly 102 approved peptides, since 1923, a mere 11 have been found to be suitable for oral administration. This represents only 3.4% of all approvals. While traditional chemical methods have been employed to improve peptide stability, there has been a lack of exploration into innovative chemistries.

For this Special Issue, we invite authors to present and/or review novel strategies for addressing this challenge. This includes introducing new synthetic methodologies and formulation strategies. Additionally, computational studies aimed at achieving the same objective are also encouraged.

Dr. Othman Al Musaimi
Dr. Da’san M.M. Jaradat
Dr. Vera D’Aloisio
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 250 words) can be sent to the Editorial Office for assessment.

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. Pharmaceuticals is an international peer-reviewed open access monthly 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 2900 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

  • peptides
  • enzymatic degradation
  • drug discovery
  • formulation
  • draggability

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Related Special Issue

Published Papers (8 papers)

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Research

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23 pages, 1882 KB  
Article
A Machine Learning-Enabled Venom Peptide Platform for Rapid Drug Discovery
by Fei Cai, Lijuan Zhou, Bryce Delgado, Wenping Chang, Jeffrey Tom, Evelyn Hernandez, Prajakta Joshi, Aimin Song, Matthieu Masureel, Henry R. Maun, Andrew Chang and Yingnan Zhang
Pharmaceuticals 2026, 19(2), 288; https://doi.org/10.3390/ph19020288 - 9 Feb 2026
Viewed by 1036
Abstract
Background/Objectives: Nature has evolved millions of venom-derived peptides with diverse biological functions, a substantial fraction of which target complex membrane proteins such as G-protein-coupled receptors and ion channels. Many of these peptides are stabilized by multiple disulfide bonds, endowing them with exceptional [...] Read more.
Background/Objectives: Nature has evolved millions of venom-derived peptides with diverse biological functions, a substantial fraction of which target complex membrane proteins such as G-protein-coupled receptors and ion channels. Many of these peptides are stabilized by multiple disulfide bonds, endowing them with exceptional structural stability and favorable pharmacological properties. Methods: Leveraging this natural diversity, we developed a robust venom peptide therapeutics discovery system built on phage display technology and constructed a library using approximately 482 venom-derived scaffolds. The library design was guided by a machine learning (ML) model capable of predicting mutation-tolerant residues that preserve peptide foldability, maximizing structural integrity and sequence diversity. Results: The resulting VCX library was evaluated through screening against four diverse targets (CD47, DLL3, IL33, and P2X7R), yielding strong binders for all four, a success rate of 100%. Furthermore, by integrating high-throughput recombinant expression of thioredoxin–venom fusion proteins along with ML-assisted affinity maturation, we rapidly identified potential leads for DLL3 binders. Conclusions: This venom-based discovery platform offers significant advantages in both functionality and developability compared with conventional peptide discovery approaches. By combining natural structural diversity, ML-guided design, and recombinant expression, it enables efficient identification of “antibody-like” binders with molecular weights much smaller than those of antibodies. Consequently, it provides a powerful strategy for developing next-generation peptide therapeutics targeting challenging protein–protein interactions and complex membrane proteins. Full article
(This article belongs to the Special Issue Peptide Synthesis and Drug Development: Exploring Progress and Potential)
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15 pages, 4045 KB  
Article
Design of Artificial Peptide Against HIV-1 Based on the Heptad-Repeat Rules and Membrane-Anchor Strategies
by Jiali Zhao, Yan Zhao, Xiao Qi, Xiaojie Lv, Yanbai Tang, Wei Zhang, Qingge Dai, Jiaqi Xu, Dongmin Zhao, Qilu Yan, Guodong Liang and Jianping Chen
Pharmaceuticals 2025, 18(12), 1881; https://doi.org/10.3390/ph18121881 - 12 Dec 2025
Viewed by 644
Abstract
Objective: The six-helix bundle (6-HB) is critical for HIV-1 membrane fusion. To disrupt this process, peptide inhibitors have been meticulously designed to target interactions within the 6-HB regions, thereby blocking membrane fusion and exerting inhibitory effects. Current peptide inhibitors like Enfuvirtide suffer from [...] Read more.
Objective: The six-helix bundle (6-HB) is critical for HIV-1 membrane fusion. To disrupt this process, peptide inhibitors have been meticulously designed to target interactions within the 6-HB regions, thereby blocking membrane fusion and exerting inhibitory effects. Current peptide inhibitors like Enfuvirtide suffer from drug resistance and short in vivo half-life. This study aims to design novel anti-HIV-1 peptides by integrating heptad-repeat rules and membrane-anchor strategies. Methods: Artificial peptides were designed using HR rules from the HIV-1 gp41 6-HB motif and membrane-anchor modifications. Results: EK35S-Palm has emerged as a highly promising candidate for HIV-1 inhibition, exhibiting robust binding affinity to the target and effectively impeding the 6-HB spontaneous formation. Discussion: HR-based design avoids viral sequence homology, and membrane anchoring enhances local agent concentration, improving pharmacokinetics. The HR binding and membrane stabilization of EK35S-Palm provide synergistic inhibition. Conclusions: Integrating HR structural design with membrane-anchor strategies yields potent HIV-1 fusion inhibitors. EK35S-Palm demonstrates superior efficacy and stability over current therapies. These approaches hold great potential for overcoming the current therapy limitations and advancing the more effective and durable HIV-1 fusion inhibitors. Full article
(This article belongs to the Special Issue Peptide Synthesis and Drug Development: Exploring Progress and Potential)
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24 pages, 2734 KB  
Article
Synthetic Linear Lipopeptides and Lipopeptoids Induce Apoptosis and Oxidative Stress: In Vitro Cytotoxicity and SAR Evaluation Against Cancer Cell Lines
by Ali Hmedat, Sebastian Stark, Tuvshinjargal Budragchaa, Nebojša Đ. Pantelić, Ludger A. Wessjohann and Goran N. Kaluđerović
Pharmaceuticals 2025, 18(12), 1840; https://doi.org/10.3390/ph18121840 - 2 Dec 2025
Cited by 1 | Viewed by 861
Abstract
Background: Cancer remains a major global health challenge, with current therapies often limited by high toxicity and poor selectivity. Lipopeptides, due to their amphiphilic architecture and synthetic accessibility, have emerged as promising anticancer agents. In this study, the in vitro cytotoxic potential [...] Read more.
Background: Cancer remains a major global health challenge, with current therapies often limited by high toxicity and poor selectivity. Lipopeptides, due to their amphiphilic architecture and synthetic accessibility, have emerged as promising anticancer agents. In this study, the in vitro cytotoxic potential and structure–activity relationships (SARs) of a library of 60 synthetic linear lipopeptides (LLPs), including lipopeptide–peptoid chimeras generated via the Ugi four-component reaction, were evaluated against four cancer cell lines (B16F10, HeLa, HT-29, and PC3). Methods: Cytotoxicity was assessed using MTT and crystal violet (CV) assays, and the natural cyclic lipopeptide surfactin was included as a reference. SAR analysis explored the effects of C-terminal functional groups, lipophilic tail length, peptide core size, and side chain modifications. Mechanistic studies involved cell cycle analysis, apoptosis markers (Annexin V/PI staining, caspase-3 activation), and oxidative stress assessment (ROS/RNS and NO production). Results: Several synthetic LLPs showed potent and selective anticancer activity, with IC50 values approximately 3–15 times lower than that of surfactin and with minimal toxicity toward non-cancerous NIH3T3 fibroblasts. Key structural determinants for activity included the presence of a C-terminal ester group, a lipophilic tail of 14–19 carbon atoms, and a tetrapeptide core. LLPs containing phenyl or azide side chains further enhanced cytotoxicity in a cell line-dependent manner. Mechanistic investigations confirmed that active LLPs induce caspase-dependent apoptosis, cell cycle arrest, and oxidative stress. These findings highlight that the synthetic LLPs demonstrate high in vitro anticancer efficacy with favorable selectivity. Conclusions: Synthetic LLPs exhibit potent and selective anticancer activity in vitro. SAR insights and mechanistic findings support their development as next-generation lipopeptide-based therapeutics. Full article
(This article belongs to the Special Issue Peptide Synthesis and Drug Development: Exploring Progress and Potential)
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19 pages, 3449 KB  
Article
PEPAD: A Promising Therapeutic Approach for the Treatment of Murine Melanoma (B16F10-Nex2)
by Camila de Oliveira Gutierrez, Rafael Araujo Pereira, Claudiane Vilharroel Almeida, Luís Henrique de Oliveira Almeida, Caio Fernando Ramalho de Oliveira, Ana Cristina Jacobowski, Patrícia Maria Guedes Paiva, Durvanei Augusto Maria, Rodrigo Juliano Oliveira, Thais de Andrade Farias Rodrigues, Tamaeh Monteiro-Alfredo, Ana Paula de Araújo Boleti and Maria Ligia Rodrigues Macedo
Pharmaceuticals 2025, 18(8), 1203; https://doi.org/10.3390/ph18081203 - 14 Aug 2025
Cited by 1 | Viewed by 1189
Abstract
Background/Objectives: Cancer is one of the leading causes of death worldwide, and skin cancer is especially prevalent and lethal in Brazil. Despite advancements in treatment, there is still a need for new anticancer agents that are effective, selective, and less toxic. This [...] Read more.
Background/Objectives: Cancer is one of the leading causes of death worldwide, and skin cancer is especially prevalent and lethal in Brazil. Despite advancements in treatment, there is still a need for new anticancer agents that are effective, selective, and less toxic. This study aimed to evaluate the cytotoxic and therapeutic potential of the peptide PEPAD. Methods: The cytotoxicity of PEPAD was assessed by MTT assay in murine melanoma (B16F10-Nex2), human melanoma (SK-MEL-28), breast (MCF-7), and cervical (HeLa) cancer cell lines. Selectivity was evaluated in healthy cells (RAW 264.7 and FN1). Morphological changes were analyzed by microscopy. Cell migration was assessed using scratch assays. Apoptotic features were evaluated using MitoTracker Deep Red, NucBlue, CaspACETM labeling, and flow cytometry. Immunogenic cell death was investigated by calreticulin and HMGB1 release. Molecular dynamics simulations explored peptide structure and interaction with lipid membranes. Results: PEPAD showed IC50 values of 7.4 µM and 18 µM in B16F10-Nex2 and SK-MEL-28 cells, respectively, and >60 µM in MCF-7 and HeLa cells. Low toxicity was observed in healthy cells (IC50 > 56 µM), indicating high selectivity. Apoptotic morphology and reduced cell migration were observed. Flow cytometry and fluorescence probes confirmed apoptosis and mitochondrial swelling. Calreticulin and HMGB1 release indicated immunogenic cell death. Simulations showed that PEPAD maintains a stable α-helical conformation and interacts with membranes. Conclusions: These findings highlight PEPAD’s selective cytotoxicity and its potential as an anticancer agent with apoptotic and immunogenic properties, making it a promising candidate for therapeutic development. Full article
(This article belongs to the Special Issue Peptide Synthesis and Drug Development: Exploring Progress and Potential)
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17 pages, 3151 KB  
Article
Towards a Consensus for the Analysis and Exchange of TFA as a Counterion in Synthetic Peptides and Its Influence on Membrane Permeation
by Vanessa Erckes, Alessandro Streuli, Laura Chamera Rendueles, Stefanie Dorothea Krämer and Christian Steuer
Pharmaceuticals 2025, 18(8), 1163; https://doi.org/10.3390/ph18081163 - 5 Aug 2025
Cited by 2 | Viewed by 3995
Abstract
Background: With the increasing shift in drug design away from classical drug targets towards the modulation of protein-protein interactions, synthetic peptides are gaining increasing relevance. The synthesis and purification of peptides via solid-phase peptide synthesis (SPPS) strongly rely on trifluoroacetic acid (TFA) as [...] Read more.
Background: With the increasing shift in drug design away from classical drug targets towards the modulation of protein-protein interactions, synthetic peptides are gaining increasing relevance. The synthesis and purification of peptides via solid-phase peptide synthesis (SPPS) strongly rely on trifluoroacetic acid (TFA) as a cleavage agent and ion-pairing reagent, respectively, resulting in peptides being obtained as TFA salts. Although TFA has excellent properties for peptide production, numerous studies highlight the negative impact of using peptides from TFA− salts in biological assays. Methods: Investigated peptides were synthesized via SPPS and the TFA− counterion was exchanged for Cl− via freeze-drying in different concentrations of HCl. Detection and quantification of residual TFA− were carried out via FT-IR, 19F-NMR, and HPLC using an evaporative light-scattering detector (ELSD). A liposomal fluorescence assay was used to test for the influence of the counterion on the peptides’ passive membrane permeability. Results: All TFA− detection methods were successfully validated according to ICH guidelines. TFA− removal with 10 mM HCl was determined to be the optimal condition. No impact on peptide purity was observed at all HCl concentrations. Influences on permeability coefficients depending on peptide sequence and salt form were found. Conclusions: This study presents a systematic investigation of the removal of TFA− counterions from synthetic peptides and their replacement with Cl− counterions. Detected counterion contents were used to understand the impact of sequence differences, especially positive charges, on the amount and potential localization of counterions. Our findings emphasize the importance of counterion quantification and specification in assays with synthetic peptides. Full article
(This article belongs to the Special Issue Peptide Synthesis and Drug Development: Exploring Progress and Potential)
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24 pages, 6370 KB  
Article
Influence of Peptide Conjugation Sites on Lunatin–Alumina Nanoparticles: Implications for Membrane Interaction and Antimicrobial Activity
by Carolina Silva Ferreira, Lívia Mara Fontes Costa, Lúcio Otávio Nunes, Kelton Rodrigues de Souza, Giovanna Paula Araújo, Evgeniy S. Salnikov, Kelly Cristina Kato, Helen Rodrigues Martins, Adriano Monteiro de Castro Pimenta, Jarbas Magalhães Resende, Burkhard Bechinger and Rodrigo Moreira Verly
Pharmaceuticals 2025, 18(7), 952; https://doi.org/10.3390/ph18070952 - 24 Jun 2025
Cited by 1 | Viewed by 1213
Abstract
Background/Objectives: The increasing prevalence of multidrug-resistant bacteria presents a major global health challenge, prompting a search for innovative antimicrobial strategies. This study aimed to develop and evaluate a novel nanobiostructure combining alumina nanoparticles (NPs) with the antimicrobial peptide lunatin-1 (Lun-1), forming peptide-functionalized nanofilaments. [...] Read more.
Background/Objectives: The increasing prevalence of multidrug-resistant bacteria presents a major global health challenge, prompting a search for innovative antimicrobial strategies. This study aimed to develop and evaluate a novel nanobiostructure combining alumina nanoparticles (NPs) with the antimicrobial peptide lunatin-1 (Lun-1), forming peptide-functionalized nanofilaments. The main objective was to investigate how the site of peptide functionalization (C-terminal vs. N-terminal) affects membrane interactions and antibacterial activity. Methods: NP–peptide conjugates were synthesized via covalent bonding between lun-1 and alumina NP and characterized using transmission electron microscopy (TEM), X-ray diffraction (XRD), zeta potential analysis, dynamic light scattering (DLS), Fourier-transform infrared (FTIR), and solid-state 13C NMR. Antibacterial activities were assessed against different Gram-positive and Gram-negative strains. Biophysical analyses, including circular dichroism (CD), isothermal titration calorimetry (ITC), differential scanning calorimetry (DSC), and solid-state 2H NMR, were employed to evaluate peptide–membrane interactions in the presence of membrane-mimetic vesicles composed of POPC:POPG (3:1) and DMPC:DMPG (3:1). Results: Characterization confirmed the successful formation of NP–peptide nanofilaments. Functionalization at the N-terminal significantly influenced both antibacterial activity and peptide conformation compared to C-terminal attachment. Biophysical data demonstrated stronger membrane interaction and greater membrane disruption when lun-1 was conjugated at the N-terminal. Conclusions: The site of peptide conjugation plays a crucial role in modulating the biological and biophysical properties of NP–lunatin-1 conjugates. C-terminal attachment of lunatin-1 retains both membrane interaction and antibacterial efficacy, making it a promising strategy for the design of peptide-based nanotherapeutics targeting resistant pathogens. Full article
(This article belongs to the Special Issue Peptide Synthesis and Drug Development: Exploring Progress and Potential)
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Review

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24 pages, 2492 KB  
Review
Antioxidant Peptides Derived from Woody Oil Resources: Mechanisms of Redox Protection and Emerging Therapeutic Opportunities
by Jia Tu, Jie Peng, Li Wen, Changzhu Li, Zhihong Xiao, Ying Wu, Zhou Xu, Yuxi Hu, Yan Zhong, Yongjun Miao, Jingjing Xiao and Sisi Liu
Pharmaceuticals 2025, 18(6), 842; https://doi.org/10.3390/ph18060842 - 4 Jun 2025
Cited by 2 | Viewed by 1904
Abstract
Antioxidant peptides derived from woody oil resource by-products exhibit strong free radical scavenging abilities and offer potential applications in functional foods, nutraceuticals, and cosmetics. This review summarizes the latest advances in preparation technologies, including enzymatic hydrolysis, microbial fermentation, chemical synthesis, recombinant expression, and [...] Read more.
Antioxidant peptides derived from woody oil resource by-products exhibit strong free radical scavenging abilities and offer potential applications in functional foods, nutraceuticals, and cosmetics. This review summarizes the latest advances in preparation technologies, including enzymatic hydrolysis, microbial fermentation, chemical synthesis, recombinant expression, and molecular imprinting, each with distinct advantages in yield, selectivity, and scalability. The structure–activity relationships of antioxidant peptides are explored with respect to amino acid composition, molecular weight, and 3D conformation, which collectively determine their bioactivity and stability. Additionally, emerging delivery systems—such as nanoliposomes, microencapsulation, and cell-penetrating peptides—are discussed for their role in enhancing peptide stability, absorption, and targeted release. Mechanistic studies reveal that antioxidant peptides from woody oil resources act through network pharmacology, engaging core signaling pathways, including Nrf2/ARE, PI3K/Akt, AMPK, and JAK/STAT, to regulate oxidative stress, mitochondrial health, and inflammation. Preliminary safety data from in vitro, animal, and early clinical studies suggest low toxicity and favorable tolerability. The integration of omics technologies, molecular docking, and bioinformatics is accelerating the mechanism-driven design and functional validation of peptides. In conclusion, antioxidant peptides derived from woody oil resources represent a sustainable, multifunctional, and scalable solution for improving human health and promoting a circular bioeconomy. Future research should focus on structural optimization, delivery enhancement, and clinical validation to facilitate their industrial translation. Full article
(This article belongs to the Special Issue Peptide Synthesis and Drug Development: Exploring Progress and Potential)
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38 pages, 4414 KB  
Review
Recent Advances in Peptide-Loaded PLGA Nanocarriers for Drug Delivery and Regenerative Medicine
by Hossein Omidian, Renae L. Wilson and Ana M. Castejon
Pharmaceuticals 2025, 18(1), 127; https://doi.org/10.3390/ph18010127 - 18 Jan 2025
Cited by 31 | Viewed by 9699
Abstract
Peptide-loaded poly(lactide-co-glycolide) (PLGA) nanocarriers represent a transformative approach to addressing the challenges of peptide-based therapies. These systems offer solutions to peptide instability, enzymatic degradation, and limited bioavailability by providing controlled release, targeted delivery, and improved stability. The versatility of PLGA nanocarriers extends across [...] Read more.
Peptide-loaded poly(lactide-co-glycolide) (PLGA) nanocarriers represent a transformative approach to addressing the challenges of peptide-based therapies. These systems offer solutions to peptide instability, enzymatic degradation, and limited bioavailability by providing controlled release, targeted delivery, and improved stability. The versatility of PLGA nanocarriers extends across therapeutic domains, including cancer therapy, neurodegenerative diseases, vaccine development, and regenerative medicine. Innovations in polymer chemistry, surface functionalization, and advanced manufacturing techniques, such as microfluidics and electrospraying, have further enhanced the efficacy and scalability of these systems. This review highlights the key physicochemical properties, preparation strategies, and proven benefits of peptide-loaded PLGA systems, emphasizing their role in sustained drug release, immune activation, and tissue regeneration. Despite remarkable progress, challenges such as production scalability, cost, and regulatory hurdles remain. Full article
(This article belongs to the Special Issue Peptide Synthesis and Drug Development: Exploring Progress and Potential)
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