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New Progress in Peptide Drugs

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: 30 June 2026 | Viewed by 1420

Special Issue Editor


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Guest Editor
1. Laboratory of Toxinology, Physiological Sciences Department, Biological Sciences Institute, University of Brasilia, Brasilia 70910‐900, DF, Brazil
2. Laboratory of Protein Chemistry and Biochemistry, Cellular Biology Department, Biological Sciences Institute, University of Brasilia, Brasilia 70910‐900, DF, Brazil
Interests: amphibians; peptide chemistry; antimicrobial peptides; peptide synthesis; peptide analogues; anti‐inflammatory peptides; wound‐healing; antiparasitic therapies
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Special Issue Information

Dear Colleagues,

The upcoming Special Issue New Progress in Peptide Drugs will showcase recent advances in the discovery, design, synthesis, and clinical application of therapeutic peptides. Peptides are emerging as a powerful class of drugs due to their high specificity, favorable safety profile, and broad therapeutic potential. Clinically approved peptides such as semaglutide, tirzepatide, buserelin, and abaloparatide have demonstrated success in treating metabolic, oncological, and endocrine disorders. The commercial prominence of semaglutide (Ozempic®/Wegovy®) and tirzepatide (Mounjaro®) reflects the increasing investment in multifunctional peptides and their promise as key therapeutic agents for complex metabolic diseases. This progress has been made possible through innovations in solid-phase synthesis, chemical modification strategies (e.g., PEGylation, cyclization, D-amino acid substitution), and novel delivery systems.

Potential topics for this Special Issue include, but are not limited to, the following:

  • Novel therapeutic peptides and mechanisms of action;
  • Antimicrobial and antiviral peptides;
  • Peptide-based therapeutics for cancer treatment;
  • Advances in peptide synthesis and engineering;
  • Peptide drug delivery systems;
  • Computational peptide design and AI-driven discovery;
  • Peptidomimetics and backbone modifications;
  • Clinical or preclinical studies involving peptide candidates.

We invite researchers to contribute their findings and insights to advance the promissing field of peptide drugs.

Prof. Dr. Mariana S. Castro
Guest Editor

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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

  • novel therapeutic peptides
  • peptide design
  • antimicrobial
  • anticancer
  • drug delivery systems
  • peptidomimetics

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Published Papers (2 papers)

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Research

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15 pages, 1799 KB  
Article
Geodiamolide A, a Marine Sponge Depsipeptide, Halts Proliferation and Triggers Cell Death in Squamous Cell Carcinoma (A431, NMSC) In Vitro
by Marisa Rangel, Alicia S. Ombredane, Ricardo B. Azevedo, Wagner Fontes, Graziella A. Joanitti and Mariana S. Castro
Int. J. Mol. Sci. 2026, 27(3), 1293; https://doi.org/10.3390/ijms27031293 - 28 Jan 2026
Cited by 1 | Viewed by 433
Abstract
Geodiamolides are depsipeptides previously isolated from marine sponges that are able to disrupt cytoskeleton microfilaments, inhibit cell migration and invasion, and reverse the malignant phenotype of human breast cancer cell lines to polarized spheroid-like structures. Such cytotoxicity to different cellular targets in breast [...] Read more.
Geodiamolides are depsipeptides previously isolated from marine sponges that are able to disrupt cytoskeleton microfilaments, inhibit cell migration and invasion, and reverse the malignant phenotype of human breast cancer cell lines to polarized spheroid-like structures. Such cytotoxicity to different cellular targets in breast cancer cells suggests that these molecules might also act in other cancer types such as non-melanoma skin cancer (NMSC), one of the cancer types with high incidence worldwide. Thus, the goal of this work was to study the effects of the marine sponge depsipeptides Geodiamolide A and H (Geo A and Geo H) in human squamous cell carcinoma (A431, NMSC) in order to investigate their effects on cell proliferation and cell death. While no significant statistical difference was observed after Geo H treatment, an expressive dose-dependent reduction in A431 cell viability (IC50 of 368 nM, MTT assay; p < 0.05) and proliferation pattern (real-time cell analysis assay) was shown after 48 h exposure with Geo A. The cell proliferation blockade was confirmed after 24 h of Geo A treatment at 500 nM, with a 46% (p < 0.0001) reduction in the total number of cells (cell counting) and G2/M phase cell cycle arrest. Other cytotoxic evidence such as DNA fragmentation, phosphatidylserine exposure (flow cytometry), and time-dependent plasma membrane damage (Trypan Blue) suggested cell death by apoptosis. Therefore, Geo A showed both cytostatic and cytotoxic effects on A431 cells. Taken together, these data point out Geo A as a promising therapeutic molecule for NMSC treatment and is the first depsipeptide (marine or terrestrial), to our knowledge, to target this type of cancer cell. Full article
(This article belongs to the Special Issue New Progress in Peptide Drugs)
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Review

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22 pages, 2563 KB  
Review
Linker Engineering in Stapled Peptides for Enhanced Membrane Permeability: Screening and Optimization Strategies
by Min Zhao, Baojian Li, Ying Gao, Rui Zhang, Subinur Ahmattohti, Jie Li and Xinbo Shi
Int. J. Mol. Sci. 2026, 27(7), 3077; https://doi.org/10.3390/ijms27073077 - 27 Mar 2026
Viewed by 588
Abstract
The optimization of membrane permeability is a pivotal approach for mitigating late-stage failures in peptide drug development. By leveraging linker chemical diversity, stapled peptides utilize linker engineering to precisely modulate key physicochemical parameters—such as lipophilicity and conformational constraints—to overcome the desolvation energy penalty. [...] Read more.
The optimization of membrane permeability is a pivotal approach for mitigating late-stage failures in peptide drug development. By leveraging linker chemical diversity, stapled peptides utilize linker engineering to precisely modulate key physicochemical parameters—such as lipophilicity and conformational constraints—to overcome the desolvation energy penalty. This review systematically evaluates linker-based strategies for enhancing the permeability of stapled peptides, categorized into two primary dimensions: (1) high-throughput screening (HTS) compatibility, focusing on the integration of functionalized linkers into mRNA display, phage display, and DNA-encoded libraries (DELs) to identify lead scaffolds with inherent permeability potential during early discovery; and (2) post-screening structural refinement, covering rational design strategies including intramolecular hydrogen-bond (IMHB) shielding, “chameleonic” adaptations, and stimuli-responsive reversible stapling. Furthermore, we analyze the paradigm shift in assessment methodologies from qualitative imaging to quantitative cytosolic delivery assays, which have deepened our understanding of mechanisms such as the charge/lipophilicity threshold balance and metabolism-driven trapping. Overall, linker engineering provides a robust technical roadmap for developing the next generation of cell-permeable stapled peptide therapeutics. Full article
(This article belongs to the Special Issue New Progress in Peptide Drugs)
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