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Biomedicines
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Peptides and Amino Acids in Drug Development: Here and Now
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Peptides and Amino Acids in Drug Development: Here and Now

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Drug Discovery, Development and Delivery".

Deadline for manuscript submissions: 6 June 2025 | Viewed by 8164

Special Issue Editor

Dr. Siva Panda

E-Mail Website
Guest Editor
Department of Chemistry and Physics, Augusta University, Augusta, GA, USA
Interests: bioorganic & medicinal chemistry; computer-aided drug design and synthesis; green chemistry
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Peptides and amino acids are ubiquitously found as important building blocks and gaining interest in pharmaceutical research and drug development. Peptide chemistry is extensively utilized for the preparation of therapeutic peptides, signaling peptides, penetrating peptides, peptide–drug conjugates, cyclic peptides, and peptidomimetics. Over 150 peptide-based drug candidates are in clinical trials. In recent years, a paradigm shift in the Pharmaceutical Industry for peptide and amino acid-based drugs because of high selectivity for the targets, improved bioavailability, and reduced toxicity. Peptides and amino acids have the potential to offer the versatility needed for a successful drug discovery approach. Peptide–drug conjugates (PDCs) are an emerging targeted therapeutic that is composed of a drug candidate, peptide, and a linker. Alternatively, to enhance the penetration and selectivity peptides and amino acids are also used as linkers in molecular hybridized compounds.

Dr. Siva Panda
Guest Editor

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Keywords

  • peptide chemistry
  • amino acids
  • drug conjugates
  • drug development
  • drug delivery
  • coupling reagents
  • peptidomimetics
  • cyclic peptides
  • peptide ligation

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Published Papers (5 papers)

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Research

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10 pages, 1445 KiB  
Article
Assessing the Impact of the Leader Peptide in Protease Inhibition by the Microviridin Family of RiPPs
by Jillian L. Stafford, Veronica K. Montoya, Jeffrey J. Bierman and Mark C. Walker
Biomedicines 2024, 12(12), 2873; https://doi.org/10.3390/biomedicines12122873 - 18 Dec 2024
Viewed by 601
Abstract
Background: Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a growing class of natural products biosynthesized from a genetically encoded precursor peptide. RiPPs have attracted attention for the ability to generate and screen libraries of these compounds for useful biological activities. To facilitate [...] Read more.
Background: Ribosomally synthesized and post-translationally modified peptides (RiPPs) are a growing class of natural products biosynthesized from a genetically encoded precursor peptide. RiPPs have attracted attention for the ability to generate and screen libraries of these compounds for useful biological activities. To facilitate this screening, it is useful to be able to do so with the leader peptide still present. We assessed the suitability of the microviridin family for these screening experiments by determining their activity with the leader peptide still present. Methods: Modified precursor peptides with the leader present were heterologously expressed in Escherichia coli. Their ability to inhibit elastase was tested with a fluorogenic substrate. HPLC was used to monitor degradation of the modified precursor peptides by elastase. SDS-PAGE was used to determine the ability of immobilized modified precursor peptide to pull down elastase. Results: We found that the fully modified precursor peptide of microviridin B can inhibit the serine protease elastase with a low nanomolar IC50, and that the fully modified precursor with an N-terminal His-tag can mediate interactions between elastase and Ni-NTA resin, all indicating leader peptide removal is not necessary for microviridins to bind their target proteases. Additionally, we found that a bicyclic variant was able to inhibit elastase with the leader peptide still present, although with a roughly 100-fold higher IC50 and being subject to hydrolysis by elastase. Conclusions: These results open a pathway to screening libraries of microviridin variants for improved protease inhibition or other characteristics that can serve as, or as inspirations for, new pharmaceuticals. Full article
(This article belongs to the Special Issue Peptides and Amino Acids in Drug Development: Here and Now)
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15 pages, 4010 KiB  
Article
Exploring the Antidiabetic and Antihypertensive Potential of Peptides Derived from Bitter Melon Seed Hydrolysate
by Wei-Ting Hung, Christoper Caesar Yudho Sutopo, Tunjung Mahatmanto, Mei-Li Wu and Jue-Liang Hsu
Biomedicines 2024, 12(11), 2452; https://doi.org/10.3390/biomedicines12112452 - 25 Oct 2024
Viewed by 887
Abstract
Background/Objectives: Type 2 diabetes (T2D) has become a critical global health issue, with an increasing prevalence that contributes to significant morbidity and mortality. Inhibiting dipeptidyl peptidase-IV (DPP4) is a promising strategy for managing T2D. This study aimed to explore the DPP4 inhibitory peptide [...] Read more.
Background/Objectives: Type 2 diabetes (T2D) has become a critical global health issue, with an increasing prevalence that contributes to significant morbidity and mortality. Inhibiting dipeptidyl peptidase-IV (DPP4) is a promising strategy for managing T2D. This study aimed to explore the DPP4 inhibitory peptide derived from bitter melon seed protein (BMSP) hydrolysate. Methods: Reversed-phase high-performance liquid chromatography (RP-HPLC) was utilized to fractionate the hydrolysate. Peptide in the highest activity fraction was analyzed using liquid chromatography-mass spectrometry (LC-MS/MS). Peptide synthetic was used for further characterizations, such as bioactivity exploration, inhibition mechanism, molecular docking, and peptide stability against in vitro simulated gastrointestinal (SGI) digestion. Results: The BMSP hydrolysate was digested with gastrointestinal proteases (GP) and assessed for DPP4 inhibitory activity, yielding an IC50 of 1448 ± 105 μg/mL. Following RP-HPLC fractionation, MPHW (MW4) and VPSGAPF (VF7) were identified from fraction F8 with DPP4 IC50 values of 128.0 ± 1.3 µM and 150.6 ± 3.4 µM, respectively. Additionally, MW4 exhibited potential antihypertensive effects through ACE inhibition with an IC50 of 172.2 ± 10.6 µM. The inhibitory kinetics and molecular docking simulations indicated that both MW4 and VF7 were competitive inhibitors of DPP4, while MW4 was also a competitive inhibitor of ACE. Importantly, both peptides remained stable during simulated gastrointestinal digestion, suggesting their resistance to human digestive processes and their capacity to maintain biological activity. Conclusions: The findings suggest that BMSP-GP hydrolysate may have potential in terms of the development of health foods or therapeutic agents. However, in vivo studies are also essential for further confirmation of efficacy. Full article
(This article belongs to the Special Issue Peptides and Amino Acids in Drug Development: Here and Now)
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16 pages, 3496 KiB  
Article
Synthesis, Hydrolytic Stability and In Vivo Biological Study of Bioconjugates of the Tetrapeptides FELL Containing Pyrrole Moiety
by Boryana Borisova, Stanislava Vladimirova, Hristina Nocheva, Marie Laronze-Cochard, Stéphane Gérard, Stoyko Petrin and Dancho Danalev
Biomedicines 2023, 11(12), 3265; https://doi.org/10.3390/biomedicines11123265 - 9 Dec 2023
Cited by 1 | Viewed by 1391
Abstract
Background: Bioconjugates are promising alternatives for the multiple targeting of any disease. Pyrrole heterocycle is well known with many activities and is a building block of a lot of medical drugs. On the other hand, peptides are short molecules with many advantages such [...] Read more.
Background: Bioconjugates are promising alternatives for the multiple targeting of any disease. Pyrrole heterocycle is well known with many activities and is a building block of a lot of medical drugs. On the other hand, peptides are short molecules with many advantages such as small size, ability to penetrate the cell membrane and bond-specific receptors, vectorizing potential, etc. Thus, hybrid molecules between peptide and pyrrole moiety could be a promising alternative as an anti-pain tool. Methods: New bioconjugates with a general formula Pyrrole (α-/β-acid)-FELL-OH (NH2) were synthesized using Fmoc/OtBu peptide synthesis on solid support. HPLC was used to monitor the purity of newly synthesized bioconjugates. Their structures were proven by electrospray ionization mass spectrometry. The Paw Pressure test (Randall–Selitto test) was used to examinate the analgesic activity. Hydrolytic stability of targeted structures was monitored in three model systems with pH 2.0, 7.4 and 9.0, including specific enzymes by means of the HPLC-UV method. Results: The obtained results reveal that all newly synthesized bioconjugates have analgesic activity according to the used test but free pyrrole acids have the best analgesic activity. Conclusions: Although free pyrrole acids showed the best analgesic activity, they are the most unstable for hydrolysis. Combination with peptide structure leads to the hydrolytic stabilization of the bioconjugates, albeit with slightly reduced activity. Full article
(This article belongs to the Special Issue Peptides and Amino Acids in Drug Development: Here and Now)
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Review

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72 pages, 14427 KiB  
Review
Natural Cyclic Peptides: Synthetic Strategies and Biomedical Applications
by Devan Buchanan, Shogo Mori, Ahmed Chadli and Siva S. Panda
Biomedicines 2025, 13(1), 240; https://doi.org/10.3390/biomedicines13010240 - 20 Jan 2025
Viewed by 824
Abstract
Natural cyclic peptides, a diverse class of bioactive compounds, have been isolated from various natural sources and are renowned for their extensive structural variability and broad spectrum of medicinal properties. Over 40 cyclic peptides or their derivatives are currently approved as medicines, underscoring [...] Read more.
Natural cyclic peptides, a diverse class of bioactive compounds, have been isolated from various natural sources and are renowned for their extensive structural variability and broad spectrum of medicinal properties. Over 40 cyclic peptides or their derivatives are currently approved as medicines, underscoring their significant therapeutic potential. These compounds are employed in diverse roles, including antibiotics, antifungals, antiparasitics, immune modulators, and anti-inflammatory agents. Their unique ability to combine high specificity with desirable pharmacokinetic properties makes them valuable tools in addressing unmet medical needs, such as combating drug-resistant pathogens and targeting challenging biological pathways. Due to the typically low concentrations of cyclic peptides in nature, effective synthetic strategies are indispensable for their acquisition, characterization, and biological evaluation. Cyclization, a critical step in their synthesis, enhances metabolic stability, bioavailability, and receptor binding affinity. Advances in synthetic methodologies—such as solid-phase peptide synthesis (SPPS), chemoenzymatic approaches, and orthogonal protection strategies—have transformed cyclic peptide production, enabling greater structural complexity and precision. This review compiles recent progress in the total synthesis and biological evaluation of natural cyclic peptides from 2017 onward, categorized by cyclization strategies: head-to-tail; head-to-side-chain; tail-to-side-chain; and side-chain-to-side-chain strategies. Each account includes retrosynthetic analyses, synthetic advancements, and biological data to illustrate their therapeutic relevance and innovative methodologies. Looking ahead, the future of cyclic peptides in drug discovery is bright. Emerging trends, including integrating computational tools for rational design, novel cyclization techniques to improve pharmacokinetic profiles, and interdisciplinary collaboration among chemists, biologists, and computational scientists, promise to expand the scope of cyclic peptide-based therapeutics. These advancements can potentially address complex diseases and advance the broader field of biological drug development. Full article
(This article belongs to the Special Issue Peptides and Amino Acids in Drug Development: Here and Now)
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19 pages, 2972 KiB  
Review
Role of Functionalized Peptides in Nanomedicine for Effective Cancer Therapy
by Kibeom Kim and Myoung-Hwan Park
Biomedicines 2024, 12(1), 202; https://doi.org/10.3390/biomedicines12010202 - 16 Jan 2024
Cited by 2 | Viewed by 3083
Abstract
Peptide-functionalized nanomedicine, which addresses the challenges of specificity and efficacy in drug delivery, is emerging as a pivotal approach for cancer therapy. Globally, cancer remains a leading cause of mortality, and conventional treatments, such as chemotherapy, often lack precision and cause adverse effects. [...] Read more.
Peptide-functionalized nanomedicine, which addresses the challenges of specificity and efficacy in drug delivery, is emerging as a pivotal approach for cancer therapy. Globally, cancer remains a leading cause of mortality, and conventional treatments, such as chemotherapy, often lack precision and cause adverse effects. The integration of peptides into nanomedicine offers a promising solution for enhancing the targeting and delivery of therapeutic agents. This review focuses on the three primary applications of peptides: cancer cell-targeting ligands, building blocks for self-assembling nanostructures, and elements of stimuli-responsive systems. Nanoparticles modified with peptides improved targeting of cancer cells, minimized damage to healthy tissues, and optimized drug delivery. The versatility of self-assembled peptide structures makes them an innovative vehicle for drug delivery by leveraging their biocompatibility and diverse nanoarchitectures. In particular, the mechanism of cell death induced by self-assembled structures offers a novel approach to cancer therapy. In addition, peptides in stimuli-responsive systems enable precise drug release in response to specific conditions in the tumor microenvironment. The use of peptides in nanomedicine not only augments the efficacy and safety of cancer treatments but also suggests new research directions. In this review, we introduce systems and functionalization methods using peptides or peptide-modified nanoparticles to overcome challenges in the treatment of specific cancers, including breast cancer, lung cancer, colon cancer, prostate cancer, pancreatic cancer, liver cancer, skin cancer, glioma, osteosarcoma, and cervical cancer. Full article
(This article belongs to the Special Issue Peptides and Amino Acids in Drug Development: Here and Now)
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