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Therapeutic Innovation & Regulatory... Mar 2020Phage display (PD) is a technology based on the presentation of functional exogenous peptides on the capsid surface of bacteriophages. PD is performed by introducing a... (Review)
Review
Phage display (PD) is a technology based on the presentation of functional exogenous peptides on the capsid surface of bacteriophages. PD is performed by introducing a DNA sequence of interest at a specific position within a functional viral gene. In addition, peptide phage libraries are powerful tools for expressing a wide range of random peptides and for specific peptide screening. Specifically, PD applications include the analysis of binding and interactions between proteins, the identification of bioactive peptides that bind to receptors, the identification of disease-associated antigens, and the identification of cell-specific peptides. Since its emergence, PD technology has revolutionized several fields in the biological sciences, such as oncology, cell biology, and pharmacology, the innumerable applications for which will be described throughout this review.
Topics: Bacteriophages; Peptide Library; Peptides
PubMed: 32072579
DOI: 10.1007/s43441-019-00059-5 -
Molecules (Basel, Switzerland) Oct 2023Peptides are at the cutting edge of contemporary research for new potent, selective, and safe therapeutical agents. Their rise has reshaped the pharmaceutical landscape,... (Review)
Review
Peptides are at the cutting edge of contemporary research for new potent, selective, and safe therapeutical agents. Their rise has reshaped the pharmaceutical landscape, providing solutions to challenges that traditional small molecules often cannot address. A wide variety of natural and modified peptides have been obtained and studied, and many others are advancing in clinical trials, covering multiple therapeutic areas. As the demand for peptide-based therapies grows, so does the need for sustainable and environmentally friendly synthesis methods. Traditional peptide synthesis, while effective, often involves environmentally draining processes, generating significant waste and consuming vast resources. The integration of green chemistry offers sustainable alternatives, prioritizing eco-friendly processes, waste reduction, and energy conservation. This review delves into the transformative potential of applying green chemistry principles to peptide synthesis by discussing relevant examples of the application of such approaches to the production of active pharmaceutical ingredients (APIs) with a peptide structure and how these efforts are critical for an effective green transition era in the pharmaceutical field.
Topics: Peptides; Chemistry Techniques, Synthetic; Pharmaceutical Preparations
PubMed: 37894644
DOI: 10.3390/molecules28207165 -
Pharmacological Research May 2024Peptide stapling, by employing a stable, preformed alpha-helical conformation, results in the production of peptides with improved membrane permeability and enhanced... (Review)
Review
Peptide stapling, by employing a stable, preformed alpha-helical conformation, results in the production of peptides with improved membrane permeability and enhanced proteolytic stability, compared to the original peptides, and provides an effective solution to accelerate the rapid development of peptide drugs. Various reviews present peptide stapling chemistries, anchoring residues and one- or two-component cyclization, however, therapeutic stapled peptides have not been systematically summarized, especially focusing on various disease-related targets. This review highlights the latest advances in therapeutic peptide drug development facilitated by the application of stapling technology, including different stapling techniques, synthetic accessibility, applicability to biological targets, potential for solving biological problems, as well as the current status of development. Stapled peptides as therapeutic drug candidates have been classified and analysed mainly by receptor- and ligand-based stapled peptide design against various diseases, including cancer, infectious diseases, inflammation, and diabetes. This review is expected to provide a comprehensive reference for the rational design of stapled peptides for different diseases and targets to facilitate the development of therapeutic peptides with enhanced pharmacokinetic and biological properties.
Topics: Humans; Animals; Peptides; Drug Design
PubMed: 38522761
DOI: 10.1016/j.phrs.2024.107137 -
Soft Matter Nov 2023Modelin-5 (M5-NH) killed with a minimum lethal concentration (MLC) of 5.86 μM and strongly bound its cytoplasmic membrane (CM) with a of 23.5 μM. The peptide adopted...
Modelin-5 (M5-NH) killed with a minimum lethal concentration (MLC) of 5.86 μM and strongly bound its cytoplasmic membrane (CM) with a of 23.5 μM. The peptide adopted high levels of amphiphilic α-helical structure (75.0%) and penetrated the CM hydrophobic core (8.0 mN m). This insertion destabilised CM structure increased lipid packing and decreased fluidity (Δ < 0), which promoted high levels of lysis (84.1%) and cell death. M5-NH showed a very strong affinity ( = 3.5 μM) and very high levels of amphiphilic α-helical structure with cardiolipin membranes (96.0%,) which primarily drove the peptide's membranolytic action against . In contrast, M5-NH killed with an MLC of 147.6 μM and weakly bound its CM with a of 117.6 μM, The peptide adopted low levels of amphiphilic α-helical structure (35.0%) and only penetrated the upper regions of the CM (3.3 mN m). This insertion stabilised CM structure decreased lipid packing and increased fluidity (Δ > 0) and promoted only low levels of lysis (24.3%). The insertion and lysis of the CM by M5-NH showed a strong negative correlation with its lysyl phosphatidylglycerol (Lys-PG) content ( > 0.98). In combination, these data suggested that Lys-PG mediated mechanisms inhibited the membranolytic action of M5-NH against , thereby rendering the organism resistant to the peptide. These results are discussed in relation to structure/function relationships of M5-NH and CM lipids that underpin bacterial susceptibility and resistance to the peptide.
Topics: Staphylococcus aureus; Antimicrobial Cationic Peptides; Cell Membrane; Membrane Lipids; Anti-Bacterial Agents
PubMed: 37869970
DOI: 10.1039/d3sm01007d -
ACS Chemical Biology Oct 2019Peptides constitute an important class of drugs for the treatment of multiple metabolic, oncological, and neurodegenerative diseases, and several hundred novel...
Peptides constitute an important class of drugs for the treatment of multiple metabolic, oncological, and neurodegenerative diseases, and several hundred novel therapeutic peptides are currently in the preclinical and clinical stages of development. However, many leads fail to advance clinically because of poor cellular membrane and tissue permeability. Therefore, assessment of the ability of a peptide to cross cellular membranes is critical when developing novel peptide-based therapeutics. Current methods to assess peptide cellular permeability are limited by multiple factors, such as the need to introduce rather large modifications (e.g., fluorescent dyes) that require complex chemical reactions as well as an inability to provide kinetic information on the internalization of a compound or distinguish between internalized and membrane-bound compounds. In addition, many of these methods are based on end point assays and require multiple sample manipulation steps. Herein, we report a novel "Split Luciferin Peptide" (SLP) assay that enables the real-time noninvasive imaging and quantification of peptide uptake both and using a very sensitive bioluminescence readout. This method is based on a straightforward, stable chemical modification of the peptide of interest with a d-cysteine tag that preserves the overall peptidic character of the original molecule. This method can be easily adapted for screening peptide libraries and can thus become an important tool for preclinical peptide drug development.
Topics: Animals; Biological Assay; Cell Line, Tumor; Cysteine; Female; Firefly Luciferin; Humans; Luciferases, Firefly; Luminescent Measurements; Mice; Nitriles; Peptides; Protein Transport
PubMed: 31498986
DOI: 10.1021/acschembio.9b00439 -
Current Medicinal Chemistry 2022G protein-coupled receptors are the largest protein family in the human body and represent the most important class of drug targets. They receive extracellular signals... (Review)
Review
G protein-coupled receptors are the largest protein family in the human body and represent the most important class of drug targets. They receive extracellular signals and transduce them into the cytosol. The guanine nucleotide-binding Gα proteins represent the main relays by which GPCRs induce intracellular effects. More than 800 different GPCRs interact with 16 Gα proteins belonging to 4 families, Gα, Gα, Gα, and Gα. The direct inhibition of Gα protein subunits rather than the modulation of GPCR subtypes has been proposed as a novel strategy for the treatment of complex diseases, including inflammation and cancer. This mini-review presents an introduction to G protein structure and function and describes achievements in the development of peptidic and peptide-derived Gα protein inhibitors. They have become indispensable pharmacological tools, and some of them exhibit significant potential as future drugs.
Topics: Humans; Protein Subunits; Receptors, G-Protein-Coupled; Peptides; Heterotrimeric GTP-Binding Proteins; Guanine Nucleotides
PubMed: 35260051
DOI: 10.2174/0929867329666220308112424 -
International Journal of Molecular... Dec 2022Cytokine imbalance is one of the causes of inflammation. Inflammation has yet to be adequately treated without side effects. Therefore, we tried to develop a peptide...
Cytokine imbalance is one of the causes of inflammation. Inflammation has yet to be adequately treated without side effects. Therefore, we tried to develop a peptide drug with minimal side effects. Peptide drugs have the advantage of being bio-friendly and bio-specific. In a previous study, three peptides with anti-inflammatory activity were derived based on a truncated IK (tIK) protein, which was a fragment of the IK protein with anti-inflammatory effects. The objective of this study was to optimize the process of expressing, isolating, and purifying the three peptides using bacterial strains and describe the process. Circular dichroism and solution state nuclear magnetic resonance spectroscopy were performed on the final purified high-purity peptide and its secondary structure was also identified.
Topics: Humans; Anti-Inflammatory Agents; Peptides; Inflammation; Cytokines; Protein Structure, Secondary; Circular Dichroism
PubMed: 36614076
DOI: 10.3390/ijms24010636 -
Biochemical Society Transactions Oct 2020The conformation with which natural agonistic peptides interact with G protein-coupled receptor(s) (GPCR(s)) partly results from intramolecular interactions such as... (Review)
Review
The conformation with which natural agonistic peptides interact with G protein-coupled receptor(s) (GPCR(s)) partly results from intramolecular interactions such as hydrogen bridges or is induced by ligand-receptor interactions. The conformational freedom of a peptide can be constrained by intramolecular cross-links. Conformational constraints enhance the receptor specificity, may lead to biased activity and confer proteolytic resistance to peptidic GPCR agonists. Chemical synthesis allows to introduce a variety of cross-links into a peptide and is suitable for bulk production of relatively simple lead peptides. Lanthionines are thioether bridged alanines of which the two alanines can be introduced at different distances in chosen positions in a peptide. Thioether bridges are much more stable than disulfide bridges. Biosynthesis of lanthionine-constrained peptides exploiting engineered Gram-positive or Gram-negative bacteria that contain lanthionine-introducing enzymes constitutes a convenient method for discovery of lanthionine-stabilized GPCR agonists. The presence of an N-terminal leader peptide enables dehydratases to dehydrate serines and threonines in the peptide of interest after which a cyclase can couple the formed dehydroamino acids to cysteines forming (methyl)lanthionines. The leader peptide also guides the export of the formed lanthionine-containing precursor peptide out of Gram-positive bacteria via a lanthipeptide transporter. An engineered cleavage site in the C-terminus of the leader peptide allows to cleave off the leader peptide yielding the modified peptide of interest. Lanthipeptide GPCR agonists are an emerging class of therapeutics of which a few examples have demonstrated high efficacy in animal models of a variety of diseases. One lanthipeptide GPCR agonist has successfully passed clinical Phase Ia.
Topics: Alanine; Animals; Anti-Bacterial Agents; Bacterial Proteins; Disulfides; Drug Discovery; GTP-Binding Proteins; Gram-Negative Bacteria; Gram-Positive Bacteria; Humans; Lanthanoid Series Elements; Membrane Transport Proteins; Mice; Peptide Hydrolases; Peptides; Protein Domains; Protein Processing, Post-Translational; Protein Sorting Signals; Rats; Receptors, G-Protein-Coupled; Substrate Specificity; Sulfides
PubMed: 33125486
DOI: 10.1042/BST20200427 -
International Journal of Molecular... Jul 2023Thyrotropin-releasing hormone (TRH) is a tripeptide that regulates the neuroendocrine thyroid axis. Moreover, its widespread brain distribution has indicated that it is... (Review)
Review
Thyrotropin-releasing hormone (TRH) is a tripeptide that regulates the neuroendocrine thyroid axis. Moreover, its widespread brain distribution has indicated that it is a relevant neuromodulator of behaviors such as feeding, arousal, anxiety, and locomotion. Importantly, it is also a neurotrophic peptide, and thus may halt the development of neurodegenerative diseases and improve mood-related disorders. Its neuroprotective actions on those pathologies and behaviors have been limited due to its poor intestinal and blood-brain barrier permeability, and because it is rapidly degraded by a serum enzyme. As new strategies such as TRH intranasal delivery emerge, a renewed interest in the peptide has arisen. TRH analogs have proven to be safe in animals and humans, while not inducing alterations in thyroid hormones' levels. In this review, we integrate research from different approaches, aiming to demonstrate the therapeutic effects of TRH, and to summarize new efforts to prolong and facilitate the peptide's actions to improve symptoms and the progression of several pathologies.
Topics: Animals; Humans; Thyrotropin-Releasing Hormone; Brain; Thyroid Gland; Peptides; Thyroid Hormones
PubMed: 37446225
DOI: 10.3390/ijms241311047 -
Drug Discovery Today Jun 2021As of 2020, there were >100 approved peptides with therapeutic or diagnostic applications. However, a complete database providing information on marketed peptides is not... (Review)
Review
As of 2020, there were >100 approved peptides with therapeutic or diagnostic applications. However, a complete database providing information on marketed peptides is not freely available, making the peptide chemists' job of designing future peptide drug candidates challenging. Unlike the rules for small-molecule drugs, there is no general set of guidelines for designing a successful peptide-based drug. In this review, together with our freely available database (PepTherDia, http://peptherdia.herokuapp.com), we provide insights into what a successful peptide therapeutic or diagnostic agent looks like and lay the foundation for establishing a set of rules to help future medicinal chemists to design peptide candidates with increased approval rates.
Topics: Chemistry, Pharmaceutical; Databases, Factual; Drug Approval; Drug Design; Humans; Peptides
PubMed: 33647438
DOI: 10.1016/j.drudis.2021.02.019