The Application of Microsampling Disks in Circular Dichroism Spectroscopy for Peptide and Nucleic Acid Drugs DOI Open Access
Genichiro Tsuji, Takashi Misawa, Yosuke Demizu

et al.

Chemical and Pharmaceutical Bulletin, Journal Year: 2024, Volume and Issue: 72(7), P. 658 - 663

Published: July 10, 2024

In recent years, there has been a growing focus on the development of medium-sized drugs based peptides or nucleic acids owing to their potential therapeutic benefits. As some these exert effects by adopting specific secondary structures, evaluating conformational states is crucial ensure efficacy, quality, and safety drug products. It important assess structural integrity biomolecular therapeutics guarantee intended pharmacological activity maintain required standards for manufacturing. One widely utilized technique quality evaluation analysis using circular dichroism (CD) spectroscopy. Given higher production control costs associated with compared small-molecule drugs, developing analytical techniques that enable CD reduced sample volumes highly desirable. Herein, we focused microsampling disk-type cell as solution reducing volume. We investigated whether spectral disk could provide equivalent spectra standard (sample volume: approx. 300 µL). Our findings demonstrated 2-10 µL) be successfully applied peptide acid paving way more efficient cost-effective processes.

Language: Английский

Peptide design to control protein–protein interactions DOI Creative Commons
Suzanne P. van Wier, Andrew M. Beekman

Chemical Society Reviews, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Targeting of protein–protein interactions has become huge interest in every aspect medicinal and biological sciences.

Language: Английский

Citations

4
Conformationally adaptive therapeutic peptides for diseases caused by intrinsically disordered proteins (IDPs). New paradigm for drug discovery: Target the target, not the arrow DOI Creative Commons
Jacques Fantini, Fodil Azzaz, Coralie Di Scala

et al.

Pharmacology & Therapeutics, Journal Year: 2025, Volume and Issue: unknown, P. 108797 - 108797

Published: Jan. 1, 2025

The traditional model of protein structure determined by the amino acid sequence is today seriously challenged fact that approximately half human proteome made up proteins do not have a stable 3D structure, either partially or in totality. These proteins, called intrinsically disordered (IDPs), are involved numerous physiological functions and associated with severe pathologies, e.g. Alzheimer, Parkinson, Creutzfeldt-Jakob, amyotrophic lateral sclerosis (ALS), type 2 diabetes. Targeting these challenging for two reasons: i) we need to preserve their functions, ii) drug design molecular docking possible due lack reliable starting conditions. Faced this challenge, solutions proposed artificial intelligence (AI) such as AlphaFold clearly unsuitable. Instead, suggest an innovative approach consisting mimicking, short synthetic peptides, conformational flexibility IDPs. which call adaptive derived from domains IDPs become structured after interacting ligand. Adaptive peptides designed aim selectively antagonizing harmful effects IDPs, without targeting them directly but through selected ligands, affecting properties. This"target target, arrow" strategy promised open new route discovery currently undruggable proteins.

Language: Английский

Citations

4
Recent advances, strategies, and future perspectives of peptide-based drugs in clinical applications DOI
Qimeng Yang, Zhipeng Hu, Hongyu Jiang

et al.

Chinese Journal of Natural Medicines, Journal Year: 2025, Volume and Issue: 23(1), P. 31 - 42

Published: Jan. 1, 2025

Language: Английский

Citations

3
New insights into protein–protein interaction modulators in drug discovery and therapeutic advance DOI Creative Commons
Hossam Nada, Yongseok Choi, Sung-Do Kim

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: Dec. 5, 2024

Abstract Protein-protein interactions (PPIs) are fundamental to cellular signaling and transduction which marks them as attractive therapeutic drug development targets. What were once considered be undruggable targets have become increasingly feasible due the progress that has been made over last two decades rapid technological advances. This work explores influence of innovations on PPI research development. Additionally, diverse strategies for discovering, modulating, characterizing PPIs their corresponding modulators examined with aim presenting a streamlined pipeline advancing PPI-targeted therapeutics. By showcasing carefully selected case studies in modulator discovery development, we illustrate efficacy various identifying, optimizing, overcoming challenges associated design. The valuable lessons insights gained from identification, optimization, approval discussed demonstrating transitioned beyond early-stage now represent prime opportunity significant potential. examples encompass those developed cancer, inflammation immunomodulation, well antiviral applications. perspective aims establish foundation effective targeting modulation using pave way future

Language: Английский

Citations

16
Selection of Nucleotide-Encoded Mass Libraries of Macrocyclic Peptides for Inaccessible Drug Targets DOI Creative Commons
Kilian Colas, Daniel Bindl, Hiroaki Suga

et al.

Chemical Reviews, Journal Year: 2024, Volume and Issue: 124(21), P. 12213 - 12241

Published: Oct. 25, 2024

Technological advances and breakthrough developments in the pharmaceutical field are knocking at door of "undruggable" fortress with increasing insistence. Notably, 21st century has seen emergence macrocyclic compounds, among which cyclic peptides particular interest. This new class potential drug candidates occupies vast chemical space between classic small-molecule drugs larger protein-based therapeutics, such as antibodies. As research toward clinical targets that have long been considered inaccessible, well-suited to tackle these challenges a post-rule 5 landscape. Facilitating their discovery is an arsenal high-throughput screening methods exploit massive randomized libraries genetically encoded compounds. These techniques benefit from incorporation non-natural moieties, non- proteinogenic amino acids or stabilizing hydrocarbon staples. Exploiting features for strategic architectural design challenging protein–protein interactions, resisted efforts. Review summarizes basic principles recent main focuses on specific deployment targeting undruggable space. A focus placed development guidelines cyclization structural stabilization resulting success stories achieved against well-known inaccessible targets.

Language: Английский

Citations

8
Mixed Stereochemistry Macrocycle Acts as a Helix-Stabilizing Peptide N-Cap DOI Creative Commons
Fabian Hink, Julen Aduriz‐Arrizabalaga,

Xabier López

et al.

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: 146(35), P. 24348 - 24357

Published: Aug. 25, 2024

Interactions between proteins and α-helical peptides have been the focus of drug discovery campaigns. However, large interfaces formed multiple turns an α-helix a binding protein represent significant challenge to inhibitor discovery. Modified featuring helix-stabilizing macrocycles shown promise as inhibitors these interactions. Here, we tested ability N-terminal side-chain thioether-cyclized inhibit Mcl-1, by screening trillion-scale library. The enriched were lariats small, four-amino-acid macrocycle followed short linear sequence that resembled natural Mcl-1 ligands. These "Heliats" (helical lariats) bound with tens nM affinity, inhibited interaction peptide ligand. Macrocyclization was found stabilize structures significantly contribute affinity potency. Yet, 2nd 3rd positions within permissible variation, so minimal macrocyclic motif,

Language: Английский

Citations

4
Strategies and Challenges of Cytosolic Delivery of Proteins DOI

Yuanyuan Li,

Baojie Du,

Lichao Yu

et al.

Journal of drug targeting, Journal Year: 2025, Volume and Issue: unknown, P. 1 - 32

Published: Jan. 25, 2025

The cytosolic delivery of therapeutic proteins represents a promising strategy for addressing diseases caused by protein dysfunction. Despite significant advances, efficient remains challenging due to barriers such as cell membrane impermeability, endosomal sequestration, and instability. This review summarizes recent progress in systems, including physical, chemical, biological approaches, with particular focus on strategies that enhance escape targeting specificity. We further discuss the clinical translatability these approaches propose future directions improving efficiency safety, ultimately unlocking potential intracellular proteins.

Language: Английский

Citations

0
STAP-1-derived peptide suppresses TCR-mediated T cell activation and ameliorates immune diseases by inhibiting STAP-1–LCK binding DOI Creative Commons
Yuto Sasaki,

Kota Kagohashi,

Shoya Kawahara

et al.

ImmunoHorizons, Journal Year: 2025, Volume and Issue: 9(6)

Published: April 26, 2025

Abstract Signal-transducing adaptor protein-1 (STAP-1) is an protein specifically expressed in immune cells, such as T cells. We previously demonstrated that STAP-1 positively upregulates cell receptor (TCR)-mediated activation by interacting with LCK and phospholipase C-γ1 affecting autoimmune demyelination airway inflammation. In this study, we aimed to generate a new STAP-1-derived peptide, iSP1, inhibit the STAP-1–LCK interaction. also analyzed its function vitro vivo. iSP1 successfully interfered binding suppressed TCR-mediated signal transduction, interleukin-2 production, human murine proliferation. Additionally, prevented progression of experimental encephalomyelitis inhibiting Th1 Th17 infiltration. Our findings suggest therapeutic immunomodulatory agent for cell-mediated diseases.

Language: Английский

Citations

0
Design, Synthesis, and Biological Evaluation of Lysine-Stapled Peptide Inhibitors of p53-MDM2/MDMX Interactions with Potent Antitumor Activity In Vivo DOI
Lei Xu, Xin Fan, Yi He

et al.

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 19, 2024

We introduce novel lysine-stapled peptide inhibitors targeting

Language: Английский

Citations

1
Influence of heterochirality on the structure, dynamics, biological properties of cyclic(PFPF) tetrapeptides obtained by solvent-free ball mill mechanosynthesis DOI
Marek J. Potrzebowski, Sławomir Kaźmierski, Ewelina Wielgus

et al.

Published: April 19, 2024

Abstract Cyclic tetrapeptides c(Pro-Phe-Pro-Phe) obtained by the mechanosynthetic method using a ball mill were isolated in pure stereochemical form as homochiral system (all L -amino acids, sample A) and heterochiral with D configuration at one of stereogenic centers Phe (sample B). The structure stereochemistry both samples determined X-ray diffraction studies single crystals. In DMSO acetonitrile, A exists an equimolar mixture two conformers, while only is monitored for B. conformational space energetic preferences possible conformers calculated DFT methods. distinctly different flexibility was experimentally proven Variable Temperature (VT) 2D EXSY NMR measurements. Both docked to histone deacetylase HDAC8. Cytotoxic proved that none tested cyclic peptide toxic.

Language: Английский

Citations

0