Exploring the Chemical Features and Biomedical Relevance of Cell-Penetrating Peptides DOI Open Access
Liliana Marisol Moreno‐Vargas, Diego Prada‐Gracia

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 26(1), P. 59 - 59

Published: Dec. 25, 2024

Cell-penetrating peptides (CPPs) are a diverse group of peptides, typically composed 4 to 40 amino acids, known for their unique ability transport wide range substances—such as small molecules, plasmid DNA, interfering RNA, proteins, viruses, and nanoparticles—across cellular membranes while preserving the integrity cargo. CPPs exhibit passive non-selective behavior, often requiring functionalization or chemical modification enhance specificity efficacy. The precise mechanisms governing uptake remain ambiguous; however, electrostatic interactions between positively charged acids negatively glycosaminoglycans on membrane, particularly heparan sulfate proteoglycans, considered initial crucial step CPP uptake. Clinical trials have highlighted potential in diagnosing treating various diseases, including cancer, central nervous system disorders, eye diabetes. This review provides comprehensive overview classifications, applications, transduction mechanisms, most relevant algorithms improve accuracy reliability predictions development.

Language: Английский

A Top-Down Design Approach for Generating a Peptide PROTAC Drug Targeting Androgen Receptor for Androgenetic Alopecia Therapy DOI
Bohan Ma,

Donghua Liu,

Zhe Wang

et al.

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(12), P. 10336 - 10349

Published: June 5, 2024

While large-scale artificial intelligence (AI) models for protein structure prediction and design are advancing rapidly, the translation of deep learning practical macromolecular drug development remains limited. This investigation aims to bridge this gap by combining cutting-edge methodologies create a novel peptide-based PROTAC paradigm. Using ProteinMPNN RFdiffusion, we identified binding peptides androgen receptor (AR) Von Hippel-Lindau (VHL), followed computational modeling with Alphafold2-multimer ZDOCK predict spatial interrelationships. Experimental validation confirmed designed peptide's ability AR VHL. Transdermal microneedle patching technology was seamlessly integrated peptide delivery in androgenic alopecia treatment. In summary, our approach provides generic method generating PROTACs offers application designing potential therapeutic drugs androgenetic alopecia. showcases interdisciplinary approaches personalized medicine.

Language: Английский

Citations

10
Discovery of a peptide proteolysis-targeting chimera (PROTAC) drug of p300 for prostate cancer therapy DOI Creative Commons

Dize Zhang,

Bohan Ma,

Donghua Liu

et al.

EBioMedicine, Journal Year: 2024, Volume and Issue: 105, P. 105212 - 105212

Published: July 1, 2024

BackgroundThe E1A-associated protein p300 (p300) has emerged as a promising target for cancer therapy due to its crucial role in promoting oncogenic signaling pathways various cancers, including prostate cancer. This need is particularly significant While androgen deprivation (ADT) demonstrated efficacy cancer, long-term use can eventually lead the development of castration-resistant (CRPC) and neuroendocrine (NEPC). Notably, been identified an important co-activator receptor (AR), highlighting significance progression. Moreover, recent studies have revealed involvement AR-independent oncogenes associated with NEPC. Therefore, blockade may emerge effective therapeutic strategy address challenges posed by both CRPC NEPC.MethodsWe employed AI-assisted design develop peptide-based PROTAC (proteolysis-targeting chimera) drug that targets p300, effectively degrading vitro vivo utilizing nano-selenium peptide delivery system.FindingsOur p300-targeting degradation cell-killing capabilities CRPC, AR-negative, NEPC cells. study In AR-positive AR-negative mouse models, showed potent tumor suppression.InterpretationThe targeting feasible represents efficient NEPC.FundingThe funding details be found Acknowledgements section.

Language: Английский

Citations

7
Tackling Undruggable Targets with Designer Peptidomimetics and Synthetic Biologics DOI
Colin Swenson, Gunasheil Mandava, Deborah Thomas

et al.

Chemical Reviews, Journal Year: 2024, Volume and Issue: 124(22), P. 13020 - 13093

Published: Nov. 14, 2024

The development of potent, specific, and pharmacologically viable chemical probes therapeutics is a central focus biology therapeutic development. However, significant portion predicted disease-causal proteins have proven resistant to targeting by traditional small molecule biologic modalities. Many these so-called "undruggable" targets feature extended, dynamic protein-protein protein-nucleic acid interfaces that are their roles in normal diseased signaling pathways. Here, we discuss the synthetically stabilized peptide protein mimetics as an ever-expanding powerful region space tackle undruggable targets. These molecules aim combine synthetic tunability pharmacologic properties typically associated with binding footprints, affinities specificities biologics. In this review, historical emerging platforms approaches design, screen, select optimize "designer" peptidomimetics We examine inspiration design different classes designer peptidomimetics: (i) macrocyclic peptides, (ii) side chain (iii) non-natural peptidomimetics, (iv) proteomimetics, notable examples application challenging biomolecules. Finally, summarize key learnings remaining challenges for become useful historically

Language: Английский

Citations

5
Study of an arginine- and tryptophan-rich antimicrobial peptide in peri-implantitis DOI Creative Commons
Qian Zhang, Yuan Jiang, Xiaotong He

et al.

Frontiers in Bioengineering and Biotechnology, Journal Year: 2025, Volume and Issue: 12

Published: Jan. 7, 2025

The combination of hydrophilic arginine residues and hydrophobic tryptophan is considered to be the first choice for designing short-chain antimicrobial peptides (AMPs) due their potent antibacterial activity. Based on this, we designed an arginine- tryptophan-rich short peptide, VR-12. Peri-implantitis a significant microbial inflammatory disorder characterized by inflammation soft tissues surrounding implant, which ultimately leads progressive resorption alveolar bone. This study found through experiments, wound healing promotion anti-inflammatory experiments that VR-12 inhibited killed planktonic peri-implantitis-associated bacteria, biofilm formation, disrupted mature biofilms. Additionally, exhibited good biocompatibility with RAW264.7 cells human gingival fibroblasts (HGFs) cells, promoting proliferation both cell types. Moreover, induced HGFs migration expression migration-related factors, thereby tissue healing. also acted lipopolysaccharide (LPS)-induced exerting excellent properties affecting secretion/expression inflammation-related factors/genes. Therefore, may option warding off treatmenting peri-implantitis.

Language: Английский

Citations

0
Peptide Double-Stapling and Arginine N-Glycosylation Triggered the Development of Therapeutic Antimicrobial Peptides Capable of Killing Drug-Resistant Bacteria in Mice DOI
Xiang Li,

Yanjiao Ding,

Jingwen Xue

et al.

Journal of Medicinal Chemistry, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 5, 2025

Antimicrobial peptides SAAP-148 exhibited excellent antimicrobial activities but suffered from inherent disadvantages, including cytotoxicity and poor proteolytic stability. Herein, we developed a novel strategy combining one unique silver-catalyzed solid-phase glycosylation-enabled arginine N-glycosylation all-hydrocarbon peptide double-stapling, five-round libraries were rationally constructed containing over 50 stapled and/or N-glycosylated peptides. SLP-51 consisting of two introduced staples the C-terminal glycosylation superior in vitro against drug-resistant Gram-positive or -negative clinical isolates. also improved stability than parent SLP-0, importantly, significantly weakened hemolysis. Experimental modeling mechanism research indicated that exerted similar stronger killing abilities by destroying integrality bacterial membranes. In both skin wound pneumonia models, showcased potent therapeutic effect treating MRSA Klebsiella pneumoniae infection vivo dramatical improvement inflammatory injury.

Language: Английский

Citations

0
The Peptide PROTAC Modality: A New Strategy for Drug Discovery DOI Creative Commons
Youmin Zhu, Yu Dai,

Yun-Cai Tian

et al.

MedComm, Journal Year: 2025, Volume and Issue: 6(4)

Published: March 24, 2025

ABSTRACT In recent years, proteolysis targeting chimera (PROTAC) technology has made significant progress in the field of drug development. Traditional drugs mainly focus on inhibiting or activating specific proteins, while PROTAC provides new ideas for treating various diseases by inducing degradation target proteins. Especially peptide PROTACs, due to their unique structural and functional characteristics, they have become a hot research topic. This review detailed description key components, mechanisms, design principles elaborates applications skin‐related diseases, oncology, other potential therapeutic fields, analyzes advantages challenges, looks forward future development prospects. The not only opens up paths development, but also solving resistance safety issues faced traditional small‐molecule drugs. Compared with PROTACs such as multitargeting, biodegradability, low toxicity, flexibility design. With deepening continuous maturity technology, are expected one important strategies discovery, providing hope treatment more intractable diseases. Peptide ushering era precision medicine.

Language: Английский

Citations

0
Targeted Degradation of Protein Kinase A via a Stapled Peptide PROTAC DOI Creative Commons
Matthew K. Whittaker,

George N. Bendzunas,

Mahsa Shirani

et al.

ACS Chemical Biology, Journal Year: 2024, Volume and Issue: 19(9), P. 1888 - 1895

Published: Aug. 13, 2024

Proteolysis-targeting chimeras (PROTACs) are bifunctional molecules that bind and recruit an E3 ubiquitin ligase to a targeted protein of interest, often through the utilization small molecule inhibitor. To expand possible range kinase targets can be degraded by PROTACs, we sought develop PROTAC utilizing hydrocarbon-stapled peptide as targeting agent surface target interest. In this study, describe development proteolysis-targeting chimera, dubbed Stapled Inhibitor Peptide - or StIP-TAC, linking with ligand for degradation Protein Kinase A (PKA). This StIP-TAC stimulated E3-mediated PKA, effect could reversed addition proteasomal inhibitor MG-132. Further, treatment led significant reduction in PKA substrate phosphorylation. Since many interest lack structural features make them amenable targeting, StIP-TACs may broaden potential using PROTAC-mediated approach.

Language: Английский

Citations

2
Developing Stapled Aptamers with a Constrained Conformation for Osteogenesis Imperfect Therapeutics DOI

Amu Gubu,

Ge Zhang,

Nannan Jing

et al.

Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 67(21), P. 18883 - 18894

Published: Oct. 29, 2024

Despite the extensive development of aptamers in basic research, only a limited number have successfully progressed to clinical trials. This limitation is primarily attributed inherent instability aptamers' conformation, resulting low affinity, poor serum stability, and inconsistent potency, posing significant challenge their stabilization. Herein, we established feasible strategy develop staple using predicted binding conformations titration cross-linking (TTC) method. Through this strategy, synthesized various stapled sclerostin with over 70% yield. Importantly, demonstrated that significantly enhanced affinity (approximately 20-fold) stability (negligible degradation within 32 h). Moreover, an osteogenesis imperfecta mouse model (Col1a2+/G610C mice), aptamer (named c-0127OA) exhibited potent antagonistic effect on sclerostin, leading anabolic bone potential. Collectively, our stapling effective stabilizing c-0127OA emerging as promising therapeutic candidate for imperfecta.

Language: Английский

Citations

2
StaPep: An Open-Source Toolkit for Structure Prediction, Feature Extraction, and Rational Design of Hydrocarbon-Stapled Peptides DOI
Zhe Wang, Jianping Wu,

Mengjun Zheng

et al.

Journal of Chemical Information and Modeling, Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 6, 2024

All-hydrocarbon stapled peptides, with their covalent side-chain constraints, provide enhanced proteolytic stability and membrane permeability, making them superior to linear peptides. However, tools for extracting structural physicochemical descriptors predict the properties of hydrocarbon-stapled peptides are lacking. To address this, we present StaPep, a Python-based toolkit generating 3D structures calculating 21 features StaPep supports containing two non-standard amino acids (norleucine 2-aminoisobutyric acid) six non-natural anchoring residues (S3, S5, S8, R3, R5, R8), customization options other acids. We showcase StaPep's utility through three case studies. The first generates these mean RMSD 1.62 ± 0.86, offering essential insights drug design biological activity prediction. second develops machine learning models based on calculated molecular differentiate between membrane-permeable non-permeable achieving an AUC 0.93. third constructs regression antimicrobial against Escherichia coli, Pearson correlation 0.84. pipeline spans data retrieval, structure generation, feature calculation, modeling source codes set freely available Github: https://github.com/dahuilangda/stapep_package.

Language: Английский

Citations

2
Rational design of a new short anticancer peptide with good potential for cancer treatment DOI
Xiaoyan Wu, Yali Tian,

Kaixin Ran

et al.

European Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 273, P. 116519 - 116519

Published: May 20, 2024

Language: Английский

Citations

1