Microtubule-Targeting NAP Peptide-Ru(II)-polypyridyl Conjugate As a Bimodal Therapeutic Agent for Triple Negative Breast Carcinoma DOI

Atin Chatterjee,

Sandip Sarkar, Sangheeta Bhattacharjee

et al.

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 26, 2024

Triple-negative breast cancer (TNBC) poses significant treatment challenges due to its high metastasis, heterogeneity, and poor biomarker expression. The N-terminus of an octapeptide NAPVSIPQ (NAP) was covalently coupled a carboxylic acid derivative Ru(2,2′-bipy)32+ (Rubpy) synthesize N-stapled short peptide-Rubpy conjugate (Ru-NAP). This photosensitizer (PS) utilized treat TNBC through microtubule (MT) targeted chemotherapy photodynamic therapy (PDT). Ru-NAP formed more elaborate molecular aggregates with fibrillar morphology as compared NAP. A much higher binding affinity over NAP toward β-tubulin (KRu-NAP: (6.8 ± 0.55) × 106 M–1; KNAP: (8.2 1.1) 104 M–1) observed stronger electrostatic interactions between the MT average linear charge density ∼85 e/nm cationic Rubpy part Ru-NAP. also supported by docking, simulation, appropriate imaging studies. promoted serum stability, specific E-site βIII-tubulin followed disruption network, effective singlet oxygen generation in cells (MDA-MB-231), causing cell cycle arrest G2/M phase triggering apoptosis. Remarkably, MDA-MB-231 were sensitive noncancerous human embryonic kidney (HEK293 cells) when exposed light (LightIC50Ru-NAP[HEK293]: 17.2 2.5 μM, LightIC50Ru-NAP[MDA-MB-231]: 32.5 7.8 nM, DarkIC50Ru-NAP[HEK293]: > 80 DarkIC50Ru-NAP[MDA-MB-231]: 2.9 0.5 μM). effectively inhibited tumor growth xenograft models nude mice. Our findings provide strong evidence that has potential therapeutic role treatment.

Language: Английский

Recent Advances in Augmenting the Therapeutic Efficacy of Peptide–Drug Conjugates DOI Creative Commons
Jiahui Ma, Xuedan Wang, Yong-hua Hu

et al.

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

Published: April 23, 2025

There is an urgent need for the development of safe and effective modalities treatment diseases owing to drug resistance, undesired side effects, poor clinical outcomes. Combining cell-targeting efficient cell-killing properties, peptide-drug conjugates (PDCs) have demonstrated superior efficacy compared with peptides payloads alone. However, innovative molecular designs PDCs are essential further improving targeting precision, protease resistance stability, cell permeability, overall efficacy. Several strategies been developed address these challenges, such as multivalency approaches, bispecific targeting, long-acting PDCs. Other novel strategies, including overcoming biological barriers, conjugating functional payloads, macropinocytosis, also shown promise. This perspective compiles most recent enhancing PDC efficacy, highlights key advancements in PDC, provides insights on future directions

Language: Английский

Citations

0
Peptide–Drug Conjugates as Next-Generation Therapeutics: Exploring the Potential and Clinical Progress DOI Creative Commons
Krishna Jadhav, Ashwin Abhang, Eknath Kole

et al.

Bioengineering, Journal Year: 2025, Volume and Issue: 12(5), P. 481 - 481

Published: April 30, 2025

Peptide–drug conjugates (PDCs) have emerged as a next-generation therapeutic platform, combining the target specificity of peptides with pharmacological potency small-molecule drugs. As an evolution beyond antibody–drug (ADCs), PDCs offer distinct advantages, including enhanced cellular permeability, improved drug selectivity, and versatile design flexibility. This review provides comprehensive analysis fundamental components PDCs, homing peptide selection, linker engineering, payload optimization, alongside strategies to address their inherent challenges, such stability, bioactivity, clinical translation barriers. Therapeutic applications span oncology, infectious diseases, metabolic disorders, emerging areas like COVID-19, several advancing in trials achieving regulatory milestones. Innovations, bicyclic peptides, supramolecular architectures, novel technologies, are explored promising avenues enhance PDC design. Additionally, this examines trajectory emphasizing potential highlighting ongoing that exemplify efficacy. By addressing limitations leveraging advancements, hold immense promise targeted therapeutics capable complex disease states driving progress precision medicine.

Language: Английский

Citations

0
Key considerations based on pharmacokinetic/pharmacodynamic in the design of antibody-drug conjugates DOI Creative Commons
Yangyang Gao, Yuwei Xia, Yixin Chen

et al.

Frontiers in Oncology, Journal Year: 2025, Volume and Issue: 14

Published: Jan. 9, 2025

Antibody-drug conjugate (ADC) is an anticancer drug that links toxins to specifically targeted antibodies via linkers, offering the advantages of high target specificity and cytotoxicity. However, complexity its structural composition poses a greater difficulty for design studies. Pharmacokinetic/pharmacodynamic (PK/PD) based consideration ADCs has increasingly become hot research topic optimal in recent years, providing possible ideas obtaining with desirable properties. From assessment ADC action process on PK/PD, we introduce main strategies ADCs. In addition, investigated solve prominent problems clinic summarized evaluated specific ways optimize various PK/PD model from two perspectives optimizing structure properties drugs themselves. Through selection antigen, optimization linker, novel small molecule as payload, ADC, overcoming multi-drug resistance improving tumor penetration surface modification bystander effect provide more comprehensive accurate framework designing new We've expounded comprehensively applying pharmacokinetics or pharmacodynamics while obtain higher efficacy fewer side effects. ADC's property coming into play vivo study strategy, methods recommendations it been study-approved exert subtle role development whether preclinical trials clinical promotion. The unfolds detailed mechanism action, making easier control related parameters limited inevitable off-target toxicity remain challenging bottleneck.

Language: Английский

Citations

0
Repair of genomic interstrand crosslinks DOI
Marina A. Bellani,

Althaf Shaik,

Ishani Majumdar

et al.

DNA repair, Journal Year: 2024, Volume and Issue: 141, P. 103739 - 103739

Published: July 30, 2024

Language: Английский

Citations

1
Recent Progress in the Development of Peptide-Drug Conjugates (PDCs) for Cancer Therapy DOI

Haiqi He,

Xin Deng, Zhijie Wang

et al.

European Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 284, P. 117204 - 117204

Published: Dec. 24, 2024

Language: Английский

Citations

1
Radiosynthesis, Preparation, and Biological Evaluation of [99MTC]Tricarbonyl Pantoprazole for Stomach Ulcer Detection in Mice DOI
M. H. Sanad, H. M. Eyssa,

F. A. Marzook

et al.

Pharmaceutical Chemistry Journal, Journal Year: 2024, Volume and Issue: 58(6), P. 950 - 956

Published: Sept. 1, 2024

Language: Английский

Citations

1
His-Tagging: Exploring Precise Chemical Modification of Histidine-Containing Bioactive Peptide Sequences DOI
Sourav Chatterjee, Bishwajit Paul, Govindaswamy Shanker

et al.

Synlett, Journal Year: 2024, Volume and Issue: unknown

Published: June 3, 2024

Abstract The modification of biomolecules, particularly peptides, has garnered considerable attention from researchers, effectively serving as a connection between chemistry and biology. peptides can facilitate, among others, the generation peptide drugs, antibody–drug conjugates, probes for molecular imaging. Herein, we have carefully curated reactions chemical transformations bioactive sequences equipped with histidine amino acids that are conducive biological applications. This Account also highlights strategies might capture imagination both researchers synthetic chemists. 1 Introduction 2 Histidine Modification in Bioactive Peptides Proteins 3 Remote Protein Adjacent to 4 Conclusions Future Directions

Language: Английский

Citations

0
A Conjugate of an EGFR-Binding Peptide and Doxorubicin Shows Selective Toxicity to Triple-Negative Breast Cancer Cells DOI

Phi-Phung Than,

Shih-Jing Yao,

Emad Althagafi

et al.

ACS Medicinal Chemistry Letters, Journal Year: 2024, Volume and Issue: 16(1), P. 109 - 115

Published: Dec. 12, 2024

Selective targeting of cancer cells via overexpressed cell-surface receptors is a promising strategy to enhance chemotherapy efficacy and minimize off-target side effects. In this study, we designed peptide 31 (YHWYGYTPERVI) target the epidermal growth factor receptor (EGFR) in triple-negative breast (TNBC) cells. Peptide internalized by TNBC through EGFR-mediated endocytosis shares sequence structural similarities with human EGF (hEGF), natural EGFR ligand. Unlike hEGF, does not induce cell migration A novel conjugate doxorubicin (Dox) retains selectivity for exhibits significant toxicity comparable that unconjugated Dox. Importantly, shows no toward normal epithelial up high concentration (25 μM). Thus, serves as versatile ligand developing conjugates EGFR-positive cancers.

Language: Английский

Citations

0
Microtubule-Targeting NAP Peptide-Ru(II)-polypyridyl Conjugate As a Bimodal Therapeutic Agent for Triple Negative Breast Carcinoma DOI

Atin Chatterjee,

Sandip Sarkar, Sangheeta Bhattacharjee

et al.

Journal of the American Chemical Society, Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 26, 2024

Triple-negative breast cancer (TNBC) poses significant treatment challenges due to its high metastasis, heterogeneity, and poor biomarker expression. The N-terminus of an octapeptide NAPVSIPQ (NAP) was covalently coupled a carboxylic acid derivative Ru(2,2′-bipy)32+ (Rubpy) synthesize N-stapled short peptide-Rubpy conjugate (Ru-NAP). This photosensitizer (PS) utilized treat TNBC through microtubule (MT) targeted chemotherapy photodynamic therapy (PDT). Ru-NAP formed more elaborate molecular aggregates with fibrillar morphology as compared NAP. A much higher binding affinity over NAP toward β-tubulin (KRu-NAP: (6.8 ± 0.55) × 106 M–1; KNAP: (8.2 1.1) 104 M–1) observed stronger electrostatic interactions between the MT average linear charge density ∼85 e/nm cationic Rubpy part Ru-NAP. also supported by docking, simulation, appropriate imaging studies. promoted serum stability, specific E-site βIII-tubulin followed disruption network, effective singlet oxygen generation in cells (MDA-MB-231), causing cell cycle arrest G2/M phase triggering apoptosis. Remarkably, MDA-MB-231 were sensitive noncancerous human embryonic kidney (HEK293 cells) when exposed light (LightIC50Ru-NAP[HEK293]: 17.2 2.5 μM, LightIC50Ru-NAP[MDA-MB-231]: 32.5 7.8 nM, DarkIC50Ru-NAP[HEK293]: > 80 DarkIC50Ru-NAP[MDA-MB-231]: 2.9 0.5 μM). effectively inhibited tumor growth xenograft models nude mice. Our findings provide strong evidence that has potential therapeutic role treatment.

Language: Английский

Citations

0