The polo-box domain (PBD) of Plk1 is a promising target for cancer therapeutics. We designed and synthesized novel phosphorylated macrocyclic peptidomimetics targeting PBD based on acyclic phosphopeptide PMQSpTPL. The inhibitory activities of on Plk1-PBD is >30-fold higher than those of PMQSpTPL. Both and possess excellent selectivity for Plk1-PBD over Plk2/3-PBD. Analysis of the cocrystal structure of Plk1-PBD in complex with reveals that the 3-(trifluoromethyl)benzoyl group in interacts with Arg516 through a π-stacking interaction. This π-stacking interaction, which has not been reported previously, provides insight into the design of novel and potent Plk1-PBD inhibitors. Furthermore, , a PEGlyated macrocyclic phosphopeptide derivative, induces Plk1 delocalization and mitotic failure in HeLa cells. Also, the number of phospho-H3-positive cells in a zebrafish embryo increases in proportion to the amount of . Collectively, the novel macrocyclic peptidomimetics should serve as valuable templates for the design of potent and novel Plk1-PBD inhibitors.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10411393 | PMC |
| http://dx.doi.org/10.1021/acs.jmedchem.1c01359 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Design and functional studies of xylene-based cyclic mimetics of SOCS1 protein.
Eur J Med Chem
January 2025
Department of Pharmacy - University of Naples Federico II, 80131, Naples, Italy; Institute of Biostructures and Bioimaging - CNR, 80131, Naples, Italy. Electronic address:
Peptidomimetics of Suppressors of cytokine signaling 1 (SOCS1) protein demonstrated valid therapeutic potentials as anti-inflammatory agents. Indeed, SOCS1 has a small kinase inhibitory region (KIR) primarily involved in the inhibition of the JAnus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) pathway Herein, on the basis of previous investigations on a potent mimetic of KIR-SOCS1, named PS5, we designed and evaluated the SAR (Structure Activity Relationship) features of two xylene-based macrocycles analogues of PS5. These novel compounds bear thiol-xylene linkages with mono- and bi-cyclic scaffolds: they were in vitro functionally investigated toward JAK2 catalytic domain, as ligands with microscale thermophoresis (MST) and as inhibitors through LC-MS analyses.
View Article and Find Full Text PDFRecent advances in peptide macrocyclization strategies.
Chem Soc Rev
December 2024
Department of Chemistry, Hong Kong Baptist University, Kowloon Tong, Kowloon, Hong Kong SAR, P. R. China.
Recently, owing to their special spatial structures, peptide-based macrocycles have shown tremendous promise and aroused great interest in multidisciplinary research ranging from potent antibiotics against resistant strains to functional biomaterials with novel properties. Besides traditional monocyclic peptides, many fascinating polycyclic and remarkable higher-order cyclic, spherical and cylindric peptidic systems have come into the limelight owing to breakthroughs in various chemical (, native chemical ligation and transition metal catalysis), biological (, post-translational enzymatic modification and genetic code reprogramming), and supramolecular (, mechanically interlocked, metal-directed folding and self-assembly noncovalent interactions) macrocyclization strategies developed in recent decades. In this tutorial review, diverse state-of-the-art macrocyclization methodologies and techniques for peptides and peptidomimetics are surveyed and discussed, with insights into their practical advantages and intrinsic limitations.
View Article and Find Full Text PDFTackling Undruggable Targets with Designer Peptidomimetics and Synthetic Biologics.
Chem Rev
November 2024
Department of Chemistry, The University of Chicago, Chicago, Illinois 60637, United States.
The development of potent, specific, and pharmacologically viable chemical probes and therapeutics is a central focus of chemical biology and therapeutic development. However, a significant portion of predicted disease-causal proteins have proven resistant to targeting by traditional small molecule and biologic modalities. Many of these so-called "undruggable" targets feature extended, dynamic protein-protein and protein-nucleic acid interfaces that are central to their roles in normal and diseased signaling pathways.
View Article and Find Full Text PDFDevelopment and Prospects of Furin Inhibitors for Therapeutic Applications.
Int J Mol Sci
August 2024
ChemDiv Inc., San Diego, CA 92130, USA.
Furin, a serine protease enzyme located in the Golgi apparatus of animal cells, plays a crucial role in cleaving precursor proteins into their mature, active forms. It is ubiquitously expressed across various tissues, including the brain, lungs, gastrointestinal tract, liver, pancreas, and reproductive organs. Since its discovery in 1990, furin has been recognized as a significant therapeutic target, leading to the active development of furin inhibitors for potential use in antiviral, antibacterial, anticancer, and other therapeutic applications.
View Article and Find Full Text PDFInnovative Therapeutic Approaches Targeting K-Ras: Analysis of Macrocyclic Compounds, Peptidomimetics, and Pyridopyrimidine Inhibitors.
ACS Med Chem Lett
August 2024
Usona Institute, Fitchburg, Wisconsin 53711-5300, United States.
This Patent Highlight presents a detailed analysis of three novel classes of compounds designed to inhibit multiple forms of the K-Ras protein, as described in three patent applications. These patents cover macrocyclic compounds, peptidomimetics, and pyridopyrimidine inhibitors. This work explores each invention's design, mechanism of action, relevance to cancer treatment, and results from assays demonstrating the efficacy of these compounds.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!