Stapled peptides have the ability to mimic α-helices involved in protein binding and have proved to be effective pharmacological agents for disrupting protein-protein interactions. DNA-binding proteins such as transcription factors bind their cognate DNA sequences an α-helix interacting with the major groove of DNA. We previously developed a stapled peptide based on the bacterial alternative sigma factor RpoN capable of binding the RpoN DNA promoter sequence and inhibiting RpoN-mediated expression in . We have elucidated a structure-activity relationship for DNA binding by this stapled peptide, improving DNA binding affinity constants in the high nM range. Lead peptides were shown to have low toxicity as determined by their low hemolytic activity at 100 μM and were shown to have anti-virulence activity in a model of infection. These findings support further preclinical development of stapled peptides as antivirulence agents targeting .
Combining helical foldamers with α-peptides can produce α-helix mimetics with a reduced peptide character and enhanced resistance to proteolysis. Previously, we engineered a hybrid peptide-oligourea sequence replicating the N-terminal α-helical domain of p53 to achieve high affinity binding to hDM2. Here, we further advance this strategy by combining the foldamer approach with side chain cross-linking to create more constrained cell-permeable inhibitors capable of effectively engaging the target within cells.
Peptide stapling has emerged as a versatile approach in drug discovery to reinforce secondary structure elements especially α-helices and improve properties of linear bioactive peptides. Inspired by the prevalence of arginine in protein-protein and protein-DNA interfaces, we investigated guanidinium-stapling as a means to constrain helical peptides. Guanidinium stapling was readily achieved on solid support, utilizing two orthogonally protected lysine or unatural α-amino acid residues with an amino function.
DISFARM, Department of Pharmaceutical Sciences, "A. Marchesini" General and Organic Chemistry Section, Università degli Studi di Milano, Via Venezian 21, Milan 20133, Italy.
In nature, organisms living in extreme environmental conditions produce antifreeze proteins (AFPs) that prevent the growth of ice crystals and depress the freezing point of body fluids. In this study, three different peptides derived from the N-terminal sequence of the helical type I AFP HPLC6, along with a stapled derivative produced via on-resin microwave-assisted copper(I)-catalyzed azide-alkyne cycloaddition, were conjugated to gold nanoparticles. The aim of decorating the surface of the nanoparticles with multiple copies of the peptides was to combine the ice-binding capability of the peptides with the size of a nanoparticle, thus, mimicking the protein bulkiness to enhance the peptide antifreeze activity.
Stapling rigidifies peptides through covalent linkages between amino acids. We introduce 2-chloromethyl-6-cyanopyridine for non-symmetric stapling of N-terminal and internal cysteines. This biocompatible method produces diverse peptide macrocycles with enhanced affinity, stability and inhibitory potency.
Department of Hematology, the Second Xiangya Hospital; School of Life Sciences; Hunan Province Key Laboratory of Basic and Applied Hematology, Central South University, Changsha, Hunan, 410011, China.
Multiple myeloma (MM), the world's second most common hematologic malignancy, poses considerable clinical challenges due to its aggressive progression and resistance to therapy. Addressing these challenges requires a detailed understanding of the mechanisms driving MM initiation, progression, and therapeutic resistance. This study identifies the pseudokinase tribble homolog 3 (TRIB3) as a high-risk factor that promotes MM malignancy in vitro and in vivo.
