Journal of Peptide Science最新文献

Human bone morphogenetic protein-2 (BMP2) is an effective osteoinductor in bone formation and growth via binding to its cognate receptors and coreceptors. Traditionally, the protein is identified to possess a conformational wrist epitope and a linear knuckle epitope that can be recognized by type I and type II receptors, respectively. In this study, we defined an additional epitope termed elbow as the specific binding site of its coreceptor, which is concentrated into a small helical hairpin region of BMP2 monomer 1 and partially overlaps with wrist but is far away from knuckle. A linear lEEP peptide is derived from the elbow epitope, which, however, is intrinsically disordered and cannot be maintained in native helical hairpin conformation due to lack of BMP2 protein context support, thus only exhibiting a low affinity to coreceptor. Disulfide stapling strategy is then used to stabilize the helical hairpin conformation of linear lEEP, which results in its two cyclic counterparts. The stapling is demonstrated to effectively improve peptide affinity and also exhibits a high selection for coreceptor over type-I receptor. The cyclic peptides are found to maintain a well-ordered, native-like conformation, which can be readily recognized by coreceptor through a conformational selection mechanism.

Here, we report on an improved synthesis of the novel amino acid 2-thiohistidine and its Fmoc-derivative through the addition of sodium chloride to the isolation steps of each synthetic procedure. These compounds must be synthesized in either water or a mixture of water/organic solvent and have proven difficult to isolate by traditional methods. We serendipitously discovered that the addition of sodium chloride caused each compound to precipitate from the solution during the workup. Since 2-thiohistidine is the amino acid analogue of the natural product ergothioneine, we hypothesize that sodium cations mimic the binding of other biologically relevant metal cations to the thioimidazole moiety. Ergothioneine is known to bind Cu⁺, Zn²⁺, and Hg²⁺, and it may bind other metals. Our fortuitous discovery is not only useful for the isolation and purification of 2-thiohistidine and its derivatives; peptides that contain this unique amino acid may be designed to take advantage of binding to Group I cations and other metals.

Incretin-based therapies have become central to type 2 diabetes (T2D) management, offering benefits beyond glycemic control, including weight reduction, cardiovascular protection, and emerging roles in renal and neurological health. This review addresses the question: What are the recent advances in GLP-1, GIP, and glucagon receptor agonists, and how do formulation strategies overcome biopharmaceutical challenges? We systematically analyzed late-stage clinical trials and formulation approaches for peptide-based therapies. The review focuses on therapeutic efficacy, structural and physicochemical properties influencing absorption, distribution, and metabolic stability, and strategies to mitigate degradation pathways such as enzymatic hydrolysis and peptide aggregation. Additionally, innovative delivery systems such as oral peptide formulations and long-acting injectables demonstrate promise in addressing inherent challenges of peptide drug delivery. By integrating clinical outcomes with mechanistic and formulation insights, this review highlights the evolving landscape of incretin-based therapies and underscores innovative solutions for peptide stabilization and delivery. These findings provide a forward-looking perspective for clinicians, researchers, and pharmaceutical scientists engaged in T2D management and drug development.

The aim of our work was to analyze new functionalized analogues of 1-nitroacridine/4-methyl-1-nitroacridine and 4-nitroacridone connected to tuftsin/retro-tuftsin derivatives as a potential anticancer therapeutics. Using the MTT assay, we have evaluated the cytotoxic activity of synthesized analogues against the Jurkat cell line and healthy donor–isolated peripheral blood mononuclear cells (PBMCs). Jurkat cells were susceptible to several of the acridine derivatives, whereas PBMCs were sensitive to two compounds only. 4-Methyl-1-nitro-acridine analogue, classified as compound 28, has exhibited the greatest anticancer potential with 4-fold higher cytotoxicity toward Jurkat cells and 12-fold lower cytotoxicity against PBMCs when compared with control therapeutics. Subsequent molecular docking analysis suggested that binding to epidermal growth factor receptor (EGFR) and proto-oncogene tyrosine-protein kinase Src molecules could be, at least partially, responsible for observed biological effects of created acridine/acridone analogues.

Peptides are important tools in biological, medical, and pharmaceutical research. Solid-phase peptide synthesis (SPPS) is the primary method for their preparation in high yields and purity. However, SPPS often encounters difficulties due to the occurrence of side reactions, which can generate by-products that are difficult to remove. Side reactions can occur under both basic and acidic conditions, resulting in reduced yields, costly purification processes, and sometimes potential inaccessibility of the target peptides. By-products include the formation of aspartimide, glutarimide, and pyroglutamic acid. The problem of unwanted intramolecular cyclizations is well known and unavoidable, in some cases minimized, as it depends on the intrinsic thermodynamics of the final structures. In this context, we report a systematic analysis of the side reactions that occur during SPPS in peptides containing the Glu-Asp-Tyr motif. This study is the first to investigate the formation of three different by-products within the same peptide sequence and to provide valuable insights into the experimental conditions that favor one reaction over the others. The study aims to identify the optimal experimental conditions to mitigate these by-products' formation. Our results highlight that the steric and conformational effects of the growing protected peptide chain play a role that is often overlooked or misinterpreted.

Short neuropeptide F (sNPF) is a peptide unique to insects, characterized by a C-terminal phenylalanine and a conserved RLRFa motif, and plays key roles in controlling feeding behavior, growth, circadian rhythms, and water–salt homeostasis. We previously identified an sNPF analog, I-3, with aphidicidal activity. In this study, 10 sNPF analogs with aromatic or nonaromatic modifications at the N-terminus were designed based on I-3, using molecular docking and peptidomimetic strategies to investigate the role of N-terminal residues. Aphicidal activity showed that A-1 has stronger activity than I-3 and pymetrozine. Structure–activity analysis indicated that a benzene ring with electronegative and lipophilic groups at the N-terminus is key for aphicidal activity. Molecular docking and molecular dynamics simulations showed A-1 binds more stably to the receptor than I-3. Toxicity tests on honeybees (Apis mellifera) confirm that compound A-1, which exhibits strong aphidicidal activity, is safe for nontarget organisms. Additionally, Admetsar3 evaluations indicate low toxicity risks for all compounds. Therefore, A-1 represents a promising, selective, and eco-friendly insecticide for controlling pea aphids, and this study validates the feasibility of developing novel green pesticides based on sNPF.