Journal of Peptide Science最新文献

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.

Peptides play essential roles in biological systems and serve as key agents in therapeutics, biomaterials, and drug delivery. Despite their broad utility, peptide design is limited by rapid degradation, low oral bioavailability, and the inefficiency of conventional synthesis and screening methods. This review provides a comprehensive overview of computational approaches that have emerged as effective alternatives, enabling the exploration of a large chemical space and the virtual screening of thousands of peptides. We detail the critical role of specialized peptide databases, computational tools, and advanced methodologies, including structure-based design, molecular dynamics (MD) simulations, and ligand-based approaches. A particular focus is placed on the transformative impact of machine learning (ML), deep learning (DL), and generative AI models, which are accelerating the discovery of novel peptides. While these methods offer promising solutions, we also address key challenges like data inconsistency, model interpretability, and the need for better forcefields. By highlighting these advancements and limitations, this review aims to provide a roadmap for leveraging computational design in peptide research.

Molecular library display systems utilizing phage, bacteria, and genetic material are powerful tools for identifying target-specific peptides. Libraries of sufficient diversity are required to isolate target-specific peptides. Although the evolution of molecular display techniques—from phage display to mRNA display—has substantially expanded achievable library diversities, the minimum diversity required to reliably isolate target-specific peptides remains unclear. Here, we propose a straightforward equation to estimate the minimum diversity (Y). Y is defined by three experimentally accessible parameters: (i) the number of important amino acids (m, consensus motif residues whose substitution markedly reduces binding), (ii) the number of independent binding sites (s) on the target molecule and (iii) the arrangement factor (a) that counts the possible positional permutations of the motif within the random region. By analyzing 35 target-specific peptides reported previously, we found that the average value of m was ≈4, whereas a and s were most frequently ≈1. These representative values imply a practical lower-bound benchmark of diversity, Y ≥ 1.6 × 10⁵ for random peptide libraries in screening. Our findings will aid researchers in rationalizing the design and construction of peptide libraries, facilitating efficient identification of high-affinity, target-specific peptides.

Heavy metal (HM) pollution, such as cadmium, significantly impacts ecosystems and poses serious risks to human health. In soil, it reduces fertility and agricultural productivity. On the other hand, bacteria employ several tolerance mechanisms in response to HM exposure, including the production of siderophores, exopolysaccharides, proteins, and peptides. This study aimed to identify the possible molecular mechanisms involved in Cd(II) tolerance in the Delftia lacustris B11CM strain using nano LC/MS–MS proteomic analysis, siderophore and exopolysaccharide assays, protein and thiol quantification, and the comparison of protein profiles obtained by SDS-PAGE. The results demonstrated the presence of siderophores, an increase in the production of exopolysaccharides, and thiol-rich compounds. A total of 80 proteins were detected in the presence of cadmium, which are involved in catalytic activity, metalloproteins or proteins that bind to different molecules, and transporters. These proteins participate in metabolism and cellular processes, with most of them located in the plasma membrane. These molecules likely enable this bacterium to survive in cadmium-contaminated environments and are directly associated with tolerance mechanisms, highlighting the potential of this strain to be used as a bioinoculant with agronomic interest or for bioremediation.

Peptide nucleic acids (PNAs) containing γ-S-modified monomers show promise for antisense applications but face synthetic challenges due to their charged backbone. This study aimed to optimize the Boc solid-phase synthesis protocol for L-Glu-based γ-S-PNA oligomers. We systematically evaluated four tetramer designs incorporating glycine or β-alanine C-terminal linkers, monitoring resin loading (0.1–0.2 mmol/g), chain elongation (via a novel N = M × Q mass-corrected metric), and cleavage stability. While monomer sequence order in the C-terminal region showed no significant impact, spacer presence proved critical: β-alanine linkers enabled target oligomer isolation (≤ 10% yields), whereas linker-free tetramers degraded during acidic cleavage. These findings establish a foundation for synthesizing γ-S-PNAs while highlighting the need for further linker optimization to improve yields.

The rise of multidrug-resistant Streptococcus pneumoniae poses a major public health threat, necessitating novel therapeutic targets. Pneumococcal Surface Adhesin A (PsaA), a conserved surface lipoprotein, plays a key role in manganese acquisition, colonization and virulence. Immunization with PsaA elicits protective immunity, while fragment-based drug design has identified inhibitors disrupting its function. PsaA emerges as a promising molecular target for innovative therapeutic strategies against pneumococcal diseases. Antimicrobial peptides (AMPs) are crucial components of the innate immune system, providing a potent defence mechanism against a broad spectrum of pathogens. Moricin, an AMP initially identified in Bombyx mori, exhibits robust antimicrobial activity against Gram-positive bacteria. This study explores the inhibitory effects of moricin on S. pneumoniae, a significant human pathogen responsible for severe infections such as pneumonia, meningitis and sepsis. In silico analyses, including molecular docking and molecular dynamics simulations, revealed a strong interaction between moricin and the PsaA. In vitro studies corroborated the computational findings, demonstrating a dose-dependent inhibition of S. pneumoniae growth. Moricin induced bacterial membrane disruption, evidenced by increased membrane permeability, release of intracellular contents and altered membrane potential, highlighting the bactericidal mode of action. Furthermore, time-kill kinetics revealed rapid bacterial eradication, underscoring moricin's efficacy. Additionally, toxicity assays on the macrophage BV2 cell line demonstrated that moricin caused no significant structural or organelle damage, emphasizing its biocompatibility and safety. The integration of in silico and in vitro approaches provides comprehensive mechanistic insights into moricin's antimicrobial action and establishes its potential as a safe and effective therapeutic agent against S. pneumoniae.