Cyclobutane-bearing restricted anchoring residues enabled geometry-specific hydrocarbon peptide stapling.

Stapled peptides are regarded as the promising next-generation therapeutics because of their improved secondary structure, membrane permeability and metabolic stability as compared with the prototype linear peptides. Usually, stapled peptides are obtained by a hydrocarbon stapling technique, anchoring from paired olefin-terminated unnatural amino acids and the consequent ring-closing metathesis (RCM). To investigate the adaptability of the rigid cyclobutane structure in RCM and expand the chemical diversity of hydrocarbon peptide stapling, we herein described the rational design and efficient synthesis of cyclobutane-based conformationally constrained amino acids, termed ()-1-amino-3-(but-3-en-1-yl)cyclobutane-1-carboxylic acid (E) and ()-1-amino-3-(but-3-en-1-yl)cyclobutane-1-carboxylic acid (Z).

Benzyl stapled modification and anticancer activity of antimicrobial peptide A4K14-Citropin 1.1.

A4K14-Citropin 1.1 (GLFAVIKKVASVIKGL-NH) is a derived antimicrobial peptide (AMP) with a more stable α-helical structure at the C-terminal compared to prototype Citropin 1.1 which was obtained from glandular skin secretions of Australian freetail lizards.

Design, synthesis and antitumor activity of Ascaphin-8 derived stapled peptides based on halogen-sulfhydryl click chemical reactions.

Ascaphin-8 (GFKDLLKGAAKALVKTVLF-NH), isolated from the norepinephrine-stimulated skin secretion of the North American-tailed frog , is a C-terminal α-helical antimicrobial peptide with potential antitumor activity. However, linear peptides are difficult to be applied directly as drugs because of their inherent defects, such as low hydrolytic enzyme tolerance and poor structural stability. In this study, we designed and synthesized a series of stapled peptides based on Ascaphin-8 thiol-halogen click chemistry.

Methionine restriction promotes cGAS activation and chromatin untethering through demethylation to enhance antitumor immunity.

Cyclic GMP-AMP synthase (cGAS) is the major sensor for cytosolic DNA and activates type I interferon signaling and plays an essential role in antitumor immunity. However, it remains unclear whether the cGAS-mediated antitumor activity is affected by nutrient status. Here, our study reports that methionine deprivation enhances cGAS activity by blocking its methylation, which is catalyzed by methyltransferase SUV39H1.

DUCNP@Mn-MOF/FOE as a Highly Selective and Bioavailable Drug Delivery System for Synergistic Combination Cancer Therapy.

Heterostructures comprising lanthanide-doped upconversion nanoparticles (DUCNPs) and metal-organic frameworks (MOFs) are emerging as promising nanosystems for integrating medical diagnosis and treatment. Here, the DUCNP@Mn-MOF nanocarrier was developed, which showed good efficiency for loading and delivering a cytotoxic antitumor agent (3-F-10-OH-evodiamine, FOE). The combined advantages of the pH-responsive and peroxidase-like properties of Mn-MOF and the unique optical features of DUCNPs granted the DUCNP@Mn-MOF/FOE system synergistic chemodynamic and chemotherapeutic effects.

Configuration-Specific Antibody for Bacterial Heptosylation: An Antiadhesion Therapeutic Strategy.

Alternative antibacterial therapies refractory to existing mechanisms of antibiotic resistance are urgently needed. One such attractive therapy is to inhibit bacterial adhesion and colonization. Ser O-heptosylation (Ser O-Hep) on autotransporters of Gram-negative bacteria is a novel glycosylation and has been proven to be essential for bacterial colonization.

Design of stapled peptide-based PROTACs for MDM2/MDMX atypical degradation and tumor suppression.

Although stapled peptides offer a powerful solution to overcome the susceptibility of linear peptides to proteolytic degradation and improve their ability to cross membranes, an efficient and durable disease treatment strategy has not yet been developed due to the inevitable elimination of peptide inhibitors and rapid accumulation of target proteins. Herein we developed stapled peptide-based proteolysis-targeting chimeras (SP-PROTACs), that simultaneously exhibited improved cellular uptake and proteolytic stability attributed to the stapled peptides, and efficient target protein degradation promoted by the PROTACs. Based on the PMI peptide with dual specificity for both MDM2 and MDMX, a series of SP-PROTACs were designed.

Stapled Peptides Targeting SARS-CoV-2 Spike Protein HR1 Inhibit the Fusion of Virus to Its Cell Receptor.

The pandemic of acute respiratory disease in 2019 caused by highly pathogenic and infectious SARS-CoV-2 has seriously endangered human public safety. The 6-HB (HR1-HR2 complex) formation occurring in the process of spike protein-mediated membrane fusion could serve as a conserved and potential target for the design of fusion inhibitors. Based on the HR2 domain of 6-HB, we designed and synthesized 32 stapled peptides using an all-hydrocarbon peptide stapling strategy.

A mirror-image protein-based information barcoding and storage technology.

A mirror-image protein-based information barcoding and storage technology wherein D-amino acids are used to encode information into mirror-image proteins that are chemically synthesized is described. These mirror-image proteins were then fused into various materials from which information-encoded objects were produced. Subsequently, the mirror-image proteins were extracted from the objects using biotin-streptavidin resin-mediated specific enrichment and cleaved using an Ni(II)-mediated selective peptide cleavage.

Design, synthesis, and biological evaluation of stapled ascaphin-8 peptides.

Ascaphin-8 is an α-helical anti-tumor and antimicrobial peptide containing 19 residues, which was isolated from norepinephrine-stimulated skin secretions of the North American tailed frog Ascaphus truei. To improve both its stability and biological activities, a series of hydrocarbon-stapled analogs of Ascaphin-8 were synthesized and investigated for their potential antiproliferative activities. The activity studies were evaluated using the CCK-8 method and colony formation assay on human cancer cell lines.

Design, synthesis, and anti-tumor activities of novel Brevinin-1BYa peptidomimetics.

Brevinin-1BYa is an amphibian skin-derived peptide that exhibits promising anti-microbial activity against gram-positive and -negative bacteria. However, the anti-tumor activity of Brevinin-1BYa remains unclear, and, more importantly, its therapeutic application is limited owing to its poor protease and reduction stability. In this study, a series of novel Brevinin-1BYa derivatives, including O-linked N-acetyl-glucosamine glyclopeptides and disulfide bond mimetics, were designed and synthesized.

Design, Synthesis, and Antitumor Activities Study of Stapled A4K14-Citropin 1.1 Peptides.

A4K14-citropin 1.1 is a structurally optimized derivative derived from amphibians' skin secreta peptide Citropin, which exhibits broad biological activities. However, the application of A4K14-citropin 1.

Stapled Helical Peptides Bearing Different Anchoring Residues.

A large proportion of protein-protein interactions (PPIs) occur between a short peptide and a globular protein domain; the peptides involved in surface interactions play important roles, and there is great promise for using peptide motifs to interfere with protein interactions. Peptide inhibitors show more promise in blocking large surface protein interactions compared to small molecule inhibitors. However, peptides have drawbacks including poor stability against circulating proteolytic enzymes and an intrinsic inability to penetrate cell membranes.

A PROTAC peptide induces durable β-catenin degradation and suppresses Wnt-dependent intestinal cancer.

Aberrant activation of Wnt/β-catenin signaling has been associated with the onset and progression of many types of tumors and thus β-catenin represents one attractive intracellular target for cancer therapy. Based on the Axin-derived peptide that binds to β-catenin, two stapled peptides SAHPA1 and xStAx were reported to enhance or impair Wnt/β-catenin signaling, respectively. In this study, we designed PROTACs (proteolysis targeting chimeras) by coupling SAHPA1 or xStAx with the VHL ligand to achieve efficient β-catenin degradation.

Dithiocarbamate-inspired side chain stapling chemistry for peptide drug design.

Two major pharmacological hurdles severely limit the widespread use of small peptides as therapeutics: poor proteolytic stability and membrane permeability. Importantly, low aqueous solubility also impedes the development of peptides for clinical use. Various elaborate side chain stapling chemistries have been developed for α-helical peptides to circumvent this problem, with considerable success in spite of inevitable limitations.

A Highly Efficient Synthesis of Polyubiquitin Chains.

A robust, microwave-assisted, highly efficient, solid-phase peptide synthesis method for preparing isopeptide-linked 62-mer and 76-mer isoubiquitins and polyubiquitin is developed. The strategy avoids the use of costly resins and pseudoprolines, and the isopeptide-linked building blocks can be assembled with high initial purity within 1 day. All seven diubiquitins are successfully synthesized on a multi-milligram scale; a four-segment, three-ligation method is used to obtain a K33-/K11-linked mixed triubiquitin in excellent yield.

Oncogene DEK is highly expressed in lung cancerous tissues and positively regulates cell proliferation as well as invasion.

DEK is a protein ubiquitously expressed in multicellular organisms as well as certain unicellular organisms. It is associated with the regulation of cell proliferation, differentiation, migration, apoptosis, senescence, self-renewal and DNA repairing. In tumor cells it is associated with the carcinogenesis process, however there have been few previous studies into the expression of DEK in lung cancer.

Structure-based development of an osteoprotegerin-like glycopeptide that blocks RANKL/RANK interactions and reduces ovariectomy-induced bone loss in mice.

Osteoporosis is a metabolic bone disease characterized by low bone mass and micro-architectural deterioration of bone, for which the underlying mechanism is an imbalance between bone resorption and bone remodeling. The protein-protein interactions between receptor activator of nuclear factor-κB ligand (RANKL), RANK (its receptor), and osteoprotegerin (OPG), are known to mediate the development and activation of osteoclasts in bone remodeling, and are regarded as a pivotal therapeutic target for the treatment of osteoporosis. Herein, we disclose the successful development of a novel glycopeptide (OM-2), the structure of which is based on the key interacting sites of the reported RANKL and OPG crystal structure.

Esculentoside A specifically binds to ribosomal protein S3a and impairs LPS-induced signaling in macrophages.

Esculentoside A (EsA), a saponin isolated from Phytolacca esculenta, is reported as a potent suppressor of pro-inflammatory functions of macrophages. However, little is known about the target proteins of EsA for its anti-inflammatory activity. In the present study, to identify the intracellular target for EsA, affinity resins bearing immobilized EsA were used to capture binding proteins of EsA from RAW264.

A novel peptide stapling strategy enables the retention of ring-closing amino acid side chains for the Wnt/β-catenin signalling pathway.

The all-hydrocarbon peptide stapling strategy has recently been extensively explored in drug discovery. There remains the potential for improvement regarding the retention of the amino acid side chains at the stapled positions. Herein, we describe a new series of amino acids that not only contain the native side chains, but also carry the alkenyl arms that are needed for the ring-closing stapling chemistry.

Total Synthesis and Antibacterial Study of Cyclohexapeptides Desotamide B, Wollamide B and Their Analogs.

As natural-product-derived antibiotics, desotamides A - D and wollamides exhibit growth inhibitory activity against Gram-posivite bacteria (IC 0.6 - 7 μm) and are noncytotoxic to mammalian cells (IC  > 30 μm). Herein we firstly report the total synthesis of above two cyclohexapeptides as well as a series of structural variants through solid phase peptide synthesis, of which 3 displayed a 2-fold increase of antibacterial activity when compared with the original peptide 1.

Resolving the α-glycosidic linkage of arginine-rhamnosylated translation elongation factor P triggers generation of the first Arg specific antibody.

A previously discovered posttranslational modification strategy - arginine rhamnosylation - is essential for elongation factor P (EF-P) dependent rescue of polyproline stalled ribosomes in clinically relevant species such as and . However, almost nothing is known about this new type of -linked glycosylation. In the present study we used NMR spectroscopy to show for the first time that the α anomer of rhamnose is attached to Arg32 of EF-P, demonstrating that the corresponding glycosyltransferase EarP inverts the sugar of its cognate substrate dTDP-β-l-rhamnose.