Search Results (82)

Cyclodepsipeptides constitute a structurally diverse class of natural products composed of amino acid and hydroxy acid residues interconnected through both amide and ester bonds. Among them, xylaroamide A, a cyclic heptadepsipeptide, was recently identified from an endolichenic Xylaria species via a molecular networking-guided discovery approach. Despite xylaroamide A exhibiting intriguing structural features and notable bioactivity potential, its total synthesis has thus far remained unexplored. Herein, we report the first total synthesis of xylaroamide A, achieved through a hybrid solid/solution-phase synthetic approach. The linear precursor was assembled in accordance with the native amino acid sequence via Fmoc-based solid-phase peptide synthesis, incorporating the preassembled ester fragment at a later stage of assembly. Subsequent macrocyclization took place under high-dilution conditions to furnish the target cyclodepsipeptide. The structure of the synthetic product was confirmed by means of optical rotation and NMR and MS spectroscopic analyses, which exhibited good agreement with the reported data for the natural product. This work establishes a reliable and efficient synthetic route to xylaroamide A and provides a foundation for further bioactivity and structure optimization investigations. Full article

Macrocyclic drugs are promising for targeting undruggable proteins, including those in cancer. Our prior work identified BE-43547A₂ (BE) as a selective inhibitor of pancreatic cancer stem cells in PANC-1 cultures, but its high lipophilicity limits clinical application. To address this, we designed derivatives retaining BE’s backbone while modifying tail groups to improve its properties. A concise total synthesis enabled a versatile late-stage intermediate (compound 17), serving as a platform for efficient diversification of BE analogs via modular click chemistry. This approach introduced a central triazole ring connected by flexible alkyl spacers. Key properties, including lipophilicity, solubility, and Caco-2 permeability, were experimentally determined. These derivatives exhibited reduced lipophilicity and improved solubility but unexpectedly lost cellular activity. Direct target engagement studies using MicroScale Thermophoresis (MST) revealed compound-dependent deactivation mechanisms: certain derivatives retained binding to eEF1A1 with only modestly reduced affinity (e.g., compound 29), while others showed no detectable binding (e.g., compound 31). Microsecond-scale molecular dynamics simulations and free-energy calculations showed that, for derivatives retaining target affinity, tail modifications disrupted the delicate balance of drug–membrane and drug–solvent interactions, resulting in substantially higher transmembrane free-energy penalties (>5 kcal/mol) compared to active compounds (<2 kcal/mol). These insights emphasize the need to simultaneously preserve both target engagement and optimal permeability when modifying side chains in cell-permeable macrocyclic peptides, positioning compound 17 as a robust scaffold for future lead optimization. This work furnishes a blueprint for balancing drug-like properties with therapeutic potency in macrocyclic therapeutics. Full article

Viral fusion proteins are indispensable mediators of viral entry that orchestrate the fusion of viral and host membranes, making them primary targets for antiviral interventions. Class I fusion proteins, displayed on the surface of enveloped viruses (such as HIV-1, RSV, SARS-CoV-2, Nipah, influenza, and Ebola viruses), share conserved structural features, including the fusion peptide or loop and heptad repeat regions. These elements are essential for the formation of the post-fusion six-helix bundle during membrane fusion. Peptide inhibitors that mimic heptad repeat motifs have consequently emerged as an effective strategy for blocking the fusion process. This review summarizes design strategies for such inhibitors and highlights how sequence and structural insights have enabled their optimization via α-helical stabilization, hydrocarbon stapling, lactam bridges, lipid conjugation, macrocyclization, and multivalency. Using representative examples across major viral systems, this review illustrates how these strategies have led to the development of potent, stable, and even broad-spectrum antiviral peptides. This review provides insights to guide the rational design of next-generation peptide-based fusion inhibitors targeting viral membrane fusion. Full article

Kappa opioid receptor (KOR) antagonists may have therapeutic potential to prevent stress-induced relapse in abstinent individuals with cocaine use disorder (CUD). The macrocyclic peptide [D-Trp]CJ-15,208 (cyclo[Phe-D-Pro-Phe-D-Trp]) is an orally bioavailable, brain–penetrant selective KOR antagonist that prevents stress-induced reinstatement of cocaine-seeking behavior in a mouse model of CUD. We synthesized and evaluated analogs of this lead compound with substitutions for the D-Trp residue to identify analogs that exhibit more potent central KOR antagonism following oral administration. The peptides were synthesized by a combination of solid phase and solution peptide synthetic methodologies, and their pharmacological activity was evaluated both in vitro (for KOR affinity, selectivity and antagonism) and in vivo (for antinociception and KOR antagonism), with promising analogs evaluated for their ability to prevent stress-induced reinstatement of cocaine-seeking behavior in the mouse conditioned place preference (CPP) assay. A variety of substituted D-Phe or modified D-Trp derivatives were tolerated by KOR with retention of significant KOR antagonism in vivo after oral administration. Macrocyclic peptide pretreatment, per os, significantly prevented stress-induced reinstatement of cocaine CPP at doses of 10 and 30 mg/kg of [D-Phe⁴]CJ-15,208, 4, and 30 mg/kg of [D-Trp(formamide)]CJ-15,208, 3, which are 6-fold and 2-fold lower, respectively, than that needed for {D-Trp]CJ-15,208. Full article

Antimicrobial resistance has emerged as one of the most critical public health challenges of the 21st century, threatening to undermine the foundations of modern medicine. In 2019, bacterial infections accounted for 13.6% of all global deaths, with more than 7.7 million fatalities directly attributable to 33 bacterial pathogens, most prominently Staphylococcus aureus, Streptococcus pneumoniae, Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa. Resistance mechanisms are multifactorial, encompassing enzymatic degradation, target modification, efflux pump overexpression, reduced membrane permeability, and biofilm formation, often in combination, leading to multidrug-resistant, extensively drug-resistant, and pandrug-resistant phenotypes. Alarmingly, projections estimate that by 2050 AMR could result in over 10 million deaths annually. This comprehensive review synthesizes global epidemiological data, insights into bacterial resistance mechanisms, and emerging therapeutic solutions, including novel antibiotics such as lasso peptides and macrocyclic peptides (e.g., zosurabalpin), naturally derived compounds (e.g., corallopyronin, clovibactin, chlorotonil A), and targeted inhibitors (e.g., Debio 1453 for Neisseria gonorrhoeae). Addressing the AMR crisis requires coordinated international efforts, accelerated drug discovery, and the integration of innovative non-antibiotic approaches to preserve the efficacy of existing therapies and ensure preparedness against future bacterial threats. Full article

Ipomoeassin F (Ipom-F) is a plant-derived macrocyclic resin glycoside that potently inhibits cancer cell growth through blockage of Sec61-mediated protein translocation at the endoplasmic reticulum. Recently, detailed structural information on how Ipom-F binds to Sec61α was obtained using Cryo-EM, which discovered that polar interactions between asparagine-300 (N300) in Sec61α and four oxygens in Ipom-F are crucial. One of the four oxygens is from the carbonyl group at C-4 of the fatty acid chain. In contrast, our previous structure–activity relationship (SAR) studies suggest that the carbonyl group is not essential. To resolve this discrepancy, we designed and synthesized two new open-chain analogues (10 and 11); 10 without the C-4 carbonyl had a dramatic activity loss, whereas 11 with an amide functional group was even more potent than Ipom-F. These new SAR data, in conjunction with some previous SAR information, imply two functional roles of the C-4 carbonyl: (1) to form H-bonds with N300; and (2) to regulate interactions of the fatty acid chain with membrane lipids. Impacts of these dual functions on antiproliferation depend on the overall structure of an Ipom-F derivative. Moreover, 11 can serve as a lead compound for developing future amino acid/peptide-modified analogues of Ipom-F with improved therapeutic properties. Full article

Peptide-based therapy is appealing in modern medicine owing to its high activity and excellent biocompatibility. Poor stability, leading to unacceptable bioavailability, severely constrains its clinical application. Here, we proposed a general supramolecular approach for improving the plasma resistance of a commercially available peptide agent, thymopentin. The ¹H NMR results indicated that the large-sized extended biphen[3]arene carboxylate (ExBP3C) can entirely encapsulate this peptide at its main chain with a binding stoichiometry of 1:1 and K_a value of (1.87 ± 0.15) × 10⁵ M⁻¹, which varied radically from recognizing specific amino acid residues by carboxylatopillar[5]arene (CP5A). Notably, host–guest complexation by ExBP3C could maintain 24.85% of the original thymopentin amount for 60 min in the presence of rat plasma, whereas free thymopentin, or co-dosed with CP5A and cucurbit[7]uril, underwent rapid degradation and became undetectable within just 30 min. In addition, cytotoxicity and hemolysis assays preliminary demonstrated that the employment of ExBP3C as a supplementary material was relatively nontoxic at a cellular level. Full article

This review describes the discovery, structure, activity, engineered constructs, and applications of KR-12, the smallest antibacterial peptide of human cathelicidin LL-37, the production of which can be induced under sunlight or by vitamin D. It is a moonlighting peptide that shows both antimicrobial and immune-regulatory effects. Compared to LL-37, KR-12 is extremely appealing due to its small size, lack of toxicity, and narrow-spectrum antimicrobial activity. Consequently, various KR-12 peptides have been engineered to tune peptide activity and stability via amino acid substitution, end capping, hybridization, conjugation, sidechain stapling, and backbone macrocyclization. We also mention recently discovered peptides KR-8 and RIK-10 that are shorter than KR-12. Nano-formulation provides an avenue to targeted delivery, controlled release, and increased bioavailability. In addition, KR-12 has been covalently immobilized on biomaterials/medical implants to prevent biofilm formation. These constructs with enhanced potency and stability are demonstrated to eradicate drug-resistant pathogens, disrupt preformed biofilms, neutralize endotoxins, and regulate host immune responses. Also highlighted are the safety and efficacy of these peptides in various topical and systemic animal models. Finaly, we summarize the achievements and discuss future developments of KR-12 peptides as cosmetic preservatives, novel antibiotics, anti-inflammatory peptides, and microbiota-restoring agents. Full article

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. This review provides a comprehensive overview of the progress in the development and characterization of furin inhibitors, encompassing peptides, linear and macrocyclic peptidomimetics, and non-peptide compounds, highlighting their potential in the treatment of both infectious and non-infectious diseases. Full article

Antimicrobial peptides (AMPs) are promising tools for combating microbial resistance. However, their therapeutic potential is hindered by two intrinsic drawbacks—low target affinity and poor in vivo stability. Macrocyclization, a process that improves the pharmacological properties and bioactivity of peptides, can address these limitations. As a result, macrocyclic peptides represent attractive drug candidates. Moreover, many drugs are macrocycles that originated from natural product scaffolds, suggesting that nature offers solutions to the challenges faced by AMPs. In this review, we explore natural cyclic peptides from the DBAASP database. DBAASP is a comprehensive repository of data on antimicrobial/cytotoxic activities and structures of peptides. We analyze the data on small (≤25 AA) ribosomal and non-ribosomal cyclic peptides from DBAASP according to their amino acid composition, bonds used for cyclization, targets they act on, and mechanisms of action. This analysis will enhance our understanding of the small cyclic peptides that nature has provided to defend living organisms. Full article

A comprehensive thermodynamic and structural study of the complexation affinities of tetra (L1), penta (L2), and hexaphenylalanine (L3) linear peptides towards several inorganic anions in acetonitrile (MeCN) and N,N-dimethylformamide (DMF) was carried out. The influence of the chain length on the complexation thermodynamics and structural changes upon anion binding are particularly addressed here. The complexation processes were characterized by means of spectrofluorimetric, ¹H NMR, microcalorimetric, and circular dichroism spectroscopy titrations. The results indicate that all three peptides formed complexes of 1:1 stoichiometry with chloride, bromide, hydrogen sulfate, dihydrogen phosphate (DHP), and nitrate anions in acetonitrile and DMF. In the case of hydrogen sulfate and DHP, anion complexes of higher stoichiometries were observed as well, namely those with 1:2 and 2:1 (peptide:anion) complexes. Anion-induced peptide backbone structural changes were studied by molecular dynamic simulations. The anions interacted with backbone amide protons and one of the N-terminal amine protons through hydrogen bonding. Due to the anion binding, the main chain of the studied peptides changed its conformation from elongated to quasi-cyclic in all 1:1 complexes. The accomplishment of such a conformation is especially important for cyclopeptide synthesis in the head-to-tail macrocyclization step, since it is most suitable for ring closure. In addition, the studied peptides can act as versatile ionophores, facilitating transmembrane anion transport. Full article

Inflammation processes of the central nervous system (CNS) play a vital role in the pathogenesis of several neurological and psychiatric disorders like depression. These processes are characterized by the activation of glia cells, such as microglia. Clinical studies showed a decrease in symptoms associated with the mentioned diseases after the treatment with anti-inflammatory drugs. Therefore, the investigation of novel anti-inflammatory drugs could hold substantial potential in the treatment of disorders with a neuroinflammatory background. In this in vitro study, we report the anti-inflammatory effects of a novel hexacyclic peptide-peptoid hybrid in lipopolysaccharide (LPS)-stimulated BV2 microglial cells. The macrocyclic compound X15856 significantly suppressed Interleukin 6 (IL-6), tumor necrosis factor-α (TNF-α), c-c motif chemokine ligand 2 (CCL2), CCL3, C-X-C motif chemokine ligand 2 (CXCL2), and CXCL10 expression and release in LPS-treated BV2 microglial cells. The anti-inflammatory effects of the compound are partially explained by the modulation of the phosphorylation of p38 mitogen-activated protein kinases (MAPK), p42/44 MAPK (ERK 1/2), protein kinase C (PKC), and the nuclear factor (NF)-κB, respectively. Due to its remarkable anti-inflammatory properties, this compound emerges as an encouraging option for additional research and potential utilization in disorders influenced by inflammation, such as depression. Full article

Zilucoplan is a synthetic macrocyclic peptide approved by the Food and Drug Administration (FDA), in October 2023, for the treatment of generalized myasthenia gravis. It is considered as an orphan drug that causes the inhibition of terminal complement cascade activation with a dual mechanism of action preventing the formation of the membrane attack complex (MAC) and the destruction of the neuromuscular junction. This drug has been demonstrated to be able to treat the generalized myasthenia gravis without significant adverse effects, with good efficacy, safety, and tolerability profile. Zilucoplan is not only innovative and promising in the therapeutics of generalized myasthenia gravis, but it could also be beneficial for the treatment of other diseases as well as a model for synthesis of analogues to improve pharmacological profile. Full article

Tuberculosis is one of the most common infectious diseases in the world, caused by Mycobacterium tuberculosis. The outbreak of multiple drug-resistant tuberculosis has become a major challenge to prevent this disease worldwide. ClpC1 is a Clp ATPase protein of Mycobacterium tuberculosis, functioning as a chaperon when combined with the Clp complex. ClpC1 has emerged as a new target to discover anti-tuberculosis drugs. This study aimed to explore the ClpC1 inhibitors from actinomycetes, which have been known to provide abundant sources of antibiotics. Two cyclic peptides, including nocardamin (1), halolitoralin A (3), and a lactone pleurone (2), were isolated from the culture of Streptomyces aureus (VTCC43181). The structures of these compounds were determined based on the detailed analysis of their spectral data and comparison with references. This is the first time these compounds have been isolated from S. aureus. Compounds 1–3 were evaluated for their affection of ATPase activity of the recombinant ClpC1 protein. Of these compounds, halolitoralin A (1), a macrocyclic peptide, was effective for the ATPase hydrolysis of the ClpC1 protein. Full article

The macrocyclic tetrapeptide CJ-15,208 (cyclo[Phe-D-Pro-Phe-Trp]) and its D-Trp isomer exhibit kappa opioid receptor (KOR) antagonism which prevents stress-induced reinstatement of extinguished cocaine-conditioned place preference. Here, we evaluated the effects of substitution of Trp and D-Trp on the peptides’ opioid activity, antinociceptive tolerance, and the ability to prevent relapse to extinguished drug-CPP. Six analogs were synthesized using a combination of solid-phase peptide synthesis and cyclization in solution. The analogs were evaluated in vitro for opioid receptor affinity in radioligand competition binding assays, efficacy in the [³⁵S]GTPγS assay, metabolic stability in mouse liver microsomes, and for opioid activity and selectivity in vivo in the mouse 55 °C warm-water tail-withdrawal assay. Potential liabilities of locomotor impairment, respiratory depression, acute tolerance, and conditioned place preference (CPP) were also assessed in vivo, and the ameliorating effect of analogs on the reinstatement of extinguished cocaine-place preference was assessed. Substitutions of other D-amino acids for D-Trp did not affect (or in one case increased) KOR affinity, while two of the three substitutions of an L-amino acid for Trp decreased KOR affinity. In contrast, all but one substitution increased mu opioid receptor (MOR) affinity in vitro. The metabolic stabilities of the analogs were similar to those of their respective parent peptides, with analogs containing a D-amino acid being much more rapidly metabolized than those containing an L-amino acid in this position. In vivo, CJ-15,208 analogs demonstrated antinociception, although potencies varied over an 80-fold range and the mediating opioid receptors differed by substitution. KOR antagonism was lost for all but the D-benzothienylalanine analog, and the 2′-naphthylalanine analog instead demonstrated significant delta opioid receptor (DOR) antagonism. Introduction of DOR antagonism coincided with reduced acute opioid antinociceptive tolerance and prevented stress-induced reinstatement of extinguished cocaine-CPP. Full article