Search Results (321)

ESKAPE pathogens represent a priority clinical threat due to their multidrug-resistance, persistence in biofilms, and ability to evade antibiotic therapy. In response to these limitations, antimicrobial peptides (AMPs) have emerged as promising platforms for the development of novel anti-infective strategies. This review analyzes the potential of AMPs against ESKAPE pathogens, integrating their main classes, mechanisms of action, design strategies, and barriers to clinical translation. Natural, synthetic, and peptidomimetic AMPs are examined, along with lytic mechanisms, intracellular targets, anti-virulence effects, quorum quenching, and immunomodulation. In addition, in silico design approaches, multi-objective prediction, and molecular optimization strategies—including stereochemical modifications, cyclization, lipidation, PEGylation, and hybrid design—are discussed. Finally, their activity against ESKAPE biofilms is addressed, together with current limitations related to stability, toxicity, delivery, and preclinical validation. Full article

Background/Objectives: Antimicrobial conjugates have attracted considerable interest in addressing the threat of antimicrobial resistance by minimising the likelihood of resistance onset. Antimicrobial peptide mimic–antibiotic conjugates offer a unique strategy to revitalise current clinical agents through increased membrane permeabilisation, prolonging the longevity of traditional antibiotics while broadening the spectrum of activity of the AMP mimic. Methods: This study explored non-cleavable, enzyme-cleavable, and pH-cleavable linked conjugates between an anthranilamide-based peptide mimic and current clinically available antibiotics to assess the viability of conjugation in enhancing antimicrobial activity as measured through MIC assays. Cleavage studies were conducted to assess the stimulus susceptibility of relevant compounds. Results: Four amide-linked non-cleavable conjugates were synthesised. Of these, a primary amide-linked conjugate between ciprofloxacin and the peptidomimetic had the most significant activity with an MIC of 15.6 µM towards Gram-positive Staphylococcus aureus and Gram-negative Pseudomonas aeruginosa, and an MIC of 7.8 µM towards Gram-negative Escherichia coli. A hydrazone-based pH-sensitive linker system was synthesised and had an MIC of 15.6 µM towards Gram-negative E. coli. Finally, an enzyme-cleavable cephalosporin conjugate system was investigated, which offered a unique method for the specific treatment of resistant bacterial strains. Cleavage studies of this conjugate suggested rapid degradation of the β-lactam ring and release of the subunit. Conclusions: This work presents conjugate systems between peptide mimics and antibiotics as a new, promising strategy to broaden the antimicrobial spectrum of novel antimicrobial agents. Full article

Protein–protein interactions (PPIs) are critical for cellular signaling, apoptosis regulation, and immune function in the body, and dysregulation is a hallmark of cancer. The large, dynamic, and shallow nature of PPI interfaces rendered them “undruggable” by conventional small molecules in the past. Recent advances in structural biology, chemical innovation, and artificial intelligence have revolutionized the landscape of PPI-directed drug discovery. This review summarizes the mechanistic roles of PPIs in oncogenesis, critically discusses novel therapeutic interventions, such as small molecules, peptidomimetics, stapled peptides, proteolysis-targeting chimeras (PROTACs), molecular glues, and AI-based drug optimization strategies, altering the druggable proteome in oncology. Therapeutics with clinically well-validated action, including Venetoclax and AMG 510, and next-generation candidates demonstrate the translational applications of these approaches. Some of the key challenges, such as interface complexity, specificity, bioavailability, and resistance, are addressed together with countermeasures like rational design, combination therapies, enhanced delivery systems, and biomarker-based patient selection. To this end, the incorporation of multi-omics data and artificial-intelligence (AI)-driven modeling technologies is revolutionizing the personalized cancer therapeutics development space. Collectively, these advances mark a paradigm shift: PPIs, once considered inaccessible, are now at the forefront of precision oncology, offering new hope for patients with previously intractable malignancies. Full article

Background/Objectives: Due to the widespread problem of antimicrobial resistance (AMR), there is an urgent need to identify new antibacterial targets that act through mechanisms distinct from those of existing antibiotics. One of these targets is the essential cell division protein FtsQ, which is a central hub of the Gram-negative divisome, but the druggability of its extensive protein–protein interaction (PPI) interfaces remains poorly defined. Here, we present a comprehensive structure-based in silico characterization of Escherichia coli FtsQ aimed at identifying and prioritizing druggable regions for PPI modulation. Methods: We analyzed E. coli FtsQ in both apo and complexed states (FtsQB, FtsQL, and FtsQBL) using a combination of pocket-mapping tools (FTMap and SiteMap), evolutionary conservation analysis (ConSurf), and structure property assessment (BLAST, ProBiS) to map and evaluate potential binding pockets of FtsQ protein. Results: Eight potential binding sites were predicted across the β and POTRA domains of FtsQ. One previously unreported site within the POTRA domain was prioritized as a candidate site, characterized by favorable druggability scores, strong evolutionary conservation, and a putative role in the FtsQ–FtsW/FtsN/FtsI interaction network. In contrast, two highly conserved sites at the FtsQ–FtsB/FtsL interaction interface were structurally flat, indicating limited suitability for classical small-molecule binding and greater compatibility with alternative modalities such as macrocycles or peptidomimetics. Conclusions: Although FtsQ lacks deep canonical binding pockets, this study proposes several conserved and potentially tractable regions as candidate sites, supporting its potential as a non-classical but promising antibacterial target for disrupting bacterial cytokinesis. Full article

Life as we know it depends on peptide and nucleic acid polymers built from a limited set of backbone residues, yet planetary environments beyond Earth motivate consideration of alternative chemical frameworks for genetic- and protein-like polymers. In this context, we synthesize four azatide dipeptide analogs (Ala^a-Gly^a (1), Gly^a-Ala^a (2), Gly^a-Gly^a (3), and Ala^a-Ala^a (4)) as candidate backbone motifs for non-standard biologically relevant polymers. We then systematically assess their stability and reactivity in 98% w/w sulfuric acid, a solvent relevant to Venusian cloud chemistry. We assess the stability of the azatides via ¹H and ¹³C NMR spectroscopy supported with ELSD-LCMS. We monitor the stability of the compounds over periods from hours to two weeks at room temperature and at elevated temperatures (50–80 °C). All four azatides readily dissolve in 98% w/w D₂SO₄ and are generally stable at room temperature. Gly^a-Ala^a (2) shows no detectable degradation over a two-week incubation in 98% w/w sulfuric acid. The other three azatide analogs display only minor decomposition. ELSD-LCMS measurements qualitatively confirm the NMR results, revealing only minor-to-moderate loss of parent compounds after two weeks at room temperature. At higher temperatures, representative of the lower Venusian cloud deck, the stability of the azatides decreases dramatically. All four compounds undergo significant decomposition at 50 °C and completely degrade within one to two weeks at 80 °C. Our findings indicate that azatides, despite being generally stable in concentrated sulfuric acid at room temperature, lack the thermal stability that might be required to serve as viable backbone motifs for biological polymers in environments spanning the full temperature range of Venusian clouds. Full article

Protein kinase inhibition can be achieved through various mechanisms, including blocking phosphorylation activity or disrupting regulatory interactions. While small molecule inhibitors have shown promise, their selectivity remains challenging due to the structural similarities among kinase catalytic sites. To design selective kinase inhibitors based on peptide terminal tail interactions with the activation segment, focusing on five kinases with different conformational states: GSK3, PAK4, TTN (OUT conformation) and PKB, FLT3 (IN conformation). Three-dimensional structures from RCSB PDB were optimized using MODELLER version 9.0. Peptide sequences were designed with PeptiDerive (Rosetta) and RosettaDesign version 3.5, followed by pharmacophore modeling based on key interaction residues. Virtual screening was then conducted with PyRx 0.8 and molecular docking with AutoDock Vina 1.1.2. Molecular dynamics simulations were performed using Desmond v6.6 (Schrödinger Suite 2016, Multisim v3.8.5.19) (100 ns, NPT ensemble, 300 K). Analysis of the five kinases revealed distinct interaction profiles with designed peptidomimetic compounds. Kinases displaying the IN conformation of the activation segment (PKB and FLT3) consistently showed superior stability and stronger interaction profiles compared to those in the OUT conformation. The designed compounds formed key hydrogen bonds and hydrophobic interactions with critical residues in the activation segment binding pocket. The most promising inhibitors demonstrated stability throughout the molecular dynamics simulations, with IN conformation kinases maintaining more consistent conformational profiles than their OUT conformation counterparts. Kinases with IN conformation of the activation segment demonstrated superior stability and interaction profiles compared to OUT conformations. These findings contribute to our understanding of selective kinase inhibition and provide a framework for developing novel inhibitors, particularly for PKB and FLT3. The implications of this study extend to rational drug design approaches that leverage natural regulatory mechanisms for therapeutic intervention, though further optimization is needed for GSK-3β, PAK4, and TTN to improve stability and binding affinity. Full article

Diabetic nephropathy (DN) is the leading cause of end-stage renal disease worldwide. During the last few years, remarkable advances have been made in the treatment of DN. Sodium–glucose cotransporter type 2 inhibitors (SGLT2i) consistently prevent or delay albuminuria and renal failure in patients with DN. Prior research from our group highlights the Janus kinase/signal transducers and activators of transcription axis as a critical target in DN. Specifically, the administration of suppression of cytokine signaling 1 (SOCS1) mimetic peptides (MiS1) modulates aberrant signaling, resulting in profound beneficial effects on renal function and structural integrity in experimental DN. The aim of this study was to evaluate the effect of empagliflozin and MiS1 on kidney damage and its associated inflammatory, oxidative stress and lipotoxic mechanisms in an advanced type 2 DN mouse model BTBR ob/ob. Mice were treated for 7 weeks with empagliflozin and MiS1, alone or in combination, and monitored for glycemia, body weight, albuminuria, histopathological damage, podocyte loss, and gene expression related to inflammation, redox balance, and lipid metabolism. Empagliflozin or MiS1 monotherapies significantly reduced albuminuria and structural renal injury, preserved podocyte number, and downregulated genes involved in inflammatory, oxidative, and mitochondrial–lipid metabolic dysregulation, with empagliflozin additionally improving metabolic parameters. Notably, the combined therapy achieved the greatest reduction in albuminuria and histological damage with enhanced suppression of pathogenic inflammatory and metabolic pathways, resulting in superior renoprotection compared with monotherapy. These findings suggested that add-on therapy with SOCS1 peptidomimetics and SGLT2i may help mitigate residual albuminuria and renal damage in type 2 DN. Full article

Host defense peptides (HDPs), ancestral effectors of innate immunity, have emerged as pleiotropic regulators transcending their antimicrobial origins. This review critically examines the complex interplay among HDPs, hemostasis, and tissue repair. We analyze molecular mechanisms governing interactions with platelets and endothelial cells, highlighting a fundamental paradigm shift: platelets and megakaryocytes are active synthesizers of a specific peptide repertoire rather than passive carriers. Functional dualities are elucidated, contrasting LL-37-driven platelet agonism via glycoprotein VI (GPVI) against the amyloid-like stabilization of fibrin by defensins. Based on these mechanisms, we propose a framework wherein HDPs function as concentration-dependent molecular switches between physiological repair and pathological thromboinflammation. Furthermore, the review addresses the hypothesis of “adaptive thrombopoiesis,” where systemic peptide surges act as danger signals to reprogram the function of newly formed platelets. Finally, therapeutic implications are evaluated, emphasizing the design of protease-resistant peptidomimetics to harness protective effects while mitigating vascular toxicity. Full article

Significant advances in coronavirus immunoprophylaxis have enabled the control of the SARS-CoV-2 pandemic. However, the continued emergence of SARS-CoV-2 variants with immune escape potential highlights the need for effective direct-acting antivirals targeting conserved viral enzymes. The SARS-CoV-2 main protease (M^pro) remains one of the most promising antiviral drug targets due to its essential role in viral replication and the high conservation of its active site across coronavirus variants. Building upon the established GC373 scaffold, we designed, synthesized, and biochemically evaluated two novel GC373-like peptidomimetic inhibitors incorporated modified glutamine-mimic residues. These analogs were designed to enhance solubility and metabolic resilience while retaining key recognition features within the M^pro active site. Both compounds demonstrated micromolar inhibitory activity in enzymatic assays, supported by molecular docking and MM-PBSA analyses consistent with stable binding. The proposed inhibitors represent viable scaffolds for further optimization of electrophilic warheads and S1/S2 residue interactions. These findings contribute to the rational design of next-generation M^pro inhibitors and align with ongoing efforts to expand the chemical space of SARS-CoV-2 antiviral agents. Full article

N-oxides are emerging as versatile tools for modulating peptide conformation due to their strong proton-accepting ability and distinct electronic properties. In this study, we report the first crystallographic evidence that an N-oxidized peptide (NOP 5) containing a proline residue forms an intramolecular six-membered hydrogen bond between the N-oxide oxygen and an adjacent amide proton. This conformational motif is not restricted to proline-containing sequences: NMR spectroscopic analyses (including DMSO-d₆ titration, VT-NMR, NOE, and concentration-dependent studies) reveal that NOPs 7 and 9, in which proline is replaced by glycine, adopt the same hydrogen-bonded ring structure in aprotic solvents. Remarkably, this conformation persists even in protic solvent (CD₃OH), indicating the robustness of the N-oxide-induced hydrogen bond. DFT calculations further support the experimental findings and rationalize the conformational preferences of NOPs 5 and 7. These results establish N-oxide as a potent and generalizable constraint for stabilizing peptide secondary structures, offering a new strategy for the design of peptidomimetics with tunable rigidity and solvent stability. Full article

Peptides are recognized as multifunctional bioactive ingredients in cosmetic science, as they offer diverse beneficial effects such as skin rejuvenation, anti-aging, and skin barrier enhancement. In this study, we applied a cheminformatics-assisted peptidomimetic design platform to design novel peptides targeting heat shock protein 47 (Hsp47), a collagen-specific molecular chaperone that is downregulated during skin aging. Using molecular fingerprint similarity-based peptide design and protein–peptide docking simulations, five candidate peptides were screened, among which ICP-1225 (TY) emerged as a potent stimulator of Hsp47 and collagen (COL1A1 and COL3A1) expression in dermal fibroblasts. To improve stability and skin penetration, fatty acid-conjugated derivatives of ICP-1225 were synthesized, and acetyl-TY (ICP-1236) demonstrated the most consistent upregulation of Hsp47 and collagen in vitro. Restoration of Hsp47 protein expression and dermal collagen levels in UVB-damaged ex vivo human skin explants was also observed. These findings highlight the potential of cheminformatics-assisted peptide design in the development of next-generation cosmetic actives. ICP-1236 represents a promising anti-wrinkle candidate through the modulation of Hsp47 and collagen pathways, warranting further clinical evaluation. Full article

Therapeutic peptides are a unique drug class due to their high-specificity binding with biological targets. However, the low bioavailability of peptides, as well as the lack of enzymatic stability, imposes a number of limitations on their biomedical application. A good strategy by which to overcome these limitations is the use of peptidomimetics, which are able to imitate the binding and activity of peptides both in vitro and in vivo. Peptidomimetics can be obtained by combining natural and synthetic amino acids in a peptide sequence. Various five-membered heterocycles are often used as structural fragments of peptide imitators to fix the chain in a certain conformation and to increase proteolytic stability. The use of 5-aminomethyl-1,2,4-triazole-3-carboxylic acid derivatives as building blocks of peptidomimetic structures may be a very attractive strategy, in which the tautomeric 1,2,4-triazole fragment is capable of flexibly forming hydrogen bonds on the protein surface of the target. In this work, a number of ethyl 5-aminomethyl-1,2,4-triazole-3-carboxylates and their derivatives were synthesized as mimetics of aliphatic amino acids. Their use as building blocks for synthesizing peptidomimetics was demonstrated. In addition, through the use of a panel of pathogenic and model strains of microorganisms and fungi, we demonstrated the lack of independent activity of the amino acid 1,2,4-triazole mimetics synthesized. This similarity of the biological properties of the obtained mimetics and their natural analogues reveals their bioisosterism. The bioisosterism and geometric similarity of 1,2,4-triazole mimetics and natural amino acid highlights the potential of their use as building blocks for therapeutic peptides. Full article

Peptidomimetics represent a promising group of biologically active compounds with broad therapeutic potential that mimic naturally occurring peptides while overcoming their limitations. In this study, novel peptidomimetics derived from salicylic acid and arginine were designed, synthesized and characterized. The synthesis was carried out through stepwise building of the peptidomimetic scaffold via Steglich amidation, with subsequent side-chain functionalization by guanidylation affording selected arginine derivatives. In conclusion, synthetic approach was verified by repetition and compounds were isolated in quality suitable for biological testing. Full article

Effective treatment of central nervous system (CNS) infections remains a major challenge, as most therapeutic agents do not efficiently cross the blood–brain barrier (BBB) and the blood–cerebrospinal fluid barrier (BCSFB). Coumarin derivatives are of particular interest due to their broad pharmacological activity, favorable safety profile, and potential to penetrate biological barriers. Eight novel coumarin-based peptidomimetics functionalized with trifluoromethyl or methyl scaffolds were synthesized and evaluated as antimicrobial agents with the ability to cross the blood–brain barrier. Antimicrobial activity of the investigated compounds was tested against Staphylococcus aureus and multiple Escherichia coli strains (K12, R2, R3, R4) using minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) assays. Cytotoxicity was assessed in vitro in BALB/c-3T3 mouse fibroblasts and αT3-1 pituitary gonadotrope cells using the MTT assay. In vivo studies were performed in sheep to assess transfer of the compounds from blood to cerebrospinal fluid (CSF). All synthesized derivatives demonstrated antimicrobial activity and acceptable cytotoxicity, comparable to those of clinically used antibiotics. CF₃-modified coumarin peptidomimetics show promise as antimicrobial agents with the potential to penetrate the BBB/BCSFB. These findings support further investigation of coumarin-based scaffolds as a platform for the development of novel therapeutics for CNS infections. Full article

Proteases constitute one of the largest sub-classes of enzymes, accounting for ca. 2% of the proteins encoded in the human genome. They play a key role in protein degradation and signaling, regulating a variety of physiological processes. Dysregulation of their activity is associated with various pathological conditions like cancer, neurodegenerative disorders, inflammatory or cardiovascular diseases. Protease activity can be controlled by regulating enzyme concentrations, but also by inhibitors, molecules that modulate enzyme function, inspiring the development of small molecule protease inhibitors for therapeutic purposes. Protease inhibitors can be designed from the corresponding substrates by isostere replacement at the scissile bond. This process yields a first-generation of inhibitors that usually exhibit poor drug-like profiles that need subsequently be improved to generate a second-generation, by smoothing their peptide-like features. This process is reviewed in the present report and exemplified in the successful discovery stories of different inhibitors that correspond to four types of proteases, including the angiotensin converting enzyme (metalloprotease); HIV protease (aspartate protease); thrombin (serine protease) and the proteasome (threonine protease). A detailed description of the stories behind their design from their initial discovery to the final product is described in this report. Moreover, despite successful discovery stories, the challenges associated with designing novel protease inhibitors are examined. Finally, the relevance of these drugs in the present drug market is also reported. Full article