Search Results (1,143)

Peptide-based biomaterials have emerged as versatile tools for pharmaceutical drug delivery due to their biocompatibility and tunable sequences, yet a comprehensive overview of their categories, mechanisms, and optimization strategies remains lacking to guide clinical translation. This review systematically collates advances in peptide-based biomaterials, covering peptide excipients (cell penetrating peptides, tight junction modulating peptides, and peptide surfactants/stabilizers), self-assembling peptides (peptide-based nanospheres, cyclic peptide nanotubes, nanovesicles and micelles, peptide-based hydrogels and depots), and peptide linkers (for antibody drug-conjugates, peptide drug-conjugates, and prodrugs). We also dissect sequence-based optimization strategies, including rational design and biophysical optimization (cyclization, stapling, D-amino acid incorporation), functional motif integration, and combinatorial discovery with AI assistance, with examples spanning marketed drugs and research-stage candidates. The review reveals that cell-penetrating peptides enable efficient intracellular payload delivery via direct penetration or endocytosis; self-assembling peptides form diverse nanostructures for controlled release; and peptide linkers achieve site-specific drug release by responding to tumor-associated enzymes or pH cues, while sequence optimization enhances stability and targeting. Peptide-based biomaterials offer precise, biocompatible and tunable solutions for drug delivery, future advancements relying on AI-driven design and multi-functional modification will accelerate their transition from basic research to clinical application. Full article

Objectives: Free-living amoeba Naegleria fowleri causes primary amoebic meningoencephalitis (PAM). While infection is rare, PAM’s fatality rate exceeds 97%. The recommended treatment includes combination therapy, which does not result in uniform survival. Thus, there is a critical unmet need for finding better therapy for PAM. Drug repurposing can expedite the discovery of effective treatment for PAM. Isavuconazonium is approved for the treatment of fungal infections. Given that isavuconazole is the major metabolite of isavuconazonium and isavuconazole penetrates into the brain with high efficiency, our objective was to determine the activity of both isavuconazonium and isavuconazole on N. fowleri trophozoites. Methods: To test the effect of both compounds, we determined their dose–responses against N. fowleri and two mammalian cells. To establish how fast the prodrug and the metabolite kill the trophozoites, we measured potency at different time points. Finally, we investigated the effect of combining isavuconazonium or isavuconazole with amphotericin B on both N. fowleri and mammalian cells. Results: Both isavuconazonium and the metabolite isavuconazole were active against multiple strains, with clinically relevant isavuconazole exhibiting potency ranging between 0.1 and 0.6 µM. They were less toxic on mammalian cells. Isavuconazonium and isavuconazole required 24 h to achieve nanomolar potency. Combination with amphotericin B was synergistic without eliciting toxicity on mammalian cells. Conclusions: Our findings, together with the use of intravenous and oral formulations of isavuconazonium to treat pediatric and adult patients, support further in vivo efficacy study of isavuconazonium for its potential use for the treatment of PAM. Full article

Human carboxylesterases (CES) are enzymes that play a central role in the metabolism and biotransformation of diverse endogenous substances and xenobiotics. The two most relevant isoforms, CES1 and CES2, are crucial in clinical pharmacotherapy as they catalyze the hydrolysis of numerous approved drugs and prodrugs. Elucidating the structural basis of CES isoform substrate specificity is essential not only for understanding and anticipating the biological fate of administered drugs, but also for designing prodrugs with optimized site-specific bioactivation. Additionally, this knowledge is also important for the design of biomedically useful molecules such as subtype-targeted CES inhibitors and fluorescent probes. In this context, both experimental and computational methodologies have been used to explore the mechanistic and thermodynamic properties of CES-mediated catalysis. Experimental designs commonly employ recombinant CES or human tissue microsomes as enzyme sources, utilizing quantification methods such as spectrophotometry (UV and fluorescence) and mass spectrometry. Computational approaches fall into two categories: (1) modeling substrate: CES recognition and affinity (molecular docking, molecular dynamics simulation, and free-energy binding calculations), and (2) modeling substrate: CES reaction coordinates (hybrid QM/MM simulations). While experimental and theoretical approaches are highly synergistic in studying the catalytic properties of CES subtypes, they represent distinct technical and scientific fields. This review aims to provide an integrated discussion of the key concepts and the interplay between the most commonly used wet-lab and dry-lab strategies for investigating CES catalytic activity. We hope this report will serve as a concise resource for researchers exploring CES isoform specificity, enabling them to effectively utilize both experimental and computational methods. Full article

Background/Objectives: Mitochondrial dysfunction is a major cause of brain injury in patients with primary mitochondrial disease. New mitochondrial therapeutics and non-invasive tools for efficacy monitoring are urgently needed. To these ends, succinate prodrug NV354 (methyl 3-[(2-acetylaminoethylthio)carbonyl]propionate) and diffuse optical techniques are promising. In this proof-of-concept study, we characterize NV354’s effects on microdialysis metrics of cerebral metabolism in a swine model of mitochondrial dysfunction and assess the associations of diffuse optical metrics with mitochondrial dysfunction and metabolic improvement. Methods: One-month-old swine received a four-hour co-infusion of rotenone with either the succinate prodrug NV354 (n = 5) or placebo (n = 5). Rotenone is a mitochondrial complex I inhibitor. Before and during co-infusion, cerebral metabolism was probed with microdialysis and diffuse optics. Microdialysis acquired interstitial lactate and pyruvate levels invasively, while diffuse optics measured changes in oxygen extraction fraction (OEF) and oxidized cytochrome-c-oxidase concentration (oxCCO). Results: Interstitial lactate continually increased in the placebo group (p < 0.01), but lactate levels plateaued in the NV354 group (p = 0.90). oxCCO also increased in the placebo group (p = 0.05), but OEF remained constant (p = 0.80). In the NV354 group, oxCCO increased (p < 0.01) while OEF decreased (p < 0.01). Conclusions: Microdialysis results suggest that NV354 treatment can increase oxygen metabolism in large animals with mitochondrial dysfunction. The optical oxCCO metric was also sensitive to metabolic changes induced by rotenone and NV354 administration. Full article

Brain disorders remain a major global health challenge, highlighting the urgent need for innovative therapeutic strategies and efficient drug-delivery approaches. Among alternative routes, intranasal administration has garnered significant interest over recent decades, not only for its systemic delivery but also for its unique ability to bypass the bloodstream and the blood–brain barrier via the Nose-to-Brain (NtB) pathway. While numerous reviews have explored the opportunities and challenges of this route, industrial considerations—critical for successful clinical implementation and commercial development—remain insufficiently addressed. This review provides a comprehensive and critical assessment of the NtB pathway from a drug development and chemistry, manufacturing, and controls perspective, addressing key constraints in pre-clinical–clinical extrapolation, formulation design, device selection, dose feasibility, chronic safety, and regulatory requirements. We also discuss recent advances in neuronal targeting mechanisms, also with a focus on the role of trigeminal nerves. Dodecyl creatine ester (DCE), a highly unstable in plasma creatine prodrug developed by Ceres Brain Therapeutics, is presented as an illustrative case study. Delivered as a nasal spray, DCE enables direct neuronal delivery, exemplifying the potential of the NtB pathway for disorders characterized by neuronal energy deficiency, including creatine transporter deficiency and mitochondrial dysfunction. Overall, the NtB pathway—or, more precisely, the “Nose-to-Neurons” pathway—offers distinct advantages for unstable molecules and metabolic supplementation, particularly in neuron-centric diseases. Its successful implementation will depend on rational molecule design, optimized nasal formulations, appropriate devices, and early integration of industrial constraints to ensure feasibility, scalability, and safety for long-term treatment. Full article

The interaction of metals with serum γ-globulins is of particular interest, as it can modulate immune system function and lead to unforeseen consequences following the intake of metal ions or their complexes, which are often considered (pro)drugs. This paper focuses on the interactions between gold(III) species and bovine or human serum γ-globulins in aqueous solutions. Using UV-Vis, fluorescence, and CD (circular dichroism) spectroscopy in diluted or 0.1 M NaCl aqueous solutions, we determined the most probable stoichiometry of the gold(III)-protein associates and their conditional binding constants. On average, 13 to 19 gold atoms bind per protein molecule, depending on the medium and protein origin, with apparent binding constants ranging from 3.6 to 4.6 (log K values; hydroxyl-containing complexes exhibit lower binding affinity). CD spectra revealed no changes in protein secondary structure induced by the increase in electrolyte concentration. However, the addition of gold(III) species resulted in a decrease in β-sheet content and a corresponding increase in turns or disordered fragments. Full article

Glucosidase II (GluII) is a heterodimeric enzyme localized in the endoplasmic reticulum (ER), essential for the sequential trimming of glucose residues during N-linked glycosylation. This critical function facilitates glycoprotein folding via the calnexin/calreticulin chaperone system, maintaining ER homeostasis. Dysregulation or inhibition of GluII has been implicated in various pathological processes, including cancer, viral infections, and glycoprotein misfolding disorders. This review summarizes the current knowledge of GluII’s structure and function, highlights a wide range of natural and synthetic GluII inhibitors—including iminosugar derivatives (e.g., deoxynojirimycin (DNJ), castanospermine (CAST)), non-iminosugar compounds (e.g., bromoconduritol, catechins), and mechanism-based cyclophellitol analogues—and evaluates their biological effects and therapeutic potential. The cellular impact of GluII inhibition is explored in the context of ER stress, unfolded protein response (UPR), tumor cell apoptosis, and viral replication. Key challenges in developing selective GluII inhibitors are discussed, with a focus on strategies to minimize off-target effects, including prodrug design, allosteric modulation, and emerging genetic approaches such as microRNA (miRNA)-mediated downregulation of GluII subunits. Taken together, these insights underscore the therapeutic relevance of GluII as a druggable target and pave the way for the rational design of next-generation inhibitors in oncology, infectious diseases, and metabolic disorders. Full article

Background: Pancreatitis, encompassing acute (AP), severe acute (SAP), and chronic (CP) forms, is a life-threatening inflammatory disorder with limited therapeutic options. Current management is largely supportive, highlighting the urgent need for novel interventions targeting underlying molecular pathways. Aim: This review summarizes recent advances in the pathogenesis of pancreatitis, focusing on calcium dysregulation, ferroptosis, and microRNA-mediated mechanisms while exploring the therapeutic potential of phytochemicals as disease-modifying agents. Summary: Aberrant calcium signaling, iron-dependent lipid peroxidation, and microRNA imbalance drive acinar cell injury, inflammatory cascades, and pancreatic fibrosis. Phytochemicals, including flavonoids, terpenoids, alkaloids, and phenolics, have shown protective effects in preclinical models through multi-targeted mechanisms. These include suppression of NF-κB-driven inflammation, activation of the Nrf2/HO-1 antioxidant pathway, modulation of ferroptosis via GPX4 and iron efflux, regulation of calcium signaling, and modulation of microRNA expression. Importantly, several phytochemicals attenuate acinar cell death, reduce cytokine release, and limit fibrosis, thereby improving outcomes in experimental pancreatitis. However, poor solubility, bioavailability, and pharmacokinetic limitations remain significant barriers. Emerging strategies such as nanotechnology-based formulations, prodrug design, and pharmacokinetic profiling, as well as bioavailability studies, may enhance their clinical applicability. Conclusions: Phytochemicals represent a promising reservoir of multitarget therapeutic agents for pancreatitis. Their ability to modulate oxidative stress, inflammatory and calcium signaling, ferroptosis, and microRNA networks highlights their translational potential. Future studies should focus on clinical validation, bioavailability optimization, and advanced delivery platforms to bridge the gap from bench to bedside. Full article

Diroximel fumarate (DRF) is an orally administered prodrug used in multiple sclerosis (MS) treatment. Although it exhibits better gastrointestinal (GI) tolerability than its analogues, many patients still discontinue therapy due to frequent GI adverse events. To overcome these limitations, alternative drug delivery systems that bypass the GI tract are needed. Direct nose-to-brain delivery represents a promising approach to circumvent the blood–brain barrier and target the central nervous system; however, limited nasal mucosal absorption and the small volume of the nasal cavity pose significant challenges. Solid lipid nanoparticles (SLNs) can potentially overcome these obstacles by enhancing drug bioavailability and protecting against enzymatic degradation. This research aimed to develop an innovative intranasal nanoformulation of DRF to improve brain targeting and patient compliance. DRF-loaded SLNs were prepared using a solvent-diffusion technique with stearic acid as the lipid phase and Poloxamer 188 as the surfactant. The obtained nanoparticles displayed favorable technological characteristics, with a mean diameter of 210 nm, a polydispersity index of 0.17, and a zeta potential of −36 mV, suggesting good long-term stability. Interactions between SLNs and biomembrane models (MLV) were also studied to elucidate their cellular uptake mechanism. Future work will focus on evaluating the in vivo efficacy of this novel nanoformulation. Full article

Cordycepin (3′-deoxyadenosine, 3′-dA), the flagship nucleoside antibiotic from Cordyceps militaris, exerts potent anti-inflammatory, antimicrobial, and antitumor activity but is rapidly inactivated by human adenosine deaminase (ADA). While prodrugs, ADA inhibitors, and nanocarriers have been pursued to prolong its half-life, the influence of solid form on delivery performance remains unexplored. Here, three polymorphs—anhydrate-I (flake-like), anhydrate-II (rod-like), and a previously unreported monohydrate (fibrillar)—were prepared, characterized (PXRD, TG-DSC, FTIR), and subjected to equilibrium solubility, slurry-conversion, and humidity-sorption mapping. The monohydrate dehydrates at 144 °C and sequentially transforms to anhydrate-I → anhydrate-II (ΔH = −127.5 J g⁻¹), establishing a monotropic relationship between the two anhydrous forms. Solubility displays a bell-shaped profile versus water activity: the monohydrate is stable above aw 0.8, whereas anhydrate-II predominates below aw 0.2. In model immediate-release tablets, anhydrate-II achieves complete dissolution within 10 min, whereas the monohydrate sustains release for 30 min. Hygroscopicity tests show the monohydrate absorbs <6% water up to 75% RH without structural change, whereas anhydrate-I converts to the monohydrate above 63% RH. The quantitative humidity–crystal form–performance correlations provide a rational platform for crystal form selection and the design of stable, efficacious cordycepin solid dosage forms. Full article

The problem of antibiotic resistance is one of the challenges that science and medicine face in the 21st century. Nucleoside analogs have already proven as antiviral and antitumor agents, and, currently, there are more and more reports on their antibacterial and antifungal activity. The substitution of an oxygen atom by a sulfur one leads to the emergence of unique properties. Here, we report the synthesis of eight new 4-thioanalogs of 5-substituted (5-alkyloxymethyl and 5-alkyltriazolylmethyl) derivatives of 2′-deoxyuridine and uridine, which were active against Mycobacterium tuberculosis and Gram-positive bacteria. The novel sulfur-containing nucleosides were synthesized via activation of the pyrimidine C4 position, followed by condensation with thioacetic acid and deblocking. To increase the solubility, oligoglycol carbonate depot forms were obtained via activation of the 3′-hydroxyl group using N,N’-carbonyldiimidazole and condensation with triethylene glycol. The highest inhibitory activity was demonstrated by 3′-triethylene glycol depot forms of 4-thio-5-undecyl- and 5-dodecyloxymethyl-2′-deoxyuridine (4a,b) against two strains of M. smegmatis. The most promising compounds were 5-[4-decyl-(1,2,3-triazol-1-yl)methyl]-4-thio-2′-deoxy- and ribouridine (3c,g) and 5-undecyloxymethyl 4-thiouridine (3e) active toward clinical M. intracellulare isolates. Overall, novel sulfur-containing nucleoside analogs were low toxic, demonstrated better inhibitory activity compared to their C4-oxo ones, and, thus, are promising compounds for the development of new antibacterial agents. Full article

The lysosome is no longer viewed as a simple degradative “trash can” of the cell. The lysosome is not only degradative; its acidic, redox-active lumen also serves as a chemical “microreactor” that can modulate anticancer drug disposition and activation. This review examines how the distinctive chemical features of the lysosome, including its acidic pH (~4.5–5), strong redox gradients, limited thiol-reducing capacity, generation of reactive oxygen (ROS), diverse acid hydrolases, and reservoirs of metal ions, converge to influence the fate and activity of anticancer drugs. The acidic lumen promotes sequestration of weak-base drugs, which can reduce efficacy by trapping agents within a protective “safe house,” yet can also be harnessed for pH-responsive drug release. Lysosomal redox chemistry, driven by intralysosomal iron and copper, catalyzes Fenton-type ROS generation that contributes to oxidative damage and ferroptosis. The lysosome’s broad enzyme repertoire enables selective prodrug activation, such as through protease-cleavable linkers in antibody–drug conjugates, while its membrane transporters, particularly P-glycoprotein (Pgp), can sequester chemotherapies and promote multidrug resistance. Emerging therapeutic strategies exploit these processes by designing lysosomotropic drug conjugates, pH- and redox-sensitive delivery systems, and combinations that trigger lysosomal membrane permeabilization (LMP) to release trapped drugs. Acridine–thiosemicarbazone hybrids exemplify this approach by combining lysosomal accumulation with metal-based redox activity to overcome Pgp-mediated resistance. Advances in chemical biology, including fluorescent probes for pH, redox state, metals, and enzymes, are providing new insights into lysosomal function. Reframing the lysosome as a chemical reactor rather than a passive recycling compartment opens new opportunities to manipulate subcellular pharmacokinetics, improve drug targeting, and overcome therapeutic resistance in cancer. Overall, this review translates the chemical principles of the lysosome into design rules for next-generation, more selective anticancer strategies. Full article

Background: To repurpose carbutamide (CBT), a discontinued sulfonylurea-class anti-diabetic drug, as an anti-inflammatory bowel disease (IBD) drug, CBT azo-linked with salicylic acid (CAA) was designed and synthesized as a colon-specific prodrug to co-release CBT and mesalazine (5-ASA) selectively in the large intestine. Methods: CAA exhibited reduced lipophilicity and decreased transintestinal transport compared to CBT, as shown in an ex vivo experiment using isolated rat jejunal segments. It also underwent cleavage into CBT and 5-ASA when incubated with cecal contents of rats. Additionally, oral administration of CAA and Sulfasalazine (SSZ), a colon-specific prodrug of 5-ASA currently used for IBD treatment, resulted in similar levels of 5-ASA accumulation in the rat cecal region. Results: In a dinitrobenzene sulfonic acid-triggered colitis model in rats, CAA produced a more pronounced improvement in colon injury and inflammation than SSZ. Furthermore, rectal co-administration of CBT and 5-ASA conferred enhanced protective outcomes compared to monotherapy with either agent alone, suggesting a combined anticolitic action. The two drugs also jointly suppressed valacyclovir uptake via peptide transporter 1 (PepT1) in the distal colon, supporting PepT1 as a target contributing to their combined anticolitic effect. Unlike CBT, which significantly reduced blood glucose following oral administration, equimolar administration of CAA did not alter glycemic levels, consistent with reduced systemic exposure to CBT. Conclusions: In conclusion, CAA functions as a colon-specific mutual prodrug that surpasses SSZ in anticolitic performance while minimizing hypoglycemia risk, thus facilitating the repurposing of CBT as a treatment for IBD. Full article

Non-tuberculous mycobacteria (NTM) comprise more than 190 species capable of causing severe pulmonary, lymphatic, cutaneous, and disseminated infections, particularly in immunocompromised populations. Over the past two decades, the global incidence of NTM infections has risen steadily, underscoring an urgent unmet medical need. Treatment remains highly challenging due to intrinsic antimicrobial resistance and the requirement for prolonged multidrug regimens that are often poorly tolerated and associated with unsatisfactory outcomes. At the same time, the development of novel therapies has lagged behind other disease areas, hindered by the high costs of antimicrobial drug discovery and the relatively low commercial return compared with treatments for chronic conditions. Over the past decade, discovery and development have diversified across novel small molecules, next-generation analogues of existing classes, and adjunctive or host-directed strategies. While most candidates remain preclinical, several agents have advanced clinically in other infections, including gepotidacin (topoisomerase inhibitor; FDA-approved 2025 for urinary tract infection (UTI)), sulbactam–durlobactam (DBO β-lactamase inhibitor; FDA-approved 2023 for Acinetobacter baumannii complex), and contezolid, supporting repurposing opportunities for NTM. Conversely, SPR720 (gyrase B prodrug) was suspended after not meeting its Phase 2 endpoint in 2024, underscoring translational risk. Overall, the NTM pipeline is expanding, with near-term progress most likely from repurposed agents and optimised combinations, alongside earlier-stage candidates that target biofilms or resistance mechanisms. This review aims to provide a critical and up-to-date overview of emerging antimicrobial strategies against NTM, highlighting recent advances, translational challenges, and opportunities to accelerate the development of effective therapeutics. Full article

Background: Malignant pleural mesothelioma (MPM) is an aggressive, asbestos-associated cancer characterized by dysregulated nitric oxide (NO) signaling and increased NO levels that facilitate tumor progression. Paradoxically, this aberrant NO environment creates a therapeutic vulnerability that can be exploited by NO-donor prodrugs, which overwhelm cellular defenses with cytotoxic concentrations of NO, inducing nitrosative stress and apoptosis. Within this framework, oxadiazole-based scaffolds have emerged as a promising platform for prodrug development owing to their versatile chemistry and potential as novel NO donors or synergistic agents. In our previous studies, we developed several series of hybrid architectures incorporating 1,2,5-oxadiazole 2-oxide (furoxan) and 1,2,4-oxadiazole scaffolds, producing compounds with diverse and tunable NO-donor activities. We further observed that the cytotoxicity of these hybrids was significantly influenced by the substituents introduced at position 3 of the furoxan ring. Methods: We designed and synthesized a series of bis(1,2,4-oxadiazolyl)furoxans to systematically investigate their NO-donating capacity, cytotoxicity against MPM cell lines, selectivity over healthy lung fibroblasts, and underlying anticancer mechanisms. Results: The bis(1,2,4-oxadiazolyl)furoxans exhibited lower overall cytotoxicity but significantly higher selectivity compared with previously studied 3-cyano-4-(1,2,4-oxadiazolyl)furoxans. Their NO-releasing properties showed a strong correlation with their ability to induce mitochondrial damage, as evidenced by membrane depolarization. Moreover, the incorporation of specific substituents, such as a furan ring, on the 1,2,4-oxadiazole moiety introduced an additional mechanism of action through the induction of reactive oxygen species. Conclusions: Analysis of cancer cell death confirmed that these compounds acted through a multimodal mechanism dependent on both NO release and the specific substituents on the 1,2,4-oxadiazole moiety. Full article