ebselen (SPI-1005) / Sound Pharma - LARVOL DELTA

Destabilized Soluble SOD1 Species as Potential Determinants of Disease Severity in Familial Amyotrophic Lateral Sclerosis. (PubMed, ACS Chem Neurosci) - "Neither CuATSM nor ebselen─targeting metal binding and disulfide formation, respectively─rescued fluorescence, suggesting broader defects in SOD1 maturation. Nevertheless, both compounds inhibited ferroptosis, a nonapoptotic form of cell death characterized by iron-dependent lipid peroxidation, in HT22 cells, indicating alternative neuroprotective mechanisms. These findings identify destabilized soluble SOD1 species as a key toxic entity in ALS and highlight the utility of GFP-tagged constructs for evaluating folding status and screening therapeutic candidates."

Journal • Amyotrophic Lateral Sclerosis • CNS Disorders • SOD1

GPX3 activates autophagy to protect cochlear spiral ganglion neurons from injury in age-related hearing loss. (PubMed, Free Radic Biol Med) - "Targeted upregulation of GPX3 in SGNs markedly reduced the hearing threshold, improved wave I amplitude, and alleviated oxidative stress and apoptosis in SGNs. Furthermore, we discovered that the small molecule drug ebselen could reduce degeneration and damage in SGNs and effectively enhance auditory function by activating autophagy in both in vivo and in vitro settings. These results offer novel targets and therapeutic strategies for the prevention and treatment of ARHL."

Journal • Otorhinolaryngology • GPX3

Structure-activity studies reveal efficient inactivation of urease by Ebsulfur-based compounds. (PubMed, J Inorg Biochem) - "In this context, the organo‑selenium compound Ebselen has shown promising urease-inhibitory properties, but its therapeutic application is limited by toxicity concerns...The X-ray crystal structures of Sporosarcina pasteurii urease co-crystallized with two of the derivatives, determined at 1.95-1.96 Å resolution, suggested a mechanism involving di‑sulfuration of the catalytically essential αCys322 residue. These findings provide insight into the potential of Ebsulfur derivatives as antimicrobial agents, addressing the persistent lack of progress in antibiotic development, and contribute to the development of alternative antimicrobial strategies targeting resistant pathogens."

Journal

Chalcogen bond-driven self-assembly of a 4-tert-butylcalix[4]arene-ebselen conjugate. (PubMed, Dalton Trans) - "Powder X-ray diffraction studies on amorphous samples (obtained from CHCl3) and crystalline samples (obtained from CHCl3 : MeOH) revealed that MeOH plays a structure-directing role in the self-assembly process. Computational and crystallographic studies show that a weak chalcogen bond between the ethereal O and Se plays a conformational control role, whereas a strong chalcogen bond between the amide O and Se governs self-assembly."

Journal

Ebselen, a promising host-directed therapeutic option against Yersinia pseudotuberculosis infection. (PubMed, Front Microbiol) - "This is evidenced by a reduction in intracellular reactive oxygen species levels and an elevation in glutathione concentrations, and increased thioredoxin reductase 1 activity. Collectively, these findings suggest that EbSe enhances the host resistance to Y. pseudotuberculosis infection, likely through immunomodulatory effects rather than direct antibacterial activity against Gram-negative bacteria."

Journal • Gastroenterology • Gastrointestinal Disorder • Infectious Disease • Inflammation • Respiratory Diseases • Tuberculosis

Discovery of Novel SARS-CoV-2 3CLpro Inhibitors from Natural Products using FRET-based Assay. (PubMed, Curr Med Chem) - "ETFGg was identified as a promising 3CLpro inhibitor with high binding stability, highlighting its potential as a lead compound for the development of anti-- COVID-19 drugs."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases

Amphiphilic Ebselen Conjugate Suppresses Tripartite Motif-Containing 21-Glutathione Peroxidase 4 Axis-Dependent Neuronal Ferroptosis and Ameliorates Epilepsy. (PubMed, ACS Nano) - "Mechanistic investigation revealed that mGPC-EBS, apart from its GPX4-mimic role, downregulated tripartite motif-containing 21 (TRIM21) and led to an increase in GPX4 as TRIM21 can ubiquitylate and degrade GPX4. The current work provides a strategy to manipulate GPX4 activity using tailored organoselenium conjugates for the effective management of refractory TLE."

Journal • CNS Disorders • Cognitive Disorders • Epilepsy • GPX4 • TRIM21

SPI-1005 Improves High Frequency Hearing in Meniere’s Disease Patients in a Multi-Center, Phase 3, Randomized, Placebo-Controlled Trial (ARO 2026) - P3 | "MD patients treated with SPI-1005 demonstrated significant improvements in bilateral high-frequency hearing and speech discrimination characteristic of ARHL during RCT and OLE. These disease-modifying observations in an aged population >50 yo support the future testing of SPI-1005 for the treatment of ARHL."

Clinical • P3 data • Otorhinolaryngology • Vertigo • GPX1

Permanent Reversal of Noise-Induced Tinnitus by 28-Days of Ebselen Treatment is Related to Significant Reductions in Outer Hair Cell Loss (ARO 2026) - "28-days of ebselen treatment can permanently reverse gap detection deficits to baseline or pre-noise exposure in 82% of mice that developed NIT, 3-months after noise exposure and the development of NIHL. In addition, the significant reduction in complete OHC loss suggests a broad therapeutic window by which to prevent injured OHCs from dying. This work is the first demonstration of an anti-inflammatory drug permanently reversing NIT after the development of age-related hearing loss."

Otorhinolaryngology

The Role of Concomitant Medications in Improving SPI-1005 Study Outcomes in Meniere’s Disease Patients in a Phase 3 Randomized Placebo-Controlled Trial (STOPMD-3) (ARO 2026) - P3 | "Adjunctive therapy with SPI-1005 on to the existing medical management for MD involving diuretics (hydrochlorothiazide, triamterene, or hydrochlorothiazide/triamterene) demonstrated significant improvements in low-frequency hearing but not speech discrimination over placebo. Non-significant improvements were observed for diazepam, betahistine, and meclizine."

Clinical • P3 data • Otorhinolaryngology • Vertigo

Systemic Ebselen Treatment Prevents Amikacin Induced Ototoxicity and Nephrotoxicity in Mice (ARO 2026) - "Background : Aminoglycosides (AGs), such as tobramycin and amikacin, commonly used to treat recurrent pulmonary infections, are ototoxic and nephrotoxic. 28-days of amikacin increased the severity and duration of ototoxicity that was significantly reduced by ebselen. Amikacin-induced nephrotoxicity (increased Cr) was significantly reduced by ebselen. Interestingly, no hyperacusis was observed in any group and may be a consequence of greater PTS."

Preclinical • Infectious Disease • Nephrology • Otorhinolaryngology • Respiratory Diseases

Glutathione peroxidase-like activity of natural and semisynthetic phenylpropanoids and cannabinoids: An analytical investigation by a GC-MS- and HPLC-DAD-based Iwaoka's assay. (PubMed, J Pharm Biomed Anal) - "Among cannabinoids, cannabidiol (CBD) and cannabigerol (CBG) enhanced DTT oxidation, with CBG displaying a nearly comparable effect to the reference catalyst Ebselen®. Structure-activity relationship analysis of semisynthetic CBG ethers and esters revealed that substitution patterns strongly influence catalytic performance, with diethyl and di-n-propyl derivatives demonstrating the highest GPx-like behavior. Overall, this work identifies cinnamic acids, CBG, and some of their etherified analogues as promising GPx mimetics and provides mechanistic insight into the redox properties of phenylpropanoids and cannabinoids, which may support future antioxidant drug design."

Journal

Design and synthesis of dual-activity biphenyl inhibitors against SARS-CoV-2 and bladder cancer. (PubMed, Eur J Med Chem) - "Among them, compound L3 shows superior 3CLpro inhibition with an IC50 of 0.15 μM, which is 13.6-fold more potent than the reference drug ebselen (IC50 = 2.04 μM). L3 also exhibits potent antiviral activity against SARS-CoV-2 (EC50 = 2.82 μM), comparable to remdesivir (EC50 = 1.47 μM)...Furthermore, L3 displays favorable therapeutic potential with low cytotoxicity in HK-2 fibroblasts (CC50 > 50 μM) and potent concentration-dependent suppression of T24 bladder cancer cell proliferation (IC50 = 10.99 μM), outperforming the reference drug mitomycin (IC50 = 16.95 μM). These results highlight fluorinated biphenyl scaffolds as privileged chemotypes for multitarget drug development, enabling concurrent inhibition of viral protease and cancer cell growth. This work provides a rational strategy for repurposing traditional medicine-derived scaffolds into dual-function therapeutics..."

Journal • Bladder Cancer • Genito-urinary Cancer • Infectious Disease • Novel Coronavirus Disease • Oncology • Respiratory Diseases • Solid Tumor

Visible-Light-Mediated C(sp3)-Se Coupling: Synthesis of GPx-Mimic Unsymmetrical Aryl-Secondary Alkyl Selenoether Antioxidants. (PubMed, J Org Chem) - "Mechanistic studies reveal that the inexpensive organic photocatalyst-induced secondary alkyl radicals add to diaryl diselenides, a pathway that could not be accessed under traditional methods because of steric crowding at the Se center. The resulting selenoethers were further evaluated as glutathione peroxidase (GPx) mimics, efficiently catalyzing reduction of hydrogen peroxide with benzenethiol and exhibiting efficient GPx-like activity compared to benchmark Se-antioxidants: diphenyl diselenide and ebselen."

Journal

Insights into the complexity of SARS-CoV-2 Mpro inhibition: Ebselen and its derivatives impair dimerisation of the enzyme. (PubMed, J Enzyme Inhib Med Chem) - "Here we show that Ebselen and selected derivatives with human neutrophil elastase (HNE) inhibition and anti-radical activity are able to bind covalently to the viral enzyme with multiple stoichiometry, exhibiting inhibitory activity towards SARS-CoV-2 Mpro with potencies in the nanomolar range. Employing a mass spectrometry-based approach, we show that, upon binding to the target, Ebselen and its derivatives induce a dose-dependent shift in the dimer-monomer equilibrium, favouring the inactive monomeric state of the viral protease and possibly contributing to the observed in vitro inhibition."

Journal • Infectious Disease • Novel Coronavirus Disease • Respiratory Diseases • ELANE

Effects of Different Forms of Selenium in Human Umbilical Cord Mesenchymal Stem Cells. (PubMed, Biomedicines) - "This study evaluated the effects of different forms of selenium (Na2SeO4, SeMet, ebselen, and chitosan-coated selenium nanoparticles (CS-SeNPs)) on the biological functions of MSCs... Selenium supplementation is an effective strategy for improving MSC expansion and alleviating senescence. The beneficial effects are dependent on the specific selenium compound used, with CS-SeNPs and Na2SeO4 showing particularly strong potential for enhancing the bioavailability and function of hUC-MSCs during in vitro cultivation."

Journal • CDKN1A • CXCL8 • IL6

Broad-spectrum antiviral activity of ebselen. (PubMed, Sci Rep) - No abstract available

Journal

Drug Development. (PubMed, Alzheimers Dement) - "In summary, we demonstrated a single-cell digital twin framework for cell type-specific target identification and drug repurposing in AD and other AD-related dementia if broadly applied."

Journal • Alzheimer's Disease • CNS Disorders • Dementia • ABCA1

Sound Pharmaceuticals Receives FDA Breakthrough Therapy Designation for SPI-1005 to Treat Meniere’s Disease (Businesswire)

Breakthrough therapy • Otorhinolaryngology

Repurposing Ebselen for a potential blending-based therapeutic strategy against gastrointestinal nematodes of small ruminants. (PubMed, Res Vet Sci) - "The combination of Ebselen and IVM resulted in a statistically significant increase in larval migration inhibition, demonstrating a synergistic effect (>30 %). The data confirm the use of Ebselen and IVM in a novel blending-based therapeutic strategy to manage GIN that affects small ruminants."

Journal • Infectious Disease

Rescue of Aging-Dependent Reduction of Claudin-10b Expression by Glutamate in Mouse Intestinal MCE301 Cells. (PubMed, J Cell Biochem) - "Glu treatment stimulated Ca2+ influx, which was inhibited by BAPTA, a Ca2+ chelator, and ebselen, a voltage-dependent Ca2+ channel inhibitor...Glu reversed the Ten-1-induced reduction of CLDN10b mRNA and restored paracellular barrier function. These results suggest that Glu enhances the intestinal paracellular barrier function through the regulation of CLDN10b expression."

Journal • Preclinical • CLDN1 • TJP1

PRDX1 promotes testosterone synthesis and attenuates aging via redox regulation of ATG4B to modulate lipophagy. (PubMed, Nat Commun) - "Collectively, our findings demonstrate that PRDX1 promotes lipophagy and testosterone synthesis by regulating ATG4B. Our findings also propose the potential application of ebselen in the prevention and treatment of aging-related disorders, including late-onset hypogonadism."

Journal • Endocrine Disorders • Infertility • Sexual Disorders • ATG4B • PRDX1

Structure-Directed Optimization of Ebselen Derivatives as Potent NDM-1 Inhibitors Reverses Meropenem Resistance. (PubMed, J Med Chem) - "Mechanistically, 27k effectively inhibits the activity of NDM-1 by forming a Se-S covalent bond with the NDM-1 protein. Collectively, these findings confirm that compound 27k is an excellent NDM-1 covalent inhibitor, offering a promising lead compound for addressing bacterial resistance driven by NDM-1."

Journal

Ebselen Suppresses Breast Cancer Tumorigenesis by Inhibiting YTHDF1-Mediated c-Fos Expression. (PubMed, Int J Mol Sci) - "In addition, ebselen suppressed anchorage-independent growth in vitro and significantly reduced tumor growth in an orthotopic mouse model. These findings highlight YTHDF1 as a promising therapeutic target and support ebselen as a potential small-molecule inhibitor for breast cancer treatment."

Journal • Breast Cancer • Oncology • Solid Tumor • ANXA5 • FOS • YTHDF1

Atomistic modulation of MIF-2 structure, catalysis, and biological signaling via cysteine residues and a small molecule, Ebselen. (PubMed, Protein Sci) - "Our findings suggest that Ebselen partially disrupts the MIF-2 homotrimer, though the overall population of such a structure is <35%, even on the timescale of many hours. Ebselen does attenuate the biological functions of MIF-2, and solution structural biology captures the conformational transitions preceding the destabilized MIF-2 trimer."

Journal • DCT • MIF