Ossirene (AS101) / Feramda, Cosmo Pharma - LARVOL DELTA

Unusual Structural Features in the Adduct of Dirhodium Tetraacetate with Lysozyme. (PubMed, Int J Mol Sci) - "Dimeric Rh-Rh units with Rh-Rh distances between 2.3 and 2.5 Å are bound to the side chains of Asp18, Asp101, Asn93, and Lys96, while a dirhodium unit with a Rh-Rh distance of 3.2-3.4 Å binds the C-terminal carboxylate and the side chain of Lys13 at the interface between two symmetry-related molecules. An additional monometallic fragment binds the side chain of Lys33. These data, which are supported by replicated structural determinations, shed light on the reactivity of dirhodium tetracarboxylates with proteins, providing useful information for the design of new Rh-containing biomaterials with an array of potential applications in the field of catalysis or of medicinal chemistry and valuable insight into the mechanism of action of these potential anticancer agents."

Journal • Oncology

IL-10 and class 1 histone deacetylases act synergistically and independently on the secretion of proinflammatory mediators in alveolar macrophages. (PubMed, PLoS One) - "Alveolar macrophages after inflammatory stimulation upregulate both IL-10 and IL-12b production, in a highly class 1 HDAC-dependent manner. Class 1 HDACs appear to help maintain the balance between the pro- and anti-inflammatory IL-12b and IL-10 respectively. Class 1 HDACs may be considered as targets for the macrophage-initiated pulmonary inflammation in ALI in a preclinical setting."

IO biomarker • Journal • Acute Lung Injury • Immunology • Inflammation • Pneumonia • Respiratory Diseases

Can Some Anticancer Treatments Preserve the Ovarian Reserve? (PubMed, Oncologist) - "Anticancer therapies are associated with infertility in 10%-70% of patients, which is the result of primordial follicles pool depletion. Alone or associated with gonadotoxic treatments, some targeted therapies may exert favorable off-targets effects on the primordial follicle pool by slowing down their exhaustion. Current evidence of these effects relies on murine models or human in vitro models. Evaluation of these protective strategies in humans is challenging; however, if these results are confirmed with clinical and biological data, it not only could be a new approach to female fertility preservation but also would change standard fertility strategies."

Journal • Review • Infertility • Oncology • Ovarian Cancer • Sexual Disorders • Women's Health

Secretory expression in Bacillus subtilis and biochemical characterization of a highly thermostable polyethylene terephthalate hydrolase from bacterium HR29. (PubMed, Enzyme Microb Technol) - "Most intriguingly, purified BhrPETase displayed a melting temperature as high as 101 °C. To our knowledge it is the most thermostable bacterial PETase characterized so far. The superior activity and thermostability of BhrPETase rendered it one of the most promising PETases for plastic waste recycling and bioremediation applications in the future."

Journal

Study of the interactions of a novel monoclonal antibody, mAb059c, with the hPD-1 receptor. (PubMed, Sci Rep) - "Structural analysis indicates 1) an epitope, comprising fragments from the C'D, BC and FG loops of PD-1, contributes to mAb059c interaction, 2) an unique conformation of the C'D loop and a different orientation of R86 enabling the capture of PD-1 by the antibody complementarity determining region (CDR) and the formation of one salt-bridge contact - ASP101(HCDR3):ARG86(PD-1), and 3) the contact of FG with light chain (LC) CDR3 is maintained by a second salt-bridge and two backbone hydrogen bonds...Mutation of N58 attenuated mAb059c binding to PD-1. These findings and the novel anti-PD-1 antibody will facilitate better understanding of the mechanisms of the molecular recognition of PD-1 receptor by anti-PD-1 mAb and, thereby, enable the development of new therapeutics with an expanded spectrum of efficacy for unmet medical needs."

IO Biomarker • Journal • Oncology

The Tellurium-based Immunomodulator, AS101 Ameliorates Adjuvant-Induced Arthritis in Rats. (PubMed, Clin Exp Immunol) - "Taken together, we report the first demonstration of the anti-rheumatic/inflammatory activity of AS101 in experimental RA model thereby supporting an alternative early therapeutic intervention and identifying a promising agent for therapeutic intervention."

Journal • Immune Modulation • Immunology • Inflammation • Inflammatory Arthritis • Rheumatoid Arthritis • Rheumatology • IL1B • IL6

Safety and Efficacy of AS101 1% Oral Solution in Patients With Neovascular Age-Related Macular Degeneration (AMD) (clinicaltrials.gov) - P1/2; N=20; Completed; Sponsor: Feramda; Terminated ➔ Completed

Clinical • Trial completion • Age-related Macular Degeneration • Complement-mediated Rare Disorders • Macular Degeneration • Ophthalmology • Retinal Disorders • Wet Age-related Macular Degeneration

Aerobic microbial life persists in oxic marine sediment as old as 101.5 million years. (PubMed, Nat Commun) - "In contrast, anaerobic microbes were only minimally revived from this oxic sediment. Our results suggest that microbial communities widely distributed in organic-poor abyssal sediment consist mainly of aerobes that retain their metabolic potential under extremely low-energy conditions for up to 101.5 Ma."

Journal

Annexin A5 regulates hepatic macrophage polarization via directly targeting PKM2 and ameliorates NASH. (PubMed, Redox Biol) - "And we following reveal that Anx A5 directly interacts with PKM2 at ASP101, LEU104 and ARG106, inhibits phosphorylation of Y105, and promotes PKM2 tetramer formation. In vivo studies also show that Anx A5 improves steatosis, inflammation and fibrosis in NASH mice due to specially regulating hepatic macrophages via interaction with PKM2. Therefore, we have revealed a novel function of Anx A5 in hepatic macrophage polarization and HFD-induced NASH, providing important insights into the metabolic reprogramming, which is important for NASH therapy."

Journal • Addiction (Opioid and Alcohol) • Fibrosis • Hepatology • Immunology • Non-alcoholic Fatty Liver Disease • Non-alcoholic Steatohepatitis

Tellurium Compounds Prevent and Reverse Type-1 Diabetes in NOD Mice by Modulating α4β7 Integrin Activity, IL-1β, and T Regulatory Cells. (PubMed, Front Immunol) - "Our current results suggest that amelioration of disease in NOD mice by this unique mechanism is due to decreased infiltration of pancreatic islets combined with increased immune regulation, leading to decreased inflammation within the islets. As these tellurium compounds show remarkable lack of toxicity in clinical trials (AS101) and pre-clinical studies (SAS), they may be suitable for the treatment of type-1 diabetes."

Journal • Preclinical • Diabetes • Immunology • Metabolic Disorders • Type 1 Diabetes Mellitus

Molecular dynamics of far positioned surface mutations of Cu/Zn SOD1 promotes altered structural stability and metal-binding site: Structural clues to the pathogenesis of amyotrophic lateral sclerosis. (PubMed, J Mol Graph Model) - "Further, these mutations could increase the fluctuations in the zinc-binding loop (loop IV), primarily due to loss of hydrogen bond between Asp101 and Arg79. The relaxed conformation of Arg79 further affects the native conformation of His80 and Asp83, that results in altered zinc site geometry and the structure of the substrate channel. Our results clearly suggest that, similar to the mutations located at metal sites/dimer interface/disulfide regions, the mutations at the far positioned site (Glu100) also induce significant conformational changes that could affect the metallation and structure of SOD1 molecule, resulting in formation of toxic intermediate species that cause ALS."

Journal • Amyotrophic Lateral Sclerosis • CNS Disorders • Complement-mediated Rare Disorders

NEDOCS: is it really useful for detecting emergency department overcrowding today? (PubMed, Medicine (Baltimore)) - "The NEDOCS mean score was determined as 101.59 and the most reached result was "extremely busy but not overcrowded" (32%)...Increasing emergency nurse and intern doctor count will decrease ED overcrowding. Also, there is an urgent need to constitute local hospitals and also public health policies to satisfy the increasingly ED's presentations."

Journal

AS101 ameliorates experimental autoimmune uveitis by regulating Th1 and Th17 responses and inducing Treg cells. (PubMed, J Autoimmun) - "Finally, AS101 promoted differentiation of retina-specific T cells to Tregs in vitro independently of TGF-β. We conclude that AS101 modulates autoimmune T cells by inhibiting acquisition and expression of effector function and by promoting Treg generation, and suggest that AS101 could be useful as a therapeutic approach for autoimmune uveitis."

Journal • Complement-mediated Rare Disorders • Immunology • Ocular Inflammation • Ophthalmology • Uveitis

Safety and Efficacy of AS101 1% Oral Solution in Patients With Neovascular Age-Related Macular Degeneration (AMD) (clinicaltrials.gov) - P1/2; N=20; Terminated; Sponsor: Feramda; N=40 ➔ 20; Recruiting ➔ Terminated; Sponsor's decision.

Clinical • Enrollment change • Trial termination • Age-related Macular Degeneration • Complement-mediated Rare Disorders • Gene Therapies • Macular Degeneration • Ophthalmology • Retinal Disorders • Wet Age-related Macular Degeneration

A Tellurium-Based Small Immunomodulatory Molecule Ameliorates Depression-Like Behavior in Two Distinct Rat Models. (PubMed, Neuromolecular Med) - "3 to attain insight into the mechanism we knocked down BDNF in the hippocampus, and demonstrated that the beneficial effect of AS101 was abrogated. Together with the previously established safety profile of AS101 in humans, these results may represent the first step towards the development of a novel treatment option for MDD and TRD."

Journal • Preclinical • CNS Disorders • Depression • Immune Modulation • Inflammation • Mood Disorders • BDNF

Structure of a ferryl mimic in the archetypal iron(II)- and 2-(oxo)-glutarate-dependent dioxygenase, TauD. (PubMed, Biochemistry) - "Intriguingly, whereas the structure of the TauD·(V-oxo)·succinate·taurine complex exhibits the expected orientation of the V≡O bond-trans to the His255 ligand and toward the C-H bond to be cleaved, in what has been termed the in-line configuration-the TauD·(V-oxo) binary complex is best modeled with its oxo ligand trans to Asp101...Whereas an off-line (trans to the proximal His), or off-line-like (trans to the carboxylate ligand) ferryl is unlikely to be important in the hydroxylation reaction of TauD, the observation that the ferryl may deviate from an in-line orientation in the absence of primary substrate may explain the enzyme's mysterious self-hydroxylation behavior should the oxo ligand lie trans to His99. This finding reinforces the potential for analogous functional off-line oxo configurations in halogenases, desaturases and/or cyclases."

Journal

"Probably because there's no such thing as 101% 😂 But seriously 😢" (@coezycoe)

DGAEE, a newly synthesized derivative of glycyrrhetinic acid, potently attenuates mouse septic shock via its main metabolite DGA in an IL-10-dependent manner. (PubMed) - "LY294002 (an inhibitor of GSK3β phosphorylation) and LiCl (an inhibitor of GSK3β activity) diminished and potentiated increase of IL-10 levels by DGA, respectively. In conclusion, DGAEE alleviates septic shock through DGA in an IL-10-dependent manner, and the mechanism is related to inactivation of GSK3β."

Journal • Biosimilar • Inflammation

Endometriosis triggers excessive activation of primordial follicles via PI3K-PTEN-Akt-Foxo3 pathway. (PubMed, J Clin Endocrinol Metab) - "The current study describes the excessive activation of primordial follicles and the role of the PI3K-PTEN-Akt-Foxo3 pathway in the reduction of ovarian reserve associated with endometriosis. Our results suggest that a PI3K-PTEN-Akt inhibitor should be considered for further investigation as promising medicines for the prevention of the ovarian reserve reduction in endometriosis patients."

Journal • Endometriosis • Gynecology

Stability of antibacterial Te(IV) compounds: A combined experimental and computational study. (PubMed, J Inorg Biochem) - "Inorganic Te(IV) compounds are important cysteine protease inhibitors and antimicrobial agents; AS-101 [ammonium trichloro (dioxoethylene-O,O')tellurate] is the first compound of a family with formula NH[CHClOTe], where a Te(IV) centre is bound to a chelate ethylene glycol, and showed several protective therapeutic applications...The combined experimental and theoretical work highlights the essential role of the solvating environment and provides mechanistic insights into the complex decomposition reaction. Antimicrobial activity of the compounds was assessed against different bacterial strains."

Journal

Pre-conceptional maternal exposure to cyclophosphamide results in modifications of DNA methylation in F1 and F2 mouse oocytes: evidence for transgenerational effects. (PubMed, Epigenetics) - "Cyclophosphamide (CPM), an agent widely used in breast cancer therapy, has strong gonadotoxic effects. Pre-conceptional maternal exposure to fertoprotective agents AS101 and crocetin prior to CPM was not able to fully counteract alterations in offspring oocyte imprinting. For the first time, current study evidences that pre-conceptional CPM maternal exposure can affect the competence of offspring's oocytes and warns on possible long-term effects on the health of next generations."

Journal • Preclinical • Breast Cancer • Oncology • Solid Tumor

Mapping the Structural Path for Allosteric Inhibition of a Short-Form ATP Phosphoribosyltransferase by Histidine. (PubMed, Biochemistry) - "Following histidine binding, interaction with the histidine-binding loop may prevent the Asp101-Leu117 loop from efficiently sampling conformations conducive to catalytic activation. Tyr263Phe- PaHisZ-containing PaATPPRT, however, is less susceptible though not insensitive to histidine inhibition, suggesting the Tyr263-His104 interaction may be relevant to yet not solely responsible for transmission of the allosteric signal."

Journal

Exploring the interactions between model proteins and Pd(ii) or Pt(ii) compounds bearing charged N,N-pyridylbenzimidazole bidentate ligands by X-ray crystallography. (PubMed, Dalton Trans) - "Pt- and Pd-containing fragments bind the protein with different stoichiometries close to the side chains of His15, Asp87, Asp101 and Asn77. Altogether, our data provide a structural basis for understanding the behavior of the analyzed Pd(ii)- and Pt(ii)-based cisplatin analogues in their reactions with proteins and show the first structural characterization of an adduct comprising a cisplatin analogue that is non-covalently bound to a protein. The results suggest that functionalization of a ligand system with a sulfonate group can significantly alter the protein-binding activity and thus the overall pharmacological profile of Pd(ii)- and Pt(ii)-based drugs."

Journal • Biosimilar

Matrix metalloproteinases gene variants and dental caries in Czech children. (PubMed, BMC Oral Health) - "This study demonstrated the lack of association between the selected SNPs in candidate genes of MMPs and the susceptibility to or severity of dental caries in both primary and permanent dentitions in Czech children."

Clinical • Journal • Dental Disorders • MMP13 • MMP2 • MMP3 • MMP9 • PCR

Ovarian damage by anticancer therapy: molecular mechanisms and preventive strategies (ESG 2017) - "...Objective: The aim of the study was to investigate whether the natural carotenoid Crocetin (8,8'-diapocarotenoic acid) and the synthetic tellurium compound AS101 protect the ovary against cyclophosphamide (CPM) by modulating SIRT1 and mitochondrial markers... Results from this study aims to increase the knowledge of mechanisms underlying ovarian damage by CPM and will be helpful to develop new therapeutic opportunities for preserving fertility in cancer patients based on administration of antioxidants with anticancer properties. Also, our data suggest that SIRT1 may be a biomolecular marker for evaluating the cytotoxicity of chemotherapeutic agents other than CPM and the potential of protective molecules."

Biosimilar • Gynecologic Cancers • Long-acting Reversible Contraceptives • Oncology • Ovarian Cancer • Solid Tumor • Women's Health