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β-secretase BACE1 is required for normal cochlear function.
No full textβ-secretase BACE1 is an essential player in the amyloid cascade of Alzheimer´s disease (AD),
making the enzyme a prime therapeutic target. Given its many substrates, however, questions remain regarding the safety of chronic BACE1 suppression in AD. Here, we report that BACE1-/-
mice exhibit significant hearing deficits, as indicated by audiometric tests.
Immunohistochemistry revealed aberrant synaptic organization in the cochlea and
hypomyelination of auditory nerve fibres. To determine whether the auditory system would
be susceptible to chronic pharmacological suppression of BACE1, as envisioned for high AD
risk individuals or early-stage AD patients, we administered the established BACE1 inhibitor
NB-360 for six weeks to wild type mice. The drug efficiently suppressed the enzymatic activity
of the secretase, but did not impair hearing performance and did not produce the characteristic neuropathological abnormalities seen in the cochlea of BACE1-/- mice. These data indicate that the hearing loss of BACE1-/- mice represents a developmental phenotype
Open Innovation @ NITD Unleash the potential and empower the next generation of global health researchers
No full textOpen Innovation @ NITD was established by Novartis in partnership with the Bill & Melinda Gates Foundation to address fundamental questions in drug discovery for global health.
As an incubator-style environment within the Novartis Institute for Tropical Diseases (NITD), Open Innovation @ NITD unites basic research with the infrastructure of a world-class pharmaceutical company
A General Protocol for Robust Sonogashira Reactions in Micellar Medium
No full textA robust and general protocol for a sustainable copper-free Sonogashira cross coupling under micellar aqueous reaction conditions with high turnover was developed. By using the commercially available catalyst CataCXium A Pd G3 and THF as co-solvent, various alkyne substrates were efficiently cross-coupled with a broad range of aryl halides, providing improved yields and low catalyst loadings. The reaction parameters were optimized to render the process operationally simple, robust and scalable. The method gives access to alkynylated arenes, heterocyclic compounds and monofunctionalized products from dihalogenated substrates with an improved selectivity achieved by the micellar aqueous reaction conditions
Fe-Catalyzed Reductive Couplings of Terminal (Hetero)Aryl Alkenes and Alkyl Halides under Aqueous Micellar Conditions
No full textThe combination of a vinyl-substituted aromatic or heteroaromatic and an
alkyl bromide or iodide leads, in the presence of Zn and a catalytic amount of an Fe(II)
salt, to a net reductive coupling. The new C−C bond is regiospecifically formed at rt at
the β-site of the alkene. The coupling only occurs in an aqueous micellar medium, where
a radical process is likely, supported by several control experiments. A mechanism based
on these data is proposed
Inhibition of Inositol kinase B controls acute and chronic graft-versus-host disease
No full textT-cell activation releases inositol 1,4,5-trisphosphate (IP3), inducing cytoplasmic calcium (Ca2+) influx. In turn, inositol 1,4,5-trisphosphate 3-kinase B (Itpkb) phosphorylates IP3 to negatively regulate and thereby tightly control Ca2+ fluxes that are essential for mature T-cell activation, differentiation and protection from cell death. Itpkb pathway inhibition increases intracellular Ca2+, induces apoptosis of activated T-cells, and can control T-cell mediated autoimmunity. Here, we employed genetic and pharmacological approaches to inhibit Itpkb signaling as a means of controlling graft-versus-host disease (GVHD). Murine induced Itpkb deleted (Itpkb-/-) T-cells had attenuated acute GVHD in two models without eliminating A20-luciferase B-cell lymphoma graft-versus-leukemia (GVL). A highly potent, selective inhibitor, GNF362, ameliorated acute GVHD without impairing GVL against two acute myeloid leukemia lines (MLL-AF9-eGFP; C1498-luciferase). Compared to FK506, GNF362 more selectively deleted donor alloreactive versus nominal antigen responsive T-cells. Consistent with these data and as compared to FK506, GNF362 had favorable acute GVHD and GVL properties against MLL-AF9-eGFP cells. In chronic GVHD preclinical models that have a distinct pathophysiology from acute GVHD, Itpkb-/- donor T-cells reduced active chronic GVHD in a multi-organ system model with bronchiolitis obliterans (BO) driven by germinal center reactions, resulting in target organ fibrosis. GNF362 treatment reduced active chronic GVHD in both BO and scleroderma models. Thus, intact Itpkb signaling is required to drive acute GVHD pathogenesis and sustain active chronic GVHD, pointing toward a novel clinical application to prevent acute or treat chronic GVHD
Variability of non-clinical behavioral CNS safety assessment: An intercompany comparison
No full textIntroduction: Irwin/FOB testing is routinely conducted to investigate the neurofunctional integrity of laboratory animals during preclinical development of new drugs, however, the study design frequently varies to meet specific needs. Representatives of several European-based pharmaceutical companies performed a “state-of-the-art” assessment of how they conduct their CNS safety evaluation using Irwin/FOB tests. Methods: This assessment consisted of (1) a survey of current/historical practice, (2) an evaluation of historical studies with reference compounds (amphetamine, chlorpromazine) to determine intercompany reproducibility of results, and (3) an interlaboratory test using reference compounds (MK-801, chlorpromazine) to determine whether partially standardized conditions (animals, sex, doses, vehicles, administration route, observation time points, systemic exposure) might reduce variability of results. Results: Our survey revealed several similarities, e.g., main endpoints of home cage and openfield observations, species, and positive control substances, but also a high level of heterogeneity between different companies with regard to behavioral endpoints during handling and reflex testing, scoring, group size, and timing of studies. Analysis of heterogeneously designed historical studies with amphetamine and chlorpromazine showed the anticipated behavioral changes, albeit with quantitative variability, and identified more robust (e.g., activity, posture, muscle tone, startle reflex, body temperature) and less robust (piloerection, stereotypical behavior, palpebral closure, respiration) Irwin/FOB parameters. A partially standardized interlaboratory test with MK-801 and chlorpromazine showed the expected behavioral changes and principally confirmed the historically-based more/less robust Irwin/FOB parameters, however, it also showed exposure variability and did not show a markedly reduced quantitative variability of behavioral results. Discussion: Our survey and intercompany test results demonstrate certain heterogeneity in design and conduct of Irwin/FOB tests by pharmaceutical companies. Although the general behavioral profiles for the reference compounds were consistently found, quantitative variability of results remained even under partially standardized conditions. This suggests the importance of a high level of standardization with regard to the Irwin/FOB test modification used, scoring system, and observer training, in order to achieve an improved intercompany comparability of Irwin/FOB results
Late-stage Functionalization of Peptides and Cyclopeptides using Organozinc reagents
No full textWe have reported a new late-stage functionalization of small peptides and cyclopeptides using readily prepared iodotyrosine or iodophenylalanine containing peptides and performing Negishi cross-couplings with aryl-, heteroaryl- and alkyl-zinc pivalates or halides. In-silico and in-vitro determinations of membrane permeability data of the modified cyclopeptides showed that in most cases, the solubility was improved while the cell-membrane permeability was maintained by the introduction of polar pyridyl units
Reactivation of a developmental signaling center is required for therapeutic control of the murine periosteal niche.
No full textTwo decades after signals controlling bone length were discovered, the endogenous ligands determining bone width remain unknown. We show that postnatal establishment of normal bone width in mice, as mediated by bone-forming activity of the periosteum, requires BMP signaling at the innermost layer of the periosteal niche. This developmental signaling center becomes quiescent during adult life. Its reactivation however, is necessary for periosteal growth, enhanced bone strength, and accelerated fracture repair in response to bone-anabolic therapies used in clinical orthopedic settings. Although many BMPs are expressed in bone, periosteal BMP signaling and bone formation require only in the lineage. Mechanistically, BMP2 functions downstream of Lrp5/6 pathway to activate a conserved regulatory element upstream of via recruitment of Smad1 and Grhl3. Consistent with our findings, human variants of and are associated with increased risk of fractures
Parasite of the Month: Plasmodium vivax
No full textPlasmodium vivax is a eukaryotic human pathogen and the most frequent and widely distributed cause of the recurring disease malaria. P. vivax is one of five species of malaria parasites that commonly infect humans. Although less virulent than Plasmodium falciparum, P. vivax malaria infections can lead to severe disease and death. The disease is transmitted to humans by female anopheline mosquitoes during acquisition of a blood meal. An obligate liver stage of development precedes blood stage replication which accounts for all disease-associated morbidity and mortality and chloroquine is still used to treat the disease. Approximately 2.5 billion people are at risk of infection with P. vivax, and it is found mainly in Asia and Latin America where it accounts for 65% of malaria cases. In Africa, the widespread lack of the Duffy antigen in the population has constrained transmission. A dormant liver stage form, known as the hypnozoite can reactivate and causes disease relapses and the majority of blood stage infections are caused by relapse. The hypnozoite is thus a challenge for malaria eradication campaigns and primaquine and tafenoquine are the only drugs known to target the hypnozoite. However, these therapies are inadequate since primaquine cannot be administered to pregnant women and people with commonly occurring glucose-6-phosphate dehydrogenase deficiency and tafenoquine cannot be administered to children. There is no effective P. vivax vaccine