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Ubiquitin-Dependent and -Independent Roles of E3 Ligase RIPLET in Innate Immunity.
No full textThe conventional view posits that E3 ligases function primarily through conjugating ubiquitin (Ub) to their substrate molecules. We report here that RIPLET, an essential E3 ligase in antiviral immunity, promotes the antiviral signaling activity of the viral RNA receptor RIG-I through both Ub-dependent and -independent manners. RIPLET uses its dimeric structure and a bivalent binding mode to preferentially recognize and ubiquitinate RIG-I pre-oligomerized on dsRNA. In addition, RIPLET can cross-bridge RIG-I filaments on longer dsRNAs, inducing aggregate-like RIG-I assemblies. The consequent receptor clustering synergizes with the Ub-dependent mechanism to amplify RIG-I-mediated antiviral signaling in an RNA-length dependent manner. These observations show the unexpected role of an E3 ligase as a co-receptor that directly participates in receptor oligomerization and ligand discrimination. It also highlights a previously unrecognized mechanism by which the innate immune system measures foreign nucleic acid length, a common criterion for self versus non-self nucleic acid discrimination
RIPLET, and not TRIM25, is required for endogenous RIG-I-dependent antiviral responses.
No full textThe innate immune system is our first line of defense against viral pathogens. Host cell pattern recognition receptors sense viral components and initiate immune signaling cascades that result in the production of an array of cytokines to combat infection. Retinoic acid-inducible gene-I (RIG-I) is a pattern recognition receptor that recognizes viral RNA and, when activated, results in the production of type I and III interferons (IFNs) and the upregulation of IFN-stimulated genes. Ubiquitination of RIG-I by the E3 ligases tripartite motif-containing 25 (TRIM25) and Riplet is thought to be requisite for RIG-I activation; however, recent studies have questioned the relative importance of these two enzymes for RIG-I signaling. In this study, we show that deletion of Trim25 does not affect the IFN response to either influenza A virus (IAV), influenza B virus, Sendai virus or several RIG-I agonists. This is in contrast to deletion of either Rig-i or Riplet, which completely abrogated RIG-I-dependent IFN responses. This was consistent in both mouse and human cell lines, as well as in normal human bronchial cells. With most of the current TRIM25 literature based on exogenous expression, these findings provide critical evidence that Riplet, and not TRIM25, is required endogenously for the ubiquitination of RIG-I. Despite this, loss of TRIM25 results in greater susceptibility to IAV infection in vivo, suggesting that it may have an alternative role in host antiviral defense. This study refines our understanding of RIG-I signaling in viral infections and will inform future studies in the field
Prostaglandin D2 type 2 receptor antagonism reduces airway smooth muscle mass in asthma: mechanistic insights from in vitro and computational models
No full textIncreased airway smooth muscle mass, a feature of airway remodeling in asthma, is the strongest predictor of airflow limitation, and contributes significantly to asthma-associated morbidity and mortality. No current drug therapy for asthma affects airway smooth muscle mass. We report that the prostaglandin D2 type 2 receptor antagonist, fevipiprant, is the first drug in a randomized placebo-controlled trial to reduce airway smooth muscle mass in asthma. By integrating in vitro experiments with a novel agent-based computational modeling strategy we found this reduction in airway smooth muscle mass was a consequence of inhibiting eosinophilic inflammation in concert with reduced recruitment of myofibroblasts to the airway smooth muscle bundle. Thus, fevipiprant represents a novel therapy to ameliorate airway remodeling in asthma
Development of pharmacotherapies for the treatment of sarcopenia
No full textThe review briefly summarizes the definition of sarcopenia and commonly used assessments and provides information on preclinical studies and clinical trial findings of the more advanced drug development programs for the treatment of muscle wasting, including the bimagrumab program. No data have been included in this article that have not already been published (and approved) in article or abstract format. In addition, we discuss several related issues that are needed to facilitate the development of a safe and efficacious pharmacotherapeutic that could be used as part of a treatment plan for older men and women with sarcopenia
In vivo efficacy of novel monobactam LYS228 in murine models of carbapenemase-producing Klebsiella pneumoniae infection
No full textLYS228 has potent antibacterial activity against carbapenem-resistant strains of Enterobacteriaceae. LYS228 was efficacious in neutropenic thigh models established with K. pneumoniae producing either KPC-2 or NDM-1; pre-treatment with uranyl nitrate considerably shifted calculated static doses of LYS228. In murine ascending pyelonephritis, LYS228 reduced bacterial burden in the kidney, urine and bladder. The successful treatment of murine infection models established with carbapenem resistant K. pneumoniae further supports the clinical development of LYS228
Discovery of 5-(3,4-Difluorophenyl)-3-(pyrazol-4-yl)-7-azaindole (GNF3809) for β-Cell Survival in Type 1 Diabetes
No full textPancreatic β-cell apoptosis, a hallmark of the development of type 1 diabetes (T1D), is associated with increased levels of pro-inflammatory cytokines. Thus, an agent protecting β-cells from cytokine-induced stress should have an impact on maintaining functional β-cell mass in T1D. Screening of a ∼2 million-compound library identified a series of 7-azaindole derivatives as capable of protecting rat insulinoma β-cells from death induced by pro-inflammatory cytokines. The screening hits were optimized to result in GNF3809, a compound which preserves insulin content and viability of β-cells in both rodent and human islets under stress induced by cytokines. In vivo, orally bioavailable GNF3809 prevented elevated blood glucose level and improved oral glucose tolerance in a nonobese diabetic mouse model. This work lays the foundation for development of a new class of therapeutic interventions for T1D
Taming autoimmunity: Translating antigen-specific approaches to induce immune tolerance
No full textJosé M. Carballido, Executive Director at Novartis Institutes for BioMedical Research, and Pere Santamaria, Professor of Immunology at the University of Calgary and Founder of Parvus Therapeutics Inc., discuss the opportunities and challenges of translating antigen-specific approaches for autoimmunity with an emphasis on the need for scientific rigor in the preclinical stage
Glaucoma - Next Generation Therapeutics: Impossible to Possible
No full textThe future of next generation therapeutics for glaucoma is strong. The recent approval of two novel intraocular pressure (IOP)-lowering drugs with distinct mechanisms of action is the first in over 20 years. However, these are still being administered as topical drops. Efforts are underway to increase patient compliance and greater therapeutic benefits with the development of sustained delivery technologies. Furthermore, innovations from biologics- and gene therapy-based therapeutics are being developed in the context of disease modification, which are expected to lead to more permanent therapies for patients. Neuroprotection, including the preservation of retinal ganglion cells (RGCs) and optic nerve is another area that is actively being explored for therapeutic options. With improvements in imaging technologies and determination of new surrogate clinical endpoints, the therapeutic potential for translation of neuroprotectants is coming close to clinical realization. This review summarizes the aforementioned topics and other related aspects
Treatment of primary Sjögren’s syndrome with ianalumab (VAY736) Targeting B cells by BAFF receptor-blockade coupled with enhanced, antibody-dependent cellular cytotoxicity
No full textObjectives
To evaluate the efficacy and safety of VAY736 (ianalumab), a B-cell-depleting, BAFF-receptor blocking, monoclonal antibody, in patients with active primary Sjögren’s syndrome in a double blind, placebo-controlled, phase II, single center study.
Methods
Patients with primary Sjögren’s syndrome (pSS), disease activity ESSDAI 6, were randomized to VAY736 single infusion at either 3 mg/kg (n=6), 10 mg/kg (n=12), or placebo (n=9). Outcomes were measured blinded at baseline and weeks 6, 12, 24, and unblinded at end of study (EoS) when B-cells numbers had recovered. Clinical outcomes included ESSDAI, ESSPRI, salivary flow rate, ocular staining score, physician global assessment and patient assessments of fatigue and general quality of life. Laboratory-based measures included circulating leucocyte subsets and markers of B cell activity.
Results
A similar trend showing positive therapeutic effect by VAY736 was observed across the primary clinical outcome (ESSDAI) and all secondary clinical outcomes (ESSPRI, MFI, SF3-36, global assessments by physician and patient) versus the placebo-treated group. Rapid and profound B-cell depletion of long lasting duration occurred after a single infusion of VAY736 at either dose. Serum Ig light chains decreased with return to baseline levels at EoS. Changes in some clinical outcomes persisted through to EoS in the higher dose group. Adverse effects were largely limited to mild-to-moderate infusion reactions within 24 hours of VAY736 administration.
Conclusions
Overall results in this single dose study suggest potent and sustained B-cell depletion by VAY736 could provide therapeutic benefits in pSS patients without major side effects
Antagonizing Retinoic acid-related-orphan receptor gamma Activity Blocks the T Helper 17/Interleukin-17 Pathway Leading to Attenuated Pro-inflammatory Human Keratinocyte and Skin Responses
No full textThe nuclear hormone receptor retinoic acid receptor-related-orphan-receptor-gamma
t (RORgt) is the key transcription factor required for Th17 cell differentiation and for
production of IL-17 family cytokines by innate and adaptive immune cells. Dysregulated
Th17 immune responses have been associated with the pathogenesis of several
inflammatory and autoimmune diseases such as psoriasis, psoriatic arthritis, and
ankylosing spondylitis. In this article, we describe the in vitro pharmacology of a potent
and selective low molecular weight RORgt inhibitor identified after a structure-based
hit-to-lead optimization effort. The compound interfered with co-activator binding to
the RORgt ligand binding domain and impaired the transcriptional activity of RORgt
as evidenced by blocked IL-17A secretion and RORE-mediated transactivation of
a luciferase reporter gene. The inhibitor effectively reduced IL-17A production by
human naive and memory T-cells and attenuated transcription of pro-inflammatory
Th17 signature genes, such as IL17F, IL22, IL26, IL23R, and CCR6. The compound
selectively suppressed the Th17/IL-17 pathway and did not interfere with polarization
of other T helper cell lineages. Furthermore, the inhibitor was selective for RORgt and
did not modify the transcriptional activity of the closely related family members RORa
and RORb. Using human keratinocytes cultured with supernatants from compound
treated Th17 cells we showed that pharmacological inhibition of RORgt translated to
suppressed IL-17-regulated gene expression in keratinocyte cell cultures. Furthermore,
in ex vivo immersion skin cultures our RORgt inhibitor suppressed IL-17A production
by Th17-skewed skin resident cells which correlated with reduced human b defensin 2
expression in the skin. Our data suggests that inhibiting RORgt transcriptional activity by
a low molecular weight inhibitor may hold utility for the treatment of Th17/IL-17-mediated
skin pathologies