Small molecule neurotensin receptor 1 (NTSR1) agonists have been pursued for more than 40 years as potential therapeutics for psychiatric disorders, including drug addiction. Clinical development of ...NTSR1 agonists has, however, been precluded by their severe side effects. NTSR1, a G protein-coupled receptor (GPCR), signals through the canonical activation of G proteins and engages β-arrestins to mediate distinct cellular signaling events. Here, we characterize the allosteric NTSR1 modulator SBI-553. This small molecule not only acts as a β-arrestin-biased agonist but also extends profound β-arrestin bias to the endogenous ligand by selectively antagonizing G protein signaling. SBI-553 shows efficacy in animal models of psychostimulant abuse, including cocaine self-administration, without the side effects characteristic of balanced NTSR1 agonism. These findings indicate that NTSR1 G protein and β-arrestin activation produce discrete and separable physiological effects, thus providing a strategy to develop safer GPCR-targeting therapeutics with more directed pharmacological action.
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•The small molecule SBI-553 typifies a distinctive class of GPCR ligands•SBI-553 is a β-arrestin-biased allosteric modulator of neurotensin receptor 1 (NTSR1)•SBI-553 reduces stimulant effects without the side effects of unbiased NTSR1 agonists•Allosteric targeting of GPCRs will enable the development of superior therapeutics
An ago-allosteric modulator that biases neurotensin receptor 1 signaling toward β-arrestin shows promise as a means of treating psychostimulant addictions and avoiding G protein-mediated side effects.
Surgical care episodes place opioid-naïve patients at risk for transitioning to new persistent postoperative opioid use. With one of the central principles being the application of multimodal pain ...interventions to reduce the reliance on opioid-based medications, enhanced recovery pathways provide a framework that decreases perioperative opioid use. The fourth Perioperative Quality Initiative brought together a group of international experts representing anesthesiology, surgery, and nursing with the objective of providing consensus recommendations on this important topic. Fourth Perioperative Quality Initiative was a consensus-building conference designed around a modified Delphi process in which the group alternately convened for plenary discussion sessions in between small group discussions. The process included several iterative steps including a literature review of the topics, building consensus around the important questions related to the topic, and sequential steps of content building and refinement until agreement was achieved and a consensus document was produced. During the fourth Perioperative Quality Initiative conference and thereafter as a writing group, reference applicability to the topic was discussed in any area where there was disagreement. For this manuscript, the questions answered included (1) What are the potential strategies for preventing persistent postoperative opioid use? (2) Is opioid-free anesthesia and analgesia feasible and appropriate for routine operations? and (3) Is opioid-free (intraoperative) anesthesia associated with equivalent or superior outcomes compared to an opioid minimization in the perioperative period? We will discuss the relevant literature for each questions, emphasize what we do not know, and prioritize the areas for future research.
Full details of the development of a simple, nondestructive, and high-throughput method for establishing DNA binding affinity and sequence selectivity are described. The method is based on the loss ...of fluorescence derived from the displacement of ethidium bromide or thiazole orange from the DNA of interest or, in selected instances, the change in intrinsic fluorescence of a DNA binding agent itself and is applicable for assessing relative or absolute DNA binding affinities. Enlisting a library of hairpin deoxyoligonucleotides containing all five base pair (512 hairpins) or four base pair (136 hairpins) sequences displayed in a 96-well format, a compound's rank order binding to all possible sequences is generated, resulting in a high-resolution definition of its sequence selectivity using this fluorescent intercalator displacement (FID) assay. As such, the technique complements the use of footprinting or affinity cleavage for the establishment of DNA binding selectivity and provides the information at a higher resolution. The merged bar graphs generated by this rank order binding provide a qualitative way to compare, or profile, DNA binding affinity and selectivity. The 96-well format assay (512 hairpins) can be conducted at a minimal cost (presently ca. $100 for hairpin deoxyoligonucleotides/assay with ethiduim bromide or less with thiazole orange), with a rapid readout using a fluorescent plate reader (15 min), and is adaptable to automation (Tecan Genesis Workstation 100 robotic system). Its use in generating a profile of DNA binding selectivity for several agents including distamycin A, netropsin, DAPI, Hoechst 33258, and berenil is described. Techniques for establishing binding constants from quantitative titrations are compared, and recommendations are made for use of a Scatchard or curve fitting analysis of the titration binding curves as a reliable means to quantitate the binding affinity.
Despite the enthusiasm surrounding cancer immunotherapy, most SCLC patients show very modest response to immune checkpoint inhibitor monotherapy treatment. Therefore, there is growing interest in ...combining immune checkpoint blockade with chemotherapy and other treatments to enhance immune checkpoint blockade efficacy. Based on favorable clinical trial results, chemotherapy and immunotherapy combinations have been recently approved by the U.S. Food and Drug Administration for frontline treatment for SCLC.
Here, we show that combined treatment of SRA737, an oral CHK1 inhibitor, and anti–programmed death ligand 1 (PD-L1) leads to an antitumor response in multiple cancer models, including SCLC. We further show that combining low, non-cytotoxic doses of gemcitabine with SRA737 + anti–PD-L1/anti–PD-1 significantly increased antitumorigenic CD8+ cytotoxic T cells, dendritic cells, and M1 macrophage populations in an SCLC model. This regimen also led to a significant decrease in immunosuppressive M2 macrophage and myeloid-derived suppressor cell populations, as well as an increase in the expression of the type I interferon beta 1 gene, IFNβ, and chemokines, CCL5 and CXCL10.
Given that anti–PD-L1/anti–PD-1 drugs have recently been approved as monotherapy and in combination with chemotherapy for the treatment of SCLC, and that the SRA737 + low dose gemcitabine regimen is currently in clinical trials for SCLC and other malignancies, our preclinical data provide a strong rational for combining this regimen with inhibitors of the PD-L1/PD-1 pathway.
Obesity-associated insulin resistance plays a central role in the pathogenesis of type 2 diabetes. A promising approach to decrease insulin resistance in obesity is to inhibit the protein tyrosine ...phosphatases that negatively regulate insulin receptor signaling. The low-molecular-weight protein tyrosine phosphatase (LMPTP) acts as a critical promoter of insulin resistance in obesity by inhibiting phosphorylation of the liver insulin receptor activation motif. Here, we report development of a novel purine-based chemical series of LMPTP inhibitors. These compounds inhibit LMPTP with an uncompetitive mechanism and are highly selective for LMPTP over other protein tyrosine phosphatases. We also report the generation of a highly orally bioavailable purine-based analogue that reverses obesity-induced diabetes in mice.
Carbon dioxide (CO2) is an abundant C1 feedstock with tremendous potential to produce versatile building blocks in synthetic applications. Given the adverse impact of CO2 on the atmosphere, it is of ...paramount importance to devise strategies for upcycling it into useful materials, such as polymers and fine chemicals. To activate such stable molecule, superbases offer viable modes of binding to CO2. In this study, a superbase cyclopropenimine derivative was found to exhibit exceptional proficiency in activating CO2 and mediating its polymerization at ambient temperature and pressure for the synthesis of polyurethanes. The versatility of this reaction can be extended to monofunctional amines and alcohols, yielding a variety of functional carbonates and carbamates.
Cyclopropenimine, polyurethane, carbon dioxide, carbamates, organocatalysisCarbon dioxide (CO2) is an abundant C1 feedstock with tremendous potential to produce versatile building blocks in synthetic applications. Organo‐carbonation (OrCa) polymerization employs the superbase cyclopropenimine to bind CO2 and mediate its polymerization at ambient temperature and pressure for the synthesis of polyurethanes. Cyclopropenimine is recyclable and this procedure provides direct access to N‐alkylated polyurethanes.
Carbon dioxide (CO
) is an abundant C1 feedstock with tremendous potential to produce versatile building blocks in synthetic applications. Given the adverse impact of CO
on the atmosphere, it is of ...paramount importance to devise strategies for upcycling it into useful materials, such as polymers and fine chemicals. To activate such stable molecule, superbases offer viable modes of binding to CO
. In this study, a superbase cyclopropenimine derivative was found to exhibit exceptional proficiency in activating CO
and mediating its polymerization at ambient temperature and pressure for the synthesis of polyurethanes. The versatility of this reaction can be extended to monofunctional amines and alcohols, yielding a variety of functional carbonates and carbamates.
To measure, in the setting of typical passively scattered proton craniospinal irradiation (CSI) treatment, the secondary neutron spectra, and use these spectra to calculate dose equivalents for both ...internal and external neutrons delivered via a Mevion single-room compact proton system.
Secondary neutron spectra were measured using extended-range Bonner spheres for whole brain, upper spine, and lower spine proton fields. The detector used can discriminate neutrons over the entire range of the energy spectrum encountered in proton therapy. To separately assess internally and externally generated neutrons, each of the fields was delivered with and without a phantom. Average neutron energy, total neutron fluence, and ambient dose equivalent H* (10) were calculated for each spectrum. Neutron dose equivalents as a function of depth were estimated by applying published neutron depth–dose data to in-air H* (10) values.
For CSI fields, neutron spectra were similar, with a high-energy direct neutron peak, an evaporation peak, a thermal peak, and an intermediate continuum between the evaporation and thermal peaks. Neutrons in the evaporation peak made the largest contribution to dose equivalent. Internal neutrons had a very low to negligible contribution to dose equivalent compared with external neutrons, largely attributed to the measurement location being far outside the primary proton beam. Average energies ranged from 8.6 to 14.5 MeV, whereas fluences ranged from 6.91 × 106 to 1.04 × 107 n/cm2/Gy, and H* (10) ranged from 2.27 to 3.92 mSv/Gy.
For CSI treatments delivered with a Mevion single-gantry proton therapy system, we found measured neutron dose was consistent with dose equivalents reported for CSI with other proton beamlines.
In
, the first two and rate-limiting enzymes of the pentose phosphate pathway, glucose 6-phosphate dehydrogenase (G6PD) and the 6-phosphogluconolactonase, are bifunctionally fused to a unique enzyme ...named GluPho, differing structurally and mechanistically from the respective human orthologs. Consistent with the enzyme's essentiality for malaria parasite proliferation and propagation, human G6PD deficiency has immense impact on protection against severe malaria, making
GluPho an attractive antimalarial drug target. Herein we report on the optimized lead compound
-(((2R,4S)-1-cyclobutyl-4-hydroxypyrrolidin-2-yl)methyl)-6-fluoro-4-methyl-11-oxo-10,11-dihydrodibenzob,f1,4thiazepine-8-carboxamide (SBI-0797750), a potent and fully selective
GluPho inhibitor with robust nanomolar activity against recombinant
GluPho,
G6PD, and P. falciparum blood-stage parasites. Mode-of-action studies have confirmed that SBI-0797750 disturbs the cytosolic glutathione-dependent redox potential, as well as the cytosolic and mitochondrial H
O
homeostasis of P. falciparum blood stages, at low nanomolar concentrations. Moreover, SBI-0797750 does not harm red blood cell (RBC) integrity and phagocytosis and thus does not promote anemia. SBI-0797750 is therefore a very promising antimalarial lead compound.
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