One-pot radioiodination of aryl amines via stable diazonium salts: preparation of 125I-imaging agents

An operationally simple, one-pot, two-step tandem procedure that allows the incorporation of radioactive iodine into aryl amines via stable diazonium salts is described. The mild conditions are tolerant of various functional groups and substitution patterns, allowing late-stage, rapid access to a wide range of 125I-labelled aryl compounds and SPECT radiotracers

Proteinase-activated receptors (PARs) as targets for antiplatelet therapy

Since the identification of the proteinase-activated receptor (PAR) family as mediators of serine protease activity in the 1990s, there has been tremendous progress in the elucidation of their pathophysiological roles. The development of drugs that target PARs has been the focus of many laboratories for the potential treatment of thrombosis, cancer and other inflammatory diseases. Understanding the mechanisms of PAR activation and G protein signalling pathways evoked in response to the growing list of endogenous proteases has yielded great insight into receptor regulation at the molecular level. This has led to the development of new selective modulators of PAR activity, particularly PAR1. The mixed success of targeting PARs has been best exemplified in the context of inhibiting PAR1 as a new antiplatelet therapy. The development of the competitive PAR1 antagonist, vorapaxar (Zontivity), has clearly shown the value in targeting PAR1 in acute coronary syndrome (ACS); however the severity of associated bleeding with this drug has limited its use in the clinic. Due to the efficacy of thrombin acting via PAR1, strategies to selectively inhibit specific PAR1-mediated G protein signalling pathways or to target the second thrombin platelet receptor, PAR4, are being devised. The rationale behind these alternative approaches is to bias downstream thrombin activity via PARs to allow for inhibition of pro-thrombotic pathways but maintain other pathways that may preserve haemostatic balance and improve bleeding profiles for widespread clinical use. This review summarizes the structural determinants that regulate PARs and the modulators of PAR activity developed to date

Late stage iodination of biologically active agents using a one-pot process from aryl amines

A simple and effective one-pot tandem procedure that generates aryl iodides from readily available aryl amines via stable diazonium salts has been developed. The operationally simple procedure and mild conditions allow late-stage iodination of a wide range of aryl compounds bearing various functional groups and substitution patterns. A novel synthetic strategy involving the preparation of nitroaryl compounds followed by a chemoselective tin(II) dichloride reduction and the use of the one-pot diazotisation–iodination transformation was also developed. The general applicability of this approach was demonstrated with the preparation of a number of medicinally important compounds including CNS1261, a SPECT imaging agent of the N-methyl-D-aspartate (NMDA) receptor and IBOX, a compound used to detect amyloid plaques in the brain

The PIN domain endonuclease Utp24 cleaves pre-ribosomal RNA at two coupled sites in yeast and humans

During ribosomal RNA (rRNA) maturation, cleavages at defined sites separate the mature rRNAs from spacer regions, but the identities of several enzymes required for 18S rRNA release remain unknown. PilT N-terminus (PIN) domain proteins are frequently endonucleases and the PIN domain protein Utp24 is essential for early cleavages at three pre-rRNA sites in yeast (A0, A1 and A2) and humans (A0, 1 and 2a). In yeast, A1 is cleaved prior to A2 and both cleavages require base-pairing by the U3 snoRNA to the central pseudoknot elements of the 18S rRNA. We found that yeast Utp24 UV-crosslinked in vivo to U3 and the pseudoknot, placing Utp24 close to cleavage at site A1. Yeast and human Utp24 proteins exhibited in vitro endonuclease activity on an RNA substrate containing yeast site A2. Moreover, an intact PIN domain in human UTP24 was required for accurate cleavages at sites 1 and 2a in vivo, whereas mutation of another potential site 2a endonuclease, RCL1, did not affect 18S production. We propose that Utp24 cleaves sites A1/1 and A2/2a in yeast and human cells

Recent climate change has driven divergent hydrological shifts in high-latitude peatlands

A recent synthesis study found 54% of the high-latitude peatlands have been drying and 32% have been wetting over the past centuries, illustrating their complex ecohydrological dynamics and highly uncertain responses to a warming climate. High-latitude peatlands are changing rapidly in response to climate change, including permafrost thaw. Here, we reconstruct hydrological conditions since the seventeenth century using testate amoeba data from 103 high-latitude peat archives. We show that 54% of the peatlands have been drying and 32% have been wetting over this period, illustrating the complex ecohydrological dynamics of high latitude peatlands and their highly uncertain responses to a warming climate.Peer reviewe

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Development of novel allosteric regulators of proteinase-activated receptors

Proteinase-activated receptors (PARs), members of the G-protein coupled receptor (GPCR) superfamily of proteins, represent highly attractive targets for therapy across a wide range of diseases. Of specific interest are PAR1 and PAR2, the major signalling members of the PAR family which are associated with cardiovascular disease, cancer and inflammatory disease. However, despite significant efforts, there is only one marketed drug for the PARs available in Vorapaxar, which is used to inhibit PAR1 in the treatment of thrombosis. Thus, exploring different chemical approaches to developing better lead molecules is important to explore novel methods for modulating the PARs. Pepducins, peptidic compounds containing a palmitoyl chain, have represented a novel approach to allosteric modulation of PARs, with PZ-128 targeting PAR1 and PZ-235 targeting PAR2 as promising lead compounds. However, deviation from the general pepducin structure has not been explored and represent possible areas of improvement. Herein, 10 novel PZ-128 analogues are described as potential improvements to PZ-128 highlighting the impact of linker modification as well as cyclisation of the peptide sequence. Additionally, off-target activity of PZ-128 is also explored, highlighting some intrinsic problems with the pepducin approach. These problems were alleviated to an extent with the novel PZ-128 analogues but identifying overall improvements to the pharmacological character of the series proved challenging. Recently, two potential lead molecules were published targeting PAR2 with AZ8838 and AZ3451. These compounds have provided new insight into how we can target PAR2, allowing access to novel chemicals with improved properties. Through a series of modifications to the published chemical structures, we have accessed novel compounds that display similar biological properties to AZ8838. Herein, 15 novel analogues of AZ8838 have been synthesised and their propensity for PAR2 inhibition tested in in vitro assays, identifying one compound of comparable potency whilst exploring the SAR surrounding the AZ8838 binding pocket. Additionally, an expanded library of AZ8838 analogues has been computationally docked to assess binding within PAR2 in silico.Proteinase-activated receptors (PARs), members of the G-protein coupled receptor (GPCR) superfamily of proteins, represent highly attractive targets for therapy across a wide range of diseases. Of specific interest are PAR1 and PAR2, the major signalling members of the PAR family which are associated with cardiovascular disease, cancer and inflammatory disease. However, despite significant efforts, there is only one marketed drug for the PARs available in Vorapaxar, which is used to inhibit PAR1 in the treatment of thrombosis. Thus, exploring different chemical approaches to developing better lead molecules is important to explore novel methods for modulating the PARs. Pepducins, peptidic compounds containing a palmitoyl chain, have represented a novel approach to allosteric modulation of PARs, with PZ-128 targeting PAR1 and PZ-235 targeting PAR2 as promising lead compounds. However, deviation from the general pepducin structure has not been explored and represent possible areas of improvement. Herein, 10 novel PZ-128 analogues are described as potential improvements to PZ-128 highlighting the impact of linker modification as well as cyclisation of the peptide sequence. Additionally, off-target activity of PZ-128 is also explored, highlighting some intrinsic problems with the pepducin approach. These problems were alleviated to an extent with the novel PZ-128 analogues but identifying overall improvements to the pharmacological character of the series proved challenging. Recently, two potential lead molecules were published targeting PAR2 with AZ8838 and AZ3451. These compounds have provided new insight into how we can target PAR2, allowing access to novel chemicals with improved properties. Through a series of modifications to the published chemical structures, we have accessed novel compounds that display similar biological properties to AZ8838. Herein, 15 novel analogues of AZ8838 have been synthesised and their propensity for PAR2 inhibition tested in in vitro assays, identifying one compound of comparable potency whilst exploring the SAR surrounding the AZ8838 binding pocket. Additionally, an expanded library of AZ8838 analogues has been computationally docked to assess binding within PAR2 in silico

Prediction and Verification of the Structural Chemistry of New One-Dimensional Barium/Copper/Iridium Oxides

We propose a classification scheme for the commensurate phases in the family of pseudo one-dimensional structures formed from the mixed hcp stacking of A3O9 and oxygen-deficient A3A'O6 layers. We envisage these compounds as composites of two substructures having common a and b unit cell parameters but different parameters c1 and c2. Use of the ratio c1/c2 facilitates the prediction of new commensurate structures while allowing for the commonly incommensurate nature of materials in this family. The structures of the new commensurate phases Ba5CuIr3O12, Ba14Cu3Ir8O33, Ba16Cu3Ir10O39, and Ba9Cu2Ir5O21 are predicted and subsequently verified by powder X-ray diffraction and HRTEM. Ba5CuIr3O12 has a 10 layer structure with space group P321, a = 10.143 82(8) Å, c = 21.6553(2) Å; Ba14Cu3Ir8O33 has a 14 layer structure with space group P321, a = 10.145 85(8) Å, c = 29.9574(3) Å; Ba16Cu3Ir10O39 has a 16 layer structure with space group P321, a = 10.136 43(7) Å; c = 35.0616(3) Å; Ba9Cu2Ir5O21 has an 18 layer structure with space group R32, a = 10.144 64(11) Å, c = 38.2455(6) Å. Sequences of trigonal prismatic sites and octahedral sites run in chains parallel to z, with Ba cations located between the chains; the distribution of iridium and copper cations in the octahedral and trigonal prismatic sites is disordered in each case. Electron diffraction patterns and lattice images show evidence for modulation in the structures of Ba5CuIr3O12, Ba14Cu3Ir8O33, and Ba16Cu3Ir10O39 but not in that of Ba9Cu2Ir5O21. The magnetic susceptibilities of all four phases obey a modified Curie-Weiss law above 150 K, with no long-range magnetic order observed between 5 and 300 K. They are all electrical insulators.