Preclinical characterization and target validation of the antimalarial pantothenamide MMV693183

Drug resistance and a dire lack of transmission-blocking antimalarials hamper malaria elimination. Here, we present the pantothenamide MMV693183 as a first-in-class acetyl-CoA synthetase (AcAS) inhibitor to enter preclinical development. Our studies demonstrate attractive drug-like properties and in vivo efficacy in a humanized mouse model of Plasmodium falciparum infection. The compound shows single digit nanomolar in vitro activity against P. falciparum and P. vivax clinical isolates, and potently blocks P. falciparum transmission to Anopheles mosquitoes. Genetic and biochemical studies identify AcAS as the target of the MMV693183-derived antimetabolite, CoA-MMV693183. Pharmacokinetic-pharmacodynamic modelling predict that a single 30 mg oral dose is sufficient to cure a malaria infection in humans. Toxicology studies in rats indicate a > 30-fold safety margin in relation to the predicted human efficacious exposure. In conclusion, MMV693183 represents a promising candidate for further (pre)clinical development with a novel mode of action for treatment of malaria and blocking transmission

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

Background: Many patients with COVID-19 have been treated with plasma containing anti-SARS-CoV-2 antibodies. We aimed to evaluate the safety and efficacy of convalescent plasma therapy in patients admitted to hospital with COVID-19. Methods: This randomised, controlled, open-label, platform trial (Randomised Evaluation of COVID-19 Therapy [RECOVERY]) is assessing several possible treatments in patients hospitalised with COVID-19 in the UK. The trial is underway at 177 NHS hospitals from across the UK. Eligible and consenting patients were randomly assigned (1:1) to receive either usual care alone (usual care group) or usual care plus high-titre convalescent plasma (convalescent plasma group). The primary outcome was 28-day mortality, analysed on an intention-to-treat basis. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936. Findings: Between May 28, 2020, and Jan 15, 2021, 11558 (71%) of 16287 patients enrolled in RECOVERY were eligible to receive convalescent plasma and were assigned to either the convalescent plasma group or the usual care group. There was no significant difference in 28-day mortality between the two groups: 1399 (24%) of 5795 patients in the convalescent plasma group and 1408 (24%) of 5763 patients in the usual care group died within 28 days (rate ratio 1·00, 95% CI 0·93–1·07; p=0·95). The 28-day mortality rate ratio was similar in all prespecified subgroups of patients, including in those patients without detectable SARS-CoV-2 antibodies at randomisation. Allocation to convalescent plasma had no significant effect on the proportion of patients discharged from hospital within 28 days (3832 [66%] patients in the convalescent plasma group vs 3822 [66%] patients in the usual care group; rate ratio 0·99, 95% CI 0·94–1·03; p=0·57). Among those not on invasive mechanical ventilation at randomisation, there was no significant difference in the proportion of patients meeting the composite endpoint of progression to invasive mechanical ventilation or death (1568 [29%] of 5493 patients in the convalescent plasma group vs 1568 [29%] of 5448 patients in the usual care group; rate ratio 0·99, 95% CI 0·93–1·05; p=0·79). Interpretation: In patients hospitalised with COVID-19, high-titre convalescent plasma did not improve survival or other prespecified clinical outcomes. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research

Sinteza i biološko vrednovanje 4-(1H-indol-3-il)-6-fenil 1,2,3,4-tetrahidropirimidin-2-ona/tiona kao jakih protuuplanih tvari

Twelve new 4-(1H-indol-3-yl)-6-phenyl-1,2,3,4-tetrahydropyrimidin-2-ones/thiones (7-18) have been synthesized by reacting 1-aryl-3-(1H-indol-3-yl)-2-propen-1-one with urea and thiourea in ethanolic potassium hydroxide. Their structures have been confirmed by IR, 1H NMR and mass spectral data. The compounds were tested for their anti-inflammatory activity. Test results revealed that compounds showed 49.5 to 70.7% anti-inflammatory activity whereas the standard drug ibuprofen showed 86.4% activity at the same oral dose. Four compounds, 4-(1H-indol-3-yl)-6-(4-chlorophenyl-1,2,3,4-tetrahydropyrimidin-2-one (8), 4-(1H-indol-3-yl)-6-(4-methylphenyl-1,2,3,4-tetrahydropyrimidin-2-one (10), 4-(1H-indol-3-yl)-6-(4-chlorophenyl-1,2,3,4-tetrahydropyrimidin-2-thione (14), 4-(1H-indol-3-yl)-6-(4-methylphenyl-1,2,3,4-tetrahydropyrimidin-2-thione (16), that showed significant anti-inflammatory activity were selected to study their ulcerogenic and lipid peroxidation activities. All tested compounds showed significant reduction in the ulcerogenic potential and lipid peroxidation compared to the standard drug ibuprofen.Dvanaest novih 4-(1H-indol-3-il)-6-fenil-1,2,3,4-tetrahidropirimidin-2-ona/tiona (7-18) sintetizirano je reakcijom 1-aril-3-(1H-indol-3-il)-2-propen-1-ona s ureom i tioureom u etanolnoj otopini kalijeva hidroksida. Njihove strukture potvrđene su IR, 1H NMR i masenom spektrometrijom. Farmakološko vrednovanje pokazalo je da ti spojevi imaju od 49,5 do 70,7% protuupalnog djelovanja, dok je standardni lijek ibuprofen pokazao 86,4% djelovanja uz istu peroralno uzetu dozu. Spojevi koji pokazuju značajno protuupalno djelovanje (8, 10, 14, 16) ispitani su na ulcerogenost i djelovanje na lipidnu peroksidaciju. Svi testirani spojevi su značajno manje ulcerogeni i manje djeluju na lipidnu peroksidaciju od ibuprofena

Egr3 stimulation of GABRA4 promoter activity as a mechanism for seizure-induced up-regulation of GABA(A) receptor α4 subunit expression

GABA is the major inhibitory transmitter at CNS synapses. Changes in subunit composition of the pentameric GABA(A) receptor, including increased levels of α4 subunit in dentate granule cells and associated functional alterations such as increased zinc blockade of GABA currents, are hypothesized to be critical components of epileptogenesis. Here, we report that the minimal promoter of the human α4 subunit gene (GABRA4p), when used to drive reporter gene expression from adeno-associated viral vectors, controls condition-specific up-regulation in response to status epilepticus, defining a transcriptional mechanism for seizure-induced changes in levels of α4 subunit containing GABA(A) receptors. Transfection studies in primary hippocampal neurons show that inducible early growth response factor 3 (Egr3) up-regulates GABRA4p activity as well as the levels of endogenous α4 subunits. Given that Egr3 knockout mice display ≈50% less GABRA4 mRNAs in the hippocampus and that increases in α4 and Egr3 mRNAs in response to pilocarpine-induced status epilepticus are accompanied by increased binding of Egr3 to GABRA4 in dentate granule cells, our findings support a role for Egr3 as a major regulator of GABRA4 in developing neurons and in epilepsy