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

Background: In this study, we aimed to evaluate the effects of tocilizumab in adult patients admitted to hospital with COVID-19 with both hypoxia and systemic inflammation. 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. Those trial participants with hypoxia (oxygen saturation <92% on air or requiring oxygen therapy) and evidence of systemic inflammation (C-reactive protein ≥75 mg/L) were eligible for random assignment in a 1:1 ratio to usual standard of care alone versus usual standard of care plus tocilizumab at a dose of 400 mg–800 mg (depending on weight) given intravenously. A second dose could be given 12–24 h later if the patient's condition had not improved. The primary outcome was 28-day mortality, assessed in the intention-to-treat population. The trial is registered with ISRCTN (50189673) and ClinicalTrials.gov (NCT04381936). Findings: Between April 23, 2020, and Jan 24, 2021, 4116 adults of 21 550 patients enrolled into the RECOVERY trial were included in the assessment of tocilizumab, including 3385 (82%) patients receiving systemic corticosteroids. Overall, 621 (31%) of the 2022 patients allocated tocilizumab and 729 (35%) of the 2094 patients allocated to usual care died within 28 days (rate ratio 0·85; 95% CI 0·76–0·94; p=0·0028). Consistent results were seen in all prespecified subgroups of patients, including those receiving systemic corticosteroids. Patients allocated to tocilizumab were more likely to be discharged from hospital within 28 days (57% vs 50%; rate ratio 1·22; 1·12–1·33; p<0·0001). Among those not receiving invasive mechanical ventilation at baseline, patients allocated tocilizumab were less likely to reach the composite endpoint of invasive mechanical ventilation or death (35% vs 42%; risk ratio 0·84; 95% CI 0·77–0·92; p<0·0001). Interpretation: In hospitalised COVID-19 patients with hypoxia and systemic inflammation, tocilizumab improved survival and other clinical outcomes. These benefits were seen regardless of the amount of respiratory support and were additional to the benefits of systemic corticosteroids. Funding: UK Research and Innovation (Medical Research Council) and National Institute of Health Research

CD4 and CD8 may adopt a similar mode of binding to their MHC ligands

A theoretical scheme is proposed by which the type-specific cell surface receptors of T-lymphocytes, CD8 and CD4, bind class I and II MHC proteins in a similar manner. The scheme has equivalent residues in the C'/C" loop-C" strand-C"/D loop region in domain 1 of CD4 and CD8α binding to equivalent residues in the C and D β-strands and C/D loops in HLA-DRβ2 (class II) and HLA-A2α3 (class I) respectively through a series of electrostatic, hydrogen and hydrophobic bonds

Sex differences and the comparative turnover rates of lactate dehydrogenase isozymes in mouse tissues

1. 1. As an extension of previous studies, the turnover parameters of total soluble protein and lactate dehydrogenase and its isozymes have been determined in the major tissues of male and female mice. 2. 2. Although there were no discernable differences in the specific activities of lactate dehydrogenase between corresponding male and female tissues, significant differences were apparent in relation to half-life values, and the rate constants for synthesis and degradation of this enzyme in tissues such as liver, kidney and brain. 3. 3. There were also significant differences between male and female reproductive tissues, with the rate of degradation of lactate dehydrogenase in uterus being high by comparison with most other major tissues, whereas testis displayed a comparatively low rate of degradation. 4. 4. Marked divergences were also established in regard to the turnover characteristics of the separate LDH isozymes within the individual tissues of these animals, between corresponding tissues in male and female animals, and between different tissues of the same animal. 5. 5. These data have been compared with the comparable information on isozyme turnover which is available for the rat, and discussed in relation to these species comparisons, sex differences and the physiological correlations in the individual tissues

Non-peptidic anti-aids agents: Inhibition of HIV-1 proteinase by disulfonates

Based upon an earlier observation that sodium docosanedioate (NaO2C-(CH2)20-CO2Na) weakly inhibits HIV-1 proteinase (IC50 12μM), we have identified a class of more potent inhibitors (sulfonic acids) of this enzyme which are likewise dianionic at pH 5-6.5. Many of the compounds were moderately strong inhibitors of the enzyme (IC50 40nM-10μM) and some have previously been shown to have anti-HIV activity in lymphocytes. Proteinase inhibition was dependent on the separation between sulfonate/carboxylate substituents, consistent with the hypothesis that negative charged ends of an inhibitor might form ionic bonds with Arg 8 and Arg 108 located at either end of the substrate-binding groove of the enzyme. The binding mode remains to be established by structure elucidation. Results for enzyme inhibition are presented along with structure-activity relationships and evidence for pH dependent inhibition. The general observations reported here may be useful for developing more potent and selective non-peptidic proteinase inhibitors

Hydroxyquinones are competitive non-peptide inhibitors of HIV-1 proteinase

Quinones with one, two and three aromatic rings are a new class of micomolar non-peptidic inhibitors of HIV-1 proteinase, an enzyme essential for replication of Human Immunodeficiency Virus and an important drug target for AIDS. Substituted anthraquinones bearing hydroxyl substituents on one of their three rings were the most potent of these inhibitors. Comparisons with other small non-peptidic inhibitors that are now emerging, together with enzyme kinetic data indicating that alizarin is a competitive inhibitor, suggest that anthraquinones bind in the active-site groove of HIV-1 proteinase

Inhibition of HIV-1 proteinase by metal ions

1. 1. Certain metal ions have been identified as inhibitors (IC50 1-20 μM) of the aspartic proteinase of Human Immunodeficiency Virus Type 1 (HIV-PR). 2. 2. By contrast most simple metal ions do not inhibit this enzyme. 3. 3. Those that did inhibit have in common a high charge/size ratio or "hard" acidic nature, preferring to combine covalently with oxygen donor ligands. 4. 4. Some evidence from independent X-ray crystal structure determinations suggests that the metalloinhibitors identified here may bind in the active site of the enzyme via coordination to the carboxylate side chains of the essential active site residues Asp 25 and 125. 5. 5. Although the measured inhibition is only μM, very few enzyme-inhibitor interactions can be taking place and so more complex metalloinhibitors with ligands that can also bind to peptide side chains of the enzyme might be significantly more potent inhibitors of HIV-PR and of viral replication

Solid phase synthesis of hydroxyethylamine peptide bond isosteres: Synthesis of the potent HIV-1 protease inhibitor JG365

A protocl has been developed for the generation of hydroxyethylamine peptide bond isosteres in a polymer-supported synthesis. This has been used to produce the potent HIV-1 Protease inhibitor JG365 rapidly and in good yield

Non-peptide inhibitors of HIV-1 protease. Synthesis and structural evaluation of symmetric and non-symmetric naphthalenesulfonic acid analogues

In this study, several representative symmetric and non-symmetric naphthalenesulfonic acid derivatives belonging to various structural classes were evaluated for their potential to inhibit HIV-1 protease. The most active compounds were non-symmetrical and possessed hydrophobic pendant groups. In general, the activity of these derivatives was dependent on the number and position of the sulfonic acid moiety and the nature of the appendages. Remarkably, one of the most active compounds also displayed inhibition of DNA polymerase and RNase H activities of HIV-1 reverse transcriptase. This observation provides an insight into designing singular compounds which could inhibit multiple essential enzymes in the HIV-1 life cycle. Since it is unlikely that these agents will reach targeted cellular enzymes due to their polar nature, the discovery of in vitro protease inhibition rationalizes further modification of sulfonic acid derivatives