Thiolutin is a zinc chelator that inhibits the Rpn11 and other JAMM metalloproteases

Thiolutin is a disulfide-containing antibiotic and anti-angiogenic compound produced by Streptomyces. Its biological targets are not known. We show that reduced thiolutin is a zinc chelator that inhibits the JAB1/MPN/Mov34 (JAMM) domain–containing metalloprotease Rpn11, a deubiquitinating enzyme of the 19S proteasome. Thiolutin also inhibits the JAMM metalloproteases Csn5, the deneddylase of the COP9 signalosome; AMSH, which regulates ubiquitin-dependent sorting of cell-surface receptors; and BRCC36, a K63-specific deubiquitinase of the BRCC36-containing isopeptidase complex and the BRCA1–BRCA2-containing complex. We provide evidence that other dithiolopyrrolones also function as inhibitors of JAMM metalloproteases

PCSK9 Inhibition During the Inflammatory Stage of SARS-CoV-2 Infection

© 2023 by the American College of Cardiology Foundation. Published by Elsevier. This is the accepted manuscript version of an article which has been published in final form athttps://doi.org/10.1016/j.jacc.2022.10.030Background The intensity of inflammation during COVID-19 is related to adverse outcomes. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is involved in low-density lipoprotein receptor homeostasis, with potential influence on vascular inflammation and on COVID-19 inflammatory response. Objectives The goal of this study was to investigate the impact of PCSK9 inhibition vs placebo on clinical and laboratory outcomes in patients with severe COVID-19. Methods In this double-blind, placebo-controlled, multicenter pilot trial, 60 patients hospitalized for severe COVID-19, with ground-glass opacity pneumonia and arterial partial oxygen pressure to fraction of inspired oxygen ratio ≤300 mm Hg, were randomized 1:1 to receive a single 140-mg subcutaneous injection of evolocumab or placebo. The primary endpoint was death or need for intubation at 30 days. The main secondary endpoint was change in circulating interleukin (IL)-6 at 7 and 30 days from baseline. Results Patients randomized to receive the PCSK9 inhibitor had lower rates of death or need for intubation within 30 days vs placebo (23.3% vs 53.3%, risk difference: –30%; 95% CI: –53.40% to –6.59%). Serum IL-6 across time was lower with the PCSK9 inhibitor than with placebo (30-day decline: –56% vs –21%). Patients with baseline IL-6 above the median had lower mortality with PCSK9 inhibition vs placebo (risk difference: –37.50%; 95% CI: –68.20% to –6.70%). Conclusions PCSK9 inhibition compared with placebo reduced the primary endpoint of death or need for intubation and IL-6 levels in severe COVID-19. Patients with more intense inflammation at randomization had better survival with PCSK9 inhibition vs placebo, indicating that inflammatory intensity may drive therapeutic benefits. (Impact of PCSK9 Inhibition on Clinical Outcome in Patients During the Inflammatory Stage of the COVID-19 [IMPACT-SIRIO 5]; NCT04941105)Peer reviewe

Surface-Confined Monomers on Electrode Surfaces. 4. Electrochemical and Spectroscopic Characterization of Undec-10-ene-1-thiol Self-Assembled Monolayers on Au

The synthesis, structure, and reactivity of undec-10-ene-1-thiol monolayers assembled on planar and nanocrystalline (curved) Au is presented. Cyclic voltammetry and infrared spectroscopy are used to probe the structural changes in the monolayers (on planar Au) upon irradiation with γ-rays. Oligomerization of the monolayers during the γ-ray exposures is indicated by the observed decrease in the intensities of infrared bands associated with the olefin functionality. From infrared spectra obtained during γ-ray exposures of the undec-10-ene-1-thiol monolayers on planar Au, it is proposed that the oligomerization reaction is controlled by the distance the tethered olefin groups can move. That is to say the reaction is stress limited. Dropcast films of undec-10-ene-1-thiol/Au nanoclusters (1.3 and 3.4 nm diameter Au crystals) do not exhibit decreases in the olefin infrared bands after large γ-ray exposures. This decrease in reactivity for the olefin monolayers supported on the Au nanocrystals is suggested to be the result of interdigitation of the alkane chains from neighboring alkanethiolate Au clusters that exist in the dropcast films