Exome-wide association study to identify rare variants influencing COVID-19 outcomes : Results from the Host Genetics Initiative

Publisher Copyright: Copyright: © 2022 Butler-Laporte et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Host genetics is a key determinant of COVID-19 outcomes. Previously, the COVID-19 Host Genetics Initiative genome-wide association study used common variants to identify multiple loci associated with COVID-19 outcomes. However, variants with the largest impact on COVID-19 outcomes are expected to be rare in the population. Hence, studying rare variants may provide additional insights into disease susceptibility and pathogenesis, thereby informing therapeutics development. Here, we combined whole-exome and whole-genome sequencing from 21 cohorts across 12 countries and performed rare variant exome-wide burden analyses for COVID-19 outcomes. In an analysis of 5,085 severe disease cases and 571,737 controls, we observed that carrying a rare deleterious variant in the SARS-CoV-2 sensor toll-like receptor TLR7 (on chromosome X) was associated with a 5.3-fold increase in severe disease (95% CI: 2.75–10.05, p = 5.41x10-7). This association was consistent across sexes. These results further support TLR7 as a genetic determinant of severe disease and suggest that larger studies on rare variants influencing COVID-19 outcomes could provide additional insights.Peer reviewe

Development of a novel blood-brain-barrier permeable IRE1 inhibitors for adjuvant therapy in glioblastoma.

Le glioblastome multiple est l’un des cancers primaires les plus agressifs et le traitement actuel, basé sur le protocole de Stupp, montre ses limites avec une survie médiane proche de 15 mois et une rechute quasi-systématique. Récemment, des études ont montrées la possibilité de resensibiliser les cellules cancéreuses à la chimiothérapie par l’utilisation de petites molécules actives sur IRE1, une protéine transmembranaire du réticulum endoplasmique. Cette protéine est activée en conditions de stress protéique, intrinsèques des cellules cancéreuses, et permet à la cellule de s’adapter aux différentes modifications physiologiques qu’elle peut subir, traitements pharmacologiques compris. Depuis quelques années, les recherches effectuées au sein de l’équipe PROSAC ont permis la découverte d’une molécule nommée Z4P. Cette dernière, capable de passer la barrière hémato-encéphalique, inhibe IRE1 et ses activités associées afin de resensibiliser les cellules de glioblastome à la chimiothérapie. Lorsque Z4P est utilisé en combinaison avec un agent de chimiothérapie, le Témozolomide, on observe sur des modèles murins xénogreffés de GB humain une diminution significative de la taille des tumeurs, sans rechute. Ce manuscrit relate le travail de thèse effectué pour l’étude des Relations Structure-Activité de Z4P afin de mieux comprendre son mode de liaison et d’en améliorer les propriétés physico-chimiques.Glioblastoma multiform is one of the most aggressive primary brain cancers and the current treatment, based on Stupp protocol, marginally improves survival (15 months) with near-systematic relapse. Recently, studies have shown the possibility to resensitize cancer cells to chemotherapy using small molecules active on IRE1, a transmembrane protein of the endoplasmic reticulum. This protein is activated under proteic stress, intrinsic conditions of cancer cells, and allows the cell to adapt to the various physiological modifications it may undergo, including pharmacological treatments. Recently, research conducted by the PROSAC team has led to the discovery of a small molecule named Z4P. This blood-brain-barrier permeable compound can inhibits IRE1 and its associated activities in order to resensitize glioblastoma cells to chemotherapy. When Z4P is used in combinaison with Temozolomide, a chemotherapy agent, we observe in murine models xenografted with human GB a significant decrease in tumor size, without relapse. This manuscript relates the work carried out on the Structure-Activity Relationships study of Z4P in order to better understand its binding mode and to improve its drug-likeness

Structural and molecular bases to IRE1 activity modulation

International audienceThe Unfolded Protein response is an adaptive pathway triggered upon alteration of endoplasmic reticulum (ER) homeostasis. It is transduced by three major ER stress sensors, among which the Inositol Requiring Enzyme 1 (IRE1) is the most evolutionarily conserved. IRE1 is an ER-resident type I transmembrane protein exhibiting an ER luminal domain that senses the protein folding status and a catalytic kinase and RNase cytosolic domain. In recent years, IRE1 has emerged as a relevant therapeutic target in various diseases including degenerative, inflammatory and metabolic pathologies and cancer. As such several drugs altering IRE1 activity were developed that target either catalytic activity and showed some efficacy in preclinical pathological mouse models. In this review, we describe the different drugs identified to target IRE1 activity as well as their mode of action from a structural perspective, thereby identifying common and different modes of action. Based on this information we discuss on how new IRE1-targeting drugs could be developed that outperform the currently available molecules

A novel IRE1 kinase inhibitor for adjuvant glioblastoma treatment

Summary: Inositol-requiring enzyme 1 (IRE1) is a major mediator of the unfolded protein response (UPR), which is activated upon endoplasmic reticulum (ER) stress. Tumor cells experience ER stress due to adverse microenvironmental cues, a stress overcome by relying on IRE1 signaling as an adaptive mechanism. Herein, we report the discovery of structurally new IRE1 inhibitors identified through the structural exploration of its kinase domain. Characterization in in vitro and in cellular models showed that they inhibit IRE1 signaling and sensitize glioblastoma (GB) cells to the standard chemotherapeutic, temozolomide (TMZ). Finally, we demonstrate that one of these inhibitors, Z4P, permeates the blood–brain barrier (BBB), inhibits GB growth, and prevents relapse in vivo when administered together with TMZ. The hit compound disclosed herein satisfies an unmet need for targeted, non-toxic IRE1 inhibitors and our results support the attractiveness of IRE1 as an adjuvant therapeutic target in GB

From Quinoxaline, Pyrido[2,3-<i>b</i>]pyrazine and Pyrido[3,4-<i>b</i>]pyrazine to Pyrazino-Fused Carbazoles and Carbolines

2,3-Diphenylated quinoxaline, pyrido[2,3-b]pyrazine and 8-bromopyrido[3,4-b]pyrazine were halogenated in deprotometalation-trapping reactions using mixed 2,2,6,6-tetramethyl piperidino-based lithium-zinc combinations in tetrahydrofuran. The 2,3-diphenylated 5-iodo- quinoxaline, 8-iodopyrido[2,3-b]pyrazine and 8-bromo-7-iodopyrido[3,4-b]pyrazine thus obtained were subjected to palladium-catalyzed couplings with arylboronic acids or anilines, and possible subsequent cyclizations to afford the corresponding pyrazino[2,3-a]carbazole, pyrazino[2&#8242;,3&#8242;:5,6] pyrido[4,3-b]indole and pyrazino[2&#8242;,3&#8242;:4,5]pyrido[2,3-d]indole, respectively. 8-Iodopyrido[2,3-b] pyrazine was subjected either to a copper-catalyzed C-N bond formation with azoles, or to direct substitution to introduce alkylamino, benzylamino, hydrazine and aryloxy groups at the 8 position. The 8-hydrazino product was converted into aryl hydrazones. Most of the compounds were evaluated for their biological properties (antiproliferative activity in A2058 melanoma cells and disease-relevant kinase inhibition)

Exome-wide association study to identify rare variants influencing COVID-19 outcomes: Results from the Host Genetics Initiative.

Host genetics is a key determinant of COVID-19 outcomes. Previously, the COVID-19 Host Genetics Initiative genome-wide association study used common variants to identify multiple loci associated with COVID-19 outcomes. However, variants with the largest impact on COVID-19 outcomes are expected to be rare in the population. Hence, studying rare variants may provide additional insights into disease susceptibility and pathogenesis, thereby informing therapeutics development. Here, we combined whole-exome and whole-genome sequencing from 21 cohorts across 12 countries and performed rare variant exome-wide burden analyses for COVID-19 outcomes. In an analysis of 5,085 severe disease cases and 571,737 controls, we observed that carrying a rare deleterious variant in the SARS-CoV-2 sensor toll-like receptor TLR7 (on chromosome X) was associated with a 5.3-fold increase in severe disease (95% CI: 2.75-10.05, p = 5.41x10-7). This association was consistent across sexes. These results further support TLR7 as a genetic determinant of severe disease and suggest that larger studies on rare variants influencing COVID-19 outcomes could provide additional insights