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186 lines
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<title>25 April, 2023</title>
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<title>Covid-19 Sentry</title><meta content="width=device-width, initial-scale=1.0" name="viewport"/><link href="styles/simple.css" rel="stylesheet"/><link href="../styles/simple.css" rel="stylesheet"/><link href="https://unpkg.com/aos@2.3.1/dist/aos.css" rel="stylesheet"/><script src="https://unpkg.com/aos@2.3.1/dist/aos.js"></script></head>
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<h1 data-aos="fade-down" id="covid-19-sentry">Covid-19 Sentry</h1>
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<h1 data-aos="fade-right" data-aos-anchor-placement="top-bottom" id="contents">Contents</h1>
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<ul>
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<li><a href="#from-preprints">From Preprints</a></li>
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<li><a href="#from-clinical-trials">From Clinical Trials</a></li>
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<li><a href="#from-pubmed">From PubMed</a></li>
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<li><a href="#from-patent-search">From Patent Search</a></li>
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</ul>
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<h1 data-aos="fade-right" id="from-preprints">From Preprints</h1>
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<li><strong>Transcriptome Analysis Reveals Organ-Specific Effects of 2-Deoxyglucose Treatment in Healthy Mice</strong> -
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<div>
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Objective: Glycolytic inhibition via 2-deoxy-D-glucose (2DG) has potential therapeutic benefits for a range of diseases, including cancer, epilepsy, systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA), and COVID-19, but the systemic effects of 2DG on gene function across different tissues are unclear. Methods: This study analyzed the transcriptional profiles of nine tissues from C57BL/6J mice treated with 2DG to understand how it modulates pathways systemically. Principal component analysis (PCA), weighted gene co-network analysis (WGCNA), analysis of variance, and pathway analysis were all performed to identify modules altered by 2DG treatment. Results: PCA revealed that samples clustered predominantly by tissue, suggesting that 2DG affects each tissue uniquely. Unsupervised clustering and WGCNA revealed six distinct tissue-specific modules significantly affected by 2DG, each with unique key pathways and genes. 2DG predominantly affected mitochondrial metabolism in the heart, while in the small intestine, it affected immunological pathways. Conclusions: These findings suggest that 2DG has a systemic impact that varies across organs, potentially affecting multiple pathways and functions. The study provides insights into the potential therapeutic benefits of 2DG across different diseases and highlights the importance of understanding its systemic effects for future research and clinical applications.
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</div>
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<div class="article-link article-html-link">
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🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2023.04.24.537717v1" target="_blank">Transcriptome Analysis Reveals Organ-Specific Effects of 2-Deoxyglucose Treatment in Healthy Mice</a>
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</div></li>
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<li><strong>Health Literacy Game vs. Textbook: Gameplay Boosts Motivation and Emotional Engagement</strong> -
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<div>
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The promise of game-based learning relies on the assumption that games provide more engaging learning experiences compared to their traditional counterparts. To test this assumption, we compared the impact of a mobile health literacy game with textbook material in terms of situational interest, epistemic emotions, and satisfaction. Two hundred fifty-four Finnish students (M = 15.70 years, SD = 0.76) were randomly assigned to the game (n = 136) and textbook condition (n = 118). The game condition played Antidote COVID-19 mobile game, and the textbook condition read health-related content on Covid-19. Learning content was the same in both conditions. Situational interest was measured with a pre-and post-test whereas epistemic emotions and perceived satisfaction were only measured with a post-test. Our findings showed that situational interest increased significantly from pre- to post-test in the game condition. However, no significant change was observed in the textbook condition. Participants in the game condition also reported higher intensity of desired epistemic emotions like surprise, enjoyment, and confusion and a significantly lower intensity of undesired boredom than the textbook condition. Lastly, the game condition displayed significantly higher satisfaction with learning material than the textbook condition. Overall, these findings imply that students found the game more interesting and engaging than reading traditional textbook material. Further, the current findings indicate that utilizing game-based learning in health education might provide engaging ways to raise awareness of health issues by facilitating interest and relevant epistemic emotions that may elucidate, maintain and change personal beliefs on health topics.
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</div>
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<div class="article-link article-html-link">
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🖺 Full Text HTML: <a href="https://osf.io/gef6h/" target="_blank">Health Literacy Game vs. Textbook: Gameplay Boosts Motivation and Emotional Engagement</a>
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</div></li>
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<li><strong>Researching COVID to enhance recovery (RECOVER) pregnancy study protocol: Rationale, objectives, and design</strong> -
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<div>
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<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
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Importance: Pregnancy induces unique physiologic changes to the immune response and hormonal changes leading to plausible differences in the risk of developing post-acute sequelae of SARS-CoV-2 (PASC), or Long COVID. Exposure to SARS-CoV-2 during pregnancy may also have long-term ramifications for exposed offspring, and it is critical to evaluate the health outcomes of exposed children. The National Institutes of Health (NIH) Researching COVID to Enhance Recovery (RECOVER) Multi-site Observational Study of PASC aims to evaluate the long-term sequelae of SARS-CoV-2 infection in various populations. RECOVER-Pregnancy was designed specifically to address long-term outcomes in maternal-child dyads. Methods: RECOVER-Pregnancy cohort is a combined prospective and retrospective cohort that proposes to enroll 2,300 individuals with a pregnancy during the COVID-19 pandemic and their offspring exposed and unexposed in utero, including single and multiple gestations. Enrollment will occur both in person at 27 sites through the Eunice Kennedy Shriver National Institutes of Health Maternal-Fetal Medicine Units Network and remotely through national recruitment by the study team at the University of California San Francisco (UCSF). Adults with and without SARS-CoV-2 infection during pregnancy are eligible for enrollment in the pregnancy cohort and will follow the protocol for RECOVER-Adult including validated screening tools, laboratory analyses and symptom questionnaires followed by more in-depth phenotyping of PASC on a subset of the overall cohort. Offspring exposed and unexposed in utero to SARS-CoV-2 maternal infection will undergo screening tests for neurodevelopment and other health outcomes at 12, 18, 24, 36 and 48 months of age. Blood specimens will be collected at 24 months of age for SARS-CoV-2 antibody testing, storage and anticipated later analyses proposed by RECOVER and other investigators. Discussion: RECOVER-Pregnancy will address whether having SARS-CoV-2 during pregnancy modifies the risk factors, prevalence, and phenotype of PASC. The pregnancy cohort will also establish whether there are increased risks of adverse long-term outcomes among children exposed in utero.
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</p>
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</div>
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<div class="article-link article-html-link">
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🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2023.04.24.23289025v1" target="_blank">Researching COVID to enhance recovery (RECOVER) pregnancy study protocol: Rationale, objectives, and design</a>
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</div></li>
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<li><strong>Racial disparities, environmental exposures, and SARS-CoV-2 infection rates: A racial map study in the USA</strong> -
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<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
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Since the onset of the COVID-19 pandemic, researchers mainly examined how socio-economic, demographic, and environmental factors are related to disparities in SARS-CoV-2 infection rates. However, we don9 know the extent to which racial disparities in environmental exposure are related to racial disparities in SARS-CoV-2 infection rates. To address this critical issue, we gathered black vs. white infection records from 1416 counties in the contiguous United States. For these counties, we used 30m-spatial resolution land cover data and racial mappings to quantify the racial disparity between black and white people9s two types of environmental exposure, including exposures to various types of landscape settings and urban development intensities. We found that racial disparities in SARS-CoV-2 infection rates and racial disparities in exposure to various types of landscapes and urban development intensities were significant and showed similar patterns. Specifically, less racial disparity in exposure to forests outside park, pasture/hay, and urban areas with low and medium development intensities were significantly associated with lower racial disparities in SARS-CoV-2 infection rates. Distance was also critical. The positive association between racial disparities in environmental exposures and racial disparity in SARS-CoV-2 infection rates was strongest within a comfortable walking distance (approximately 400m).
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</p>
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</div>
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<div class="article-link article-html-link">
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🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2023.04.17.23288622v1" target="_blank">Racial disparities, environmental exposures, and SARS-CoV-2 infection rates: A racial map study in the USA</a>
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</div></li>
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<li><strong>LONG-TERM PHYSICAL AND MENTAL HEALTH IMPACT OF COVID-19 ON ADULTS IN ENGLAND: FOLLOW UP OF A LARGE RANDOM COMMUNITY SAMPLE</strong> -
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<div>
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<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
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Background: The COVID-19 pandemic is having a lasting impact on health and well-being. We compare current self-reported health, quality of life and symptom profiles for people with ongoing symptoms following COVID-19 to those who have never had COVID-19 or have recovered. Methods: A cohort study was established with participants from the REACT programme. A sample (N=800,000) of adults were contacted between August and December 2022 to complete a questionnaire about their current health and COVID-19 history. We used logistic regression to identify predictors of persistent symptoms lasting ≥12 weeks following COVID-19. We fitted Accelerated Failure Time models to assess factors associated with rate of recovery from persistent symptoms. Findings: Overall, 276,840/800,000 (34.6%) of invited participants completed the questionnaire. Median duration of COVID-related symptoms (N=130,251) was 1.3 weeks (inter-quartile range 6 days to 2 weeks), with 7.5% and 5.2% reporting ongoing symptoms ≥12 weeks and ≥52 weeks respectively. Female sex, having ≥1 comorbidity, more severe symptoms at time of COVID-19 and being infected when Wild-type variant was dominant were associated with higher probability of symptoms lasting ≥12 weeks. Longer time to recovery in those with persistent symptoms was found for females, people with comorbidities, living in more deprived areas, current smokers and for Wild-type compared to later variants. Mental health and health-related quality of life were significantly worse among participants with ongoing persistent COVID-19 symptoms compared with those who had never had COVID-19 or had recovered. Interpretation: Although COVID-19 is usually of short duration, some adults experience persistent and burdensome illness.
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</p>
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</div>
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<div class="article-link article-html-link">
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🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2023.04.24.23289043v1" target="_blank">LONG-TERM PHYSICAL AND MENTAL HEALTH IMPACT OF COVID-19 ON ADULTS IN ENGLAND: FOLLOW UP OF A LARGE RANDOM COMMUNITY SAMPLE</a>
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</div></li>
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<li><strong>Deprivation effect on COVID-19 cases incidence and severity: a geo-epidemiological study in PACA region, France</strong> -
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<div>
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<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
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Introduction. The spread of the COVID-19 pandemic, and its severity, is spatially heterogenous. At the individual level, the socioeconomic status (SES) profile is known to be associated with COVID-19 incidence and severity. The aim of this geo epidemiological study was to investigate the link between SES profile and potential confounders, and COVID-19 incidence and hospitalization rates, at a fine geographical scale. Methods. We analyzed COVID-19 incidence and severity during two epidemic waves between September 2020 and June 2021, in Provence Alpes Cotes d Azur, a 5 million inhabitants French region. The region is divided into sub-municipal areas that we have classified according to their SES profile. We then conducted a spatial analysis of COVID-19 indicators depending on SES profile, age structure, and health services provision. This analysis considered spatial autocorrelation between areas. Results. COVID-19 incidence rates in more deprived areas were similar to those in wealthiest ones. Hospitalization rates of COVID-19 cases in conventional care units were greater in more deprived vs wealthiest areas: Standardized Incidence Ratio (SIR) were respectively 1.34 [95% confidence interval 1.18 - 1.52] and 1.25 [1.13 - 1.38] depending on the epidemic wave. This gap was even greater regarding hospitalization rates of cases in critical care units: SIR = 1.64 [1.30 - 2.07] then 1.33 [1.14 - 1.55] depending on the epidemic wave. Hospitalization rates of COVID-19 cases in conventional care units were also greater in areas with high proportion of elderly people vs young people: SIR respectively 1.24 [1.11 - 1.38] and 1.22 [1.13 - 1.32] depending on the wave. Conclusion. Considering age structure and health services provision, a deprived SES profile is associated to a greater COVID-19 severity in terms of hospitals admissions, in conventional care units and in critical care units. This result implies targeting risk prevention efforts on these areas in pandemic situations and highlights the need to develop access to healthcare to deprived populations in anticipation of periods of crisis.
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</p>
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</div>
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<div class="article-link article-html-link">
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🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2023.04.18.23288723v1" target="_blank">Deprivation effect on COVID-19 cases incidence and severity: a geo-epidemiological study in PACA region, France</a>
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</div></li>
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<li><strong>SARS-CoV-2 Infects Peripheral and Central Neurons Before Viremia, Facilitated by Neuropilin-1</strong> -
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<div>
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Neurological symptoms associated with COVID-19, acute and long-term, suggest SARS-CoV-2 affects both central and peripheral nervous systems. Although studies have shown olfactory and hematogenous entry into the brain and neuroinflammation, little attention has been paid to the susceptibility of the peripheral nervous system to infection or to alternative routes of CNS invasion. We show that neurons in the central and peripheral nervous system are susceptible to productive infection with SARS-CoV-2. Infection of K18-hACE2 mice, wild-type mice, golden Syrian hamsters, and primary neuronal cultures demonstrate viral RNA, protein, and infectious virus in peripheral nervous system neurons and satellite glial cells, spinal cord, and specific brain regions. Moreover, neuropilin-1 facilitates SARS-CoV-2 neuronal infection. Our data show that SARS-CoV-2 rapidly invades and establishes a productive infection in the peripheral and central nervous system via direct invasion of neurons prior to viremia, which may underlie some cognitive and sensory symptoms associated with COVID-19.
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</div>
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<div class="article-link article-html-link">
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🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2022.05.20.492834v2" target="_blank">SARS-CoV-2 Infects Peripheral and Central Neurons Before Viremia, Facilitated by Neuropilin-1</a>
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</div></li>
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<li><strong>Computationally restoring the potency of a clinical antibody against SARS-CoV-2 Omicron subvariants</strong> -
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<div>
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The COVID-19 pandemic underscored the promise of monoclonal antibody-based prophylactic and therapeutic drugs, but also revealed how quickly viral escape can curtail effective options. With the emergence of the SARS-CoV-2 Omicron variant in late 2021, many clinically used antibody drug products lost potency, including Evusheld and its constituent, cilgavimab. Cilgavimab, like its progenitor COV2-2130, is a class 3 antibody that is compatible with other antibodies in combination4 and is challenging to replace with existing approaches. Rapidly modifying such high-value antibodies with a known clinical profile to restore efficacy against emerging variants is a compelling mitigation strategy. We sought to redesign COV2-2130 to rescue in vivo efficacy against Omicron BA.1 and BA.1.1 strains while maintaining efficacy against the contemporaneously dominant Delta variant. Here we show that our computationally redesigned antibody, 2130-1-0114-112, achieves this objective, simultaneously increases neutralization potency against Delta and many variants of concern that subsequently emerged, and provides protection in vivo against the strains tested, WA1/2020, BA.1.1, and BA.5. Deep mutational scanning of tens of thousands pseudovirus variants reveals 2130-1-0114-112 improves broad potency without incurring additional escape liabilities. Our results suggest that computational approaches can optimize an antibody to target multiple escape variants, while simultaneously enriching potency. Because our approach is computationally driven, not requiring experimental iterations or pre-existing binding data, it could enable rapid response strategies to address escape variants or pre-emptively mitigate escape vulnerabilities.
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</div>
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🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2022.10.21.513237v2" target="_blank">Computationally restoring the potency of a clinical antibody against SARS-CoV-2 Omicron subvariants</a>
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</div></li>
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<li><strong>Antibody Correlates of Protection for COVID-19 Convalescent Plasma Associated with Reduced Outpatient Hospitalizations</strong> -
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SARS-CoV-2 antibody levels associated with reduced hospitalization risk remain undefined. Our outpatient COVID-19 convalescent plasma (CCP), placebo-controlled trial observed SARS-CoV-2 antibody levels decreasing 22-fold from matched donor units into post-transfusion seronegative recipients. Unvaccinated recipients were jointly stratified by a) early or late transfusion (< 5 or >5 days from symptom onset) and b) high or low post-transfusion SARS-CoV-2 antibody levels (< or > geometric mean). Early treatment with high post-transfusion antibody levels reduced hospitalization risk-0/102 (0%) compared to all other CCP recipients-17/370 (4.6%; Fisher exact-p-0.03) and to all control plasma recipients-35/461 (7.6%; Fisher exact p-0.001). A similar donor upper/lower half antibody level and early late transfusion stratified analyses indicated significant hospital risk reduction. Pre-transfusion nasal viral loads were similar in CCP and control recipients regardless of hospitalization outcome. Therapeutic CCP should comprise the upper 30% of donor antibody levels to provide effective outpatient use for immunocompromised and immunocompetent outpatients.
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</p>
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🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2023.04.13.23288353v2" target="_blank">Antibody Correlates of Protection for COVID-19 Convalescent Plasma Associated with Reduced Outpatient Hospitalizations</a>
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</div></li>
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<li><strong>Effect of face-covering use on adherence to other COVID-19 protective behaviours: a systematic review</strong> -
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<p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom">
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During the COVID-19 pandemic, concerns were raised that face covering use may elicit risk compensation; a false sense of security resulting in reduced adherence to other protective behaviours such as physical distancing. This systematic review aimed to investigate the effect of face covering use on adherence to other COVID-19 related protective behaviours. Medline, Embase, PsychInfo, EmCare, medRxiv preprints, Research Square and WHO COVID-19 Research Database were searched. All primary research studies published from 1 January 2020 to 17th May 2022 which investigated the effect of face covering use on adherence to other protective behaviours in public settings during the COVID-19 pandemic were included. Papers were selected and screened in accordance with the PRISMA framework. Backwards and forwards citation searches of included papers were also conducted on 16th September 2022, with eligible papers published between 1st January 2020 and that date being included. A quality appraisal including risk of bias was assessed using the Academy of Nutrition and Dietetics’ Quality Criteria Checklist. This review is registered on PROSPERO, number CRD42022331961. 47 papers were included, with quality ranging from low to high. These papers investigated the effects of face covering use and face covering policies on adherence to six categories of behaviour: physical distancing; mobility; face-touching; hand hygiene; close contacts; and generalised protective behaviour. Results reveal no consistent evidence for or against risk compensation, with findings varying according to behaviour and across study types. There is a suggestion that face covering use might reduce face-touching and face covering mandates might increase mobility, though the lack of robust evidence means these are tentative claims. Evidence on the other protective behaviours is largely inconsistent, and therefore confident conclusions cannot be made in these areas. Any policy decisions related to face coverings must consider the inconsistencies and caveats in this evidence base.
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🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2023.04.11.23288200v2" target="_blank">Effect of face-covering use on adherence to other COVID-19 protective behaviours: a systematic review</a>
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</div></li>
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<li><strong>Changes in hospital staff’ mental health during the Covid-19 pandemic: longitudinal results from the international COPE-CORONA study</strong> -
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This longitudinal study aimed to explore anxiety and depressive symptoms, individual resources, and job demands in a multi-country sample of 612 healthcare workers (HCWs) during the COVID-19 pandemic. Two online surveys were distributed to HCWs in seven countries (Germany, Andorra, Ireland, Spain, Italy, Romania, Iran) during the first (May-October 2020, T1) and the second (February-April 2021, T2) phase of the pandemic, assessing sociodemographic characteristics, contact with COVID-19 patients, anxiety and depressive symptoms, self-compassion, sense of coherence, social support, risk perception, and health and safety at the workplace. HCWs reported a significant increase in depressive and anxiety symptoms. HCWs with high depressive or anxiety symptoms at T1 and T2 reported a history of mental illness and lower self-compassion and sense of coherence over time. Risk perception, self-compassion, sense of coherence, and social support were strong independent predictors of depressive and anxiety symptoms at T2, even after controlling for baseline depressive or anxiety symptoms and sociodemographic variables. These findings pointed out that HCWs during the COVID-19 outbreak experienced a high burden of psychological distress. The mental health and resilience of HCWs should be supported during disease outbreaks by instituting workplace interventions for psychological support.
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🖺 Full Text HTML: <a href="https://www.medrxiv.org/content/10.1101/2023.04.20.23288855v1" target="_blank">Changes in hospital staff’ mental health during the Covid-19 pandemic: longitudinal results from the international COPE-CORONA study</a>
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</div></li>
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<li><strong>Integration of microbial and chemical synthesis for the efficient production of plitidepsin, a promising anticancer and antiviral agent</strong> -
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<div>
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Plitidepsin, a marine-derived anticancer medicine, is being tested in phase III clinical trials for treating COVID-19. However, the current supply of plitidepsin relies on laborious chemical synthesis processes. Here, we present a new approach that combines microbial and chemical synthesis to produce plitidepsin. We screened a Tistrella strain library to identify a high-yield didemnin B producer, and then introduced a second copy of the didemnin biosynthetic gene cluster into its genome, resulting in the highest yield of didemnin B reported in the literature. Next, we developed two straightforward chemical strategies to convert didemnin B to plitidepsin, one of which involved a one-step synthetic route giving over 90% overall yield. We also synthesized two new didemnin analogues and assessed their anticancer and antiviral activities. Our findings offer a practical and sustainable solution for producing plitidepsin and its derivatives, potentially expediting didemnin drug development.
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<div class="article-link article-html-link">
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🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2023.04.24.537896v1" target="_blank">Integration of microbial and chemical synthesis for the efficient production of plitidepsin, a promising anticancer and antiviral agent</a>
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</div></li>
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<li><strong>SARS-CoV-2 Nonstructural Proteins 3 and 4 tune the Unfolded Protein Response</strong> -
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<div>
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Coronaviruses (CoV), including SARS-CoV-2, modulate host proteostasis pathways during infection through activation of stress-responsive signaling pathways such as the Unfolded Protein Response (UPR). The UPR regulates protein translation, increases protein folding capacity and enhances endoplasmic reticulum (ER) biogenesis to alleviate ER stress caused by accumulation of misfolded proteins. CoVs depend on host machinery to generate large amounts of viral protein and manipulate ER-derived membranes to form double-membrane vesicles (DMVs), which serve as replication sites, making the UPR a key host pathway for CoVs to hijack. Despite the importance of CoV nonstructural proteins (nsps) in mediating replication, little is known about the role of nsps in modulating the UPR. We characterized the impact of SARS-CoV-2 nsp4, which is a key driver of DMV formation, on the UPR using quantitative proteomics. We find nsp4 preferentially activates the ATF6 and PERK branches of the UPR. Previously, we found an N-terminal truncation of nsp3 (nsp3.1) can suppress pharmacological activation of the ATF6 pathway. To determine how nsp3.1 and nsp4 might tune the UPR in concert, both proteins were co-expressed demonstrating that nsp3.1 does not suppress nsp4-mediated ATF6 activation but does suppress PERK activation. A meta-analysis of SARS-CoV-2 infection proteomics data reveals a time-dependent activation of PERK protein markers early in infection, which subsequently fades. This temporal regulation suggests a role for nsps tuning the PERK pathway to attenuate host translation beneficial for viral replication while avoiding later apoptotic signaling caused by chronic PERK activation. This work furthers our understanding of CoV-host proteostasis interactions and identifies potential areas to target for anti-viral therapies.
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🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2023.04.22.537917v1" target="_blank">SARS-CoV-2 Nonstructural Proteins 3 and 4 tune the Unfolded Protein Response</a>
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<li><strong>Mechanism of the Covalent Inhibition of Human Transmembrane Protease Serine 2 as an Original Antiviral Strategy</strong> -
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The Transmembrane Protease Serine 2 (TMPRSS2) is a human enzyme which is involved in the maturation and post-translation of different proteins. In addition of being overexpressed in cancer cells, TMPRSS2 plays a further fundamental role in favoring viral infections by allowing the fusion of the virus envelope and the cellular membrane, notably in SARS-CoV-2. In this contribution we resort to multiscale molecular modeling to unravel the structural and dynamical features of TMPRSS2 and its interaction with a model lipid bilayer. Furthermore, we shed light into the mechanism of action of a potential inhibitor (Nafamostat), determining the free-energy profile associated with the inhibition reaction, and showing the facile poisoning of the enzyme. Our study, while providing the first atomistically resolved mechanism of TMPRSS2 inhibition, is also fundamental in furnishing a solid framework for further rational design targeting transmembrane proteases in a host-directed antiviral strategy.
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🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2023.04.23.537985v1" target="_blank">Mechanism of the Covalent Inhibition of Human Transmembrane Protease Serine 2 as an Original Antiviral Strategy</a>
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<li><strong>The enigma of the SARS-CoV-2 microcirculation dysfunction: evidence for modified endothelial junctions.</strong> -
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Published evidence indicates that Severe Acute Respiratory Syndrome-Corona Virus (SARS-CoV-2) infection causes endothelial cell (EC) injury in the Coronavirus Disease 2019 (COVID-19). Endothelial junctions (EJ) are crucial to maintain EC integrity and normal microvascular functions due to the adhesive properties of Vascular endothelial (VE)-cadherin to glue EC together. Here we report studies in vitro and in vivo that indicate VE-cadherin to be a target for cleavage by ACE2. We have identified that the extracellular domain of VE-cadherin contains these two amino acid sequences at the positions 256P-F257 and 321PMKP-325L for ACE2 substrate recognition. Incubation of purified sVE with ACE2 revealed a dose-dependent loss of immunoreactivity detected with an antibody directed against the Extracellular domain 1 (EC1) domain of sVE. We confirmed the presence of ACE2 on ECs using immunofluorescence studies, and by western blotting on ECs extracts. We also present evidence from patients with severe COVID-19 disease for a circulating form of ACE2. Its apparent molecular weight of 70 kDa is in agreement with a previously described extracellular form of ACE2 bearing the catalytic site of the ectopeptidase. Consistent with the experimental evidence for our hypothesis, the level of circulating soluble VE-cadherin fragments was increased in the blood of patients with severe COVID-19 disease. Further studies are needed to determine if increased circulating fragments of ACE2 and VE-cadherin may contribute to the future development of post-acute COVID-19 syndrome characterized by vascular endothelial injury, hypoxia, and inflammatory state.
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</div>
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<div class="article-link article-html-link">
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🖺 Full Text HTML: <a href="https://www.biorxiv.org/content/10.1101/2023.04.24.538100v1" target="_blank">The enigma of the SARS-CoV-2 microcirculation dysfunction: evidence for modified endothelial junctions.</a>
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</ul>
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<h1 data-aos="fade-right" id="from-clinical-trials">From Clinical Trials</h1>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Effectiveness and Safety of Quinine Sulfate as add-on Therapy for COVID-19 in Hospitalized Adults in Indonesia ( DEAL-COVID19 )</strong> - <b>Condition</b>: COVID-19<br/><b>Interventions</b>: Drug: Standard of Care + Quinine Sulfate; Drug: Standard of Care<br/><b>Sponsors</b>: Universitas Padjadjaran; National Research and Innovation Agency of Indonesia; Prodia Diacro Laboratories P.T.<br/><b>Recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Safety and Efficacy of Umbilical Cord Mesenchymal Stem Cell Exosomes in Treating Chronic Cough After COVID-19</strong> - <b>Condition</b>: Long COVID-19 Syndrome<br/><b>Intervention</b>: Biological: MSC-derived exosomes<br/><b>Sponsors</b>: Huazhong University of Science and Technology; REGEN-αGEEK (SHENZHEN) MEDICAL TECHNOLOGY CO., LTD.<br/><b>Recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Efficacy and Safety of Nirmatrelvir/Ritonavir for Treating Omicron Variant of COVID-19</strong> - <b>Condition</b>: Omicron Variant of COVID-19<br/><b>Intervention</b>: Drug: Nirmatrelvir/Ritonavir<br/><b>Sponsor</b>: Xiangao Jiang<br/><b>Completed</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>A Study of mRNA-1283.222 Injection Compared With mRNA-1273.222 Injection in Participants ≥12 Years of Age to Prevent COVID-19</strong> - <b>Condition</b>: COVID-19<br/><b>Interventions</b>: Biological: mRNA-1283.222; Biological: mRNA-1273.222<br/><b>Sponsor</b>: ModernaTX, Inc.<br/><b>Recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Postoperative Sugammadex After COVID-19</strong> - <b>Conditions</b>: General Anesthesia; COVID-19<br/><b>Interventions</b>: Drug: Sugammadex Sodium; Drug: neostigmine 50µg/kg + glycopyrollate 0.01mg/kg<br/><b>Sponsor</b>: Korea University Ansan Hospital<br/><b>Not yet recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Evaluation of the RD-X19 Treatment Device in Individuals With Mild COVID-19</strong> - <b>Condition</b>: COVID-19<br/><b>Interventions</b>: Device: RD-X19; Device: Sham<br/><b>Sponsor</b>: EmitBio Inc.<br/><b>Recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Clinical Study for the Efficacy and Safety of Ropeginterferon Alfa-2b in Adult COVID-19 Patients With Comorbidities</strong> - <b>Condition</b>: COVID-19<br/><b>Interventions</b>: Drug: Ropeginterferon alfa-2b; Procedure: SOC<br/><b>Sponsor</b>: National Taiwan University Hospital<br/><b>Not yet recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Assessment of Immunogenicity, Safety and Reactogenicity of a Booster Dose of Various COVID-19 Vaccine Platforms in Individuals Primed With Several Regimes.</strong> - <b>Condition</b>: COVID-19<br/><b>Interventions</b>: Biological: SCB-2019/Clover; Biological: AstraZeneca/Fiocruz; Biological: Pfizer/Wyeth<br/><b>Sponsors</b>: D’Or Institute for Research and Education; Bill and Melinda Gates Foundation<br/><b>Active, not recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>A Randomized, Double-Blind, Placebo-Controlled Phase 2/3 Study to Determine the Safety and Effectiveness of Azeliragon in the Treatment of Patients Hospitalized for Coronavirus Disease 2019 (COVID-19)</strong> - <b>Condition</b>: COVID-19<br/><b>Interventions</b>: Drug: Azeliragon; Drug: Placebo<br/><b>Sponsor</b>: Salim S. Hayek<br/><b>Recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>To Evaluate the Safety and Efficacy of Meplazumab in Treatment of Post-COVID-19</strong> - <b>Condition</b>: Post-COVID-19<br/><b>Interventions</b>: Biological: Meplazumab for injection; Other: Normal saline<br/><b>Sponsor</b>: Jiangsu Pacific Meinuoke Bio Pharmaceutical Co Ltd<br/><b>Recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Cognitive-behavioral Therapy for Mental Disorder in COVID-19 Survivors</strong> - <b>Condition</b>: Post Acute COVID-19 Syndrome<br/><b>Intervention</b>: Behavioral: mindfulness-based stress reduction (MBSR) and cognitive behavioral therapy (CBT)<br/><b>Sponsor</b>: Azienda Socio Sanitaria Territoriale di Lecco<br/><b>Recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Efficacy of Lactobacillus Paracasei PS23 for Patients With Post-COVID-19 Syndrome</strong> - <b>Condition</b>: Post-COVID-19 Syndrome<br/><b>Intervention</b>: Dietary Supplement: PS23 heat-treated<br/><b>Sponsors</b>: Mackay Memorial Hospital; Bened Biomedical Co., Ltd.<br/><b>Recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Exploring the Effect of Video Interventions on Intentions for Continued COVID-19 Vaccination</strong> - <b>Conditions</b>: Vaccine Refusal; COVID-19<br/><b>Interventions</b>: Behavioral: Informational Video; Behavioral: Altruistic Video; Behavioral: Individualistic Video<br/><b>Sponsor</b>: Sir Mortimer B. Davis - Jewish General Hospital<br/><b>Not yet recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Effect of Telerehabilitation Practice in Long COVID-19 Patients</strong> - <b>Conditions</b>: Long COVID-19; Long COVID; Post COVID-19 Condition; Post-COVID-19 Syndrome; Post-COVID Syndrome<br/><b>Interventions</b>: Behavioral: Telerehabilitation; Behavioral: Standard rehabilitation care<br/><b>Sponsor</b>: Indonesia University<br/><b>Recruiting</b></p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Rehabilitation Treatment of Patients With COVID-19</strong> - <b>Conditions</b>: Rehabilitation; Pneumonia, Viral; COVID-19; Quality of Life<br/><b>Interventions</b>: Other: exercises; Other: massage<br/><b>Sponsors</b>: I.M. Sechenov First Moscow State Medical University; MEDSI Clinical Hospital 1, ICU<br/><b>Completed</b></p></li>
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</ul>
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<h1 data-aos="fade-right" id="from-pubmed">From PubMed</h1>
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<ul>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>The human E3 ligase RNF185 is a regulator of the SARS-CoV-2 envelope protein</strong> - Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) hijacks multiple human proteins during infection and viral replication. To examine whether any viral proteins employ human E3 ubiquitin ligases, we evaluated the stability of SARS-CoV-2 proteins with inhibition of the ubiquitin proteasome pathway. Using genetic screens to dissect the molecular machinery involved in the degradation of candidate viral proteins, we identified human E3 ligase RNF185 as a regulator of protein stability for…</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Production and optimization of novel Sphorolipids from Candida parapsilosis grown on potato peel and frying oil wastes and their adverse effect on Mucorales fungal strains</strong> - CONCLUSION: The findings demonstrated the potential application of the SLs produced economically from agricultural waste as an effective and safer alternative for the treatment of infection caused by black fungus.</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Bioactive compounds from Huashi Baidu decoction possess both antiviral and anti-inflammatory effects against COVID-19</strong> - The coronavirus disease 2019 (COVID-19) pandemic is an ongoing global health concern, and effective antiviral reagents are urgently needed. Traditional Chinese medicine theory-driven natural drug research and development (TCMT-NDRD) is a feasible method to address this issue as the traditional Chinese medicine formulae have been shown effective in the treatment of COVID-19. Huashi Baidu decoction (Q-14) is a clinically approved formula for COVID-19 therapy with antiviral and anti-inflammatory…</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Design and statistical optimisation of emulsomal nanoparticles for improved anti-SARS-CoV-2 activity of <em>N</em>-(5-nitrothiazol-2-yl)-carboxamido candidates: <em>in vitro</em> and <em>in silico</em> studies</strong> - In this article, emulsomes (EMLs) were fabricated to encapsulate the N-(5-nitrothiazol-2-yl)-carboxamido derivatives (3a-3g) in an attempt to improve their biological availability and antiviral activity. Next, both cytotoxicity and anti-SARS-CoV-2 activities of the examined compounds loaded EMLs (F3a-g) were assessed in Vero E6 cells via MTT assay to calculate the CC(50) and inhibitory concentration 50 (IC(50)) values. The most potent 3e-loaded EMLs (F3e) elicited a selectivity index of 18 with…</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>The effects and mechanisms of the anti-COVID-19 traditional Chinese medicine, Dehydroandrographolide from Andrographis paniculata (Burm.f.) Wall, on acute lung injury by the inhibition of NLRP3-mediated pyroptosis</strong> - CONCLUSION: Deh from Andrographis paniculata (Burm.f.) Wall presented NLRP3-mediated pyroptosis in a model of ALI through ROS-induced mitochondrial damage through inhibition of the Akt/Nrf2 pathway by PDPK1 ubiquitination. Therefore, it can be concluded that Deh may be a potential therapeutic drug for the treatment of ALI in COVID-19 or other respiratory diseases.</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Antiviral activities of hemp cannabinoids</strong> - Hemp is an understudied source of pharmacologically active compounds and many unique plant secondary metabolites including more than 100 cannabinoids. After years of legal restriction, research on hemp has recently demonstrated antiviral activities in silico, in vitro, and in vivo for cannabidiol (CBD), Δ9-tetrahydrocannabinol (Δ9-THC), cannabidiolic acid (CBDA), cannabigerolic acid (CBGA), and several other cannabinoids against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), human…</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Prospecting native and analogous peptides with anti-SARS-CoV-2 potential derived from the trypsin inhibitor purified from tamarind seeds</strong> - The study aimed to prospect in silico native and analogous peptides with anti-SARS-CoV-2 potential derived from the trypsin inhibitor purified from tamarind seeds (TTIp). From the most stable theoretical model of TTIp (TTIp 56/287), in silico cleavage was performed for the theoretical identification of native peptides and generation of analogous peptides. The anti-SARS-CoV-2 potential was investigated through molecular dynamics (MD) simulation between the peptides and binding sites of…</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Preventive and therapeutic benefits of nelfinavir in rhesus macaques and human beings infected with SARS-CoV-2</strong> - Effective drugs with broad spectrum safety profile to all people are highly expected to combat COVID-19 caused by SARS-CoV-2. Here we report that nelfinavir, an FDA approved drug for the treatment of HIV infection, is effective against SARS-CoV-2 and COVID-19. Preincubation of nelfinavir could inhibit the activity of the main protease of the SARS-CoV-2 (IC(50) = 8.26 μM), while its antiviral activity in Vero E6 cells against a clinical isolate of SARS-CoV-2 was determined to be 2.93 μM (EC(50))….</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Role of Cytochrome P450 2C9 in COVID-19 Treatment: Current Status and Future Directions</strong> - The major human liver drug metabolising cytochrome P450 (CYP) enzymes are downregulated during inflammation and infectious disease state, especially during coronavirus disease 2019 (COVID-19) infection. The influx of proinflammatory cytokines, known as a ‘cytokine storm’, during severe COVID-19 leads to the downregulation of CYPs and triggers new cytokine release, which further dampens CYP expression. Impaired drug metabolism, along with the inevitable co-administration of drugs or ’combination…</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Rhinovirus-induced epithelial RIG-I inflammasome suppresses antiviral immunity and promotes inflammation in asthma and COVID-19</strong> - Rhinoviruses and allergens, such as house dust mite are major agents responsible for asthma exacerbations. The influence of pre-existing airway inflammation on the infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is largely unknown. We analyse mechanisms of response to viral infection in experimental in vivo rhinovirus infection in healthy controls and patients with asthma, and in in vitro experiments with house dust mite, rhinovirus and SARS-CoV-2 in human primary…</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Kv1.3 blockade by ShK186 modulates CD4+ effector memory T-cell activity of patients with Granulomatosis with polyangiitis</strong> - CONCLUSIONS: Modulation of cellular effector function by ShK-186 may constitute a novel treatment strategy for GPA with high specificity and less harmful side effects.</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Kinetics and ability of binding antibody and surrogate virus neutralization tests to predict neutralizing antibodies against the SARS-CoV-2 Omicron variant following BNT162b2 booster administration</strong> - CONCLUSIONS: This study showed a significant drop in humoral immunity 6 months after booster administration. Anti-RBD IgG and Omicron sVNT assays were highly correlated and could predict neutralizing activity with moderate performance.</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>MHC class I links with severe pathogenicity in C57BL/6N mice infected with SARS-CoV-2/BMA8</strong> - CONCLUSIONS: Taken together, our work shows that host MHC molecules play a crucial role in the pathogenicity differences of SARS-CoV-2/BMA8 infection. This provides a more profound insight into the pathogenesis of SARS-CoV-2, and contributes enlightenment and guidance for controlling the virus spread.</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Discovery and structural characterization of monkeypox virus methyltransferase VP39 inhibitors reveal similarities to SARS-CoV-2 nsp14 methyltransferase</strong> - Monkeypox is a disease with pandemic potential. It is caused by the monkeypox virus (MPXV), a double-stranded DNA virus from the Poxviridae family, that replicates in the cytoplasm and must encode for its own RNA processing machinery including the capping machinery. Here, we present crystal structures of its 2’-O-RNA methyltransferase (MTase) VP39 in complex with the pan-MTase inhibitor sinefungin and a series of inhibitors that were discovered based on it. A comparison of this 2’-O-RNA MTase…</p></li>
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<li data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><p data-aos="fade-left" data-aos-anchor-placement="bottom-bottom"><strong>Synthesis of SARS-CoV-2 M<sup>pro</sup> inhibitors bearing a cinnamic ester warhead with <em>in vitro</em> activity against human coronaviruses</strong> - COVID-19 now ranks among the most devastating global pandemics in history. The causative virus, SARS-CoV-2, is a new human coronavirus (hCoV) that spreads among humans and animals. Great efforts have been made to develop therapeutic agents to treat COVID-19, and among the available viral molecular targets, the cysteine protease SARS-CoV-2 M^(pro) is considered the most appealing one due to its essential role in viral replication. However, the inhibition of M^(pro) activity is an interesting…</p></li>
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</ul>
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<h1 data-aos="fade-right" id="from-patent-search">From Patent Search</h1>
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