Open science discovery of potent noncovalent SARS-CoV-2 main protease inhibitors

INTRODUCTION COVID-19 became a global pandemic partially as a result of the lack of easily deployable, broad-spectrum oral antivirals, which complicated its containment. Even endemically, and with effective vaccinations, it will continue to cause acute disease, death, and long-term sequelae globally unless there are accessible treatments. COVID-19 is not an isolated event but instead is the latest example of a viral pandemic threat to human health. Therefore, antiviral discovery and development should be a key pillar of pandemic preparedness efforts. RATIONALE One route to accelerate antiviral drug discovery is the establishment of open knowledge bases, the development of effective technology infrastructures, and the discovery of multiple potent antivirals suitable as starting points for the development of therapeutics. In this work, we report the results of the COVID Moonshot—a fully open science, crowdsourced, and structure-enabled drug discovery campaign—against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro). This collaboration may serve as a roadmap for the potential development of future antivirals. RESULTS On the basis of the results of a crystallographic fragment screen, we crowdsourced design ideas to progress from fragment to lead compounds. The crowdsourcing strategy yielded several key compounds along the optimization trajectory, including the starting compound of what became the primary lead series. Three additional chemically distinct lead series were also explored, spanning a diversity of chemotypes. The collaborative and highly automated nature of the COVID Moonshot Consortium resulted in >18,000 compound designs, >2400 synthesized compounds, >490 ligand-bound x-ray structures, >22,000 alchemical free-energy calculations, and >10,000 biochemical measurements—all of which were made publicly available in real time. The recently approved antiviral ensitrelvir was identified in part based on crystallographic data from the COVID Moonshot Consortium. This campaign led to the discovery of a potent [median inhibitory concentration (IC50) = 37 ± 2 nM] and differentiated (noncovalent and nonpeptidic) lead compound that also exhibited potent cellular activity, with a median effective concentration (EC50) of 64 nM in A549-ACE2-TMPRSS2 cells and 126 nM in HeLa-ACE2 cells without measurable cytotoxicity. Although the pharmacokinetics of the reported compound is not yet optimal for therapeutic development, it is a promising starting point for further antiviral discovery and development. CONCLUSION The success of the COVID Moonshot project in producing potent antivirals, building open knowledge bases, accelerating external discovery efforts, and functioning as a useful information-exchange hub is an example of the potential effectiveness of open science antiviral discovery programs. The open science, patent-free nature of the project enabled a large number of collaborators to provide in-kind support, including synthesis, assays, and in vitro and in vivo experiments. By making all data immediately available and ensuring that all compounds are purchasable from Enamine without the need for materials transfer agreements, we aim to accelerate research globally along parallel tracks. In the process, we generated a detailed map of the structural plasticity of Mpro, extensive structure-activity relationships for multiple chemotypes, and a wealth of biochemical activity data to spur further research into antivirals and discovery methodologies. We hope that this can serve as an alternative model for antiviral discovery and future pandemic preparedness. Further, the project also showcases the role of machine learning, computational chemistry, and high-throughput structural biology as force multipliers in drug design. Artificial intelligence and machine learning algorithms help accelerate chemical synthesis while balancing multiple competing molecular properties. The design-make-test-analyze cycle was accelerated by these algorithms combined with planetary-scale biomolecular simulations of protein-ligand interactions and rapid structure determination

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

SummaryBackground Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatoryactions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19.Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospitalwith COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients wererandomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once perday by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatmentgroups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment andwere twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants andlocal study staff were not masked to the allocated treatment, but all others involved in the trial were masked to theoutcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treatpopulation. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) wereeligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomlyallocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall,561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days(rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days(rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, nosignificant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilationor death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24).Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or otherprespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restrictedto patients in whom there is a clear antimicrobial indication

Insight from Smart Water Meters: Opportunities for Targeted Management Strategies

<p>This seminar will present the key insights and practical implications for targeted management strategies that have emerged from analysis of 3 years of smart water meter measurements on a representative set of 100-150 households in Adelaide. It will be of interest to a wide range of personnel within SA Water including water network planners and operators who use demand and waste water predictions to optimize planning and operational decisions, and to community engagement and policy personnel who wish to better understand the relationship between household behavior and water use. The topics to be covered include:</p> <p><b>Drivers of Indoor Use</b></p> <p>The key drivers of indoor water use were identified by combining end use measurements with household surveys of demographics, behavior, appliance usage and attitude. Key findings include:</p> <p>•     Distinct household usage groups (related to demographics such as income/age/attitude) were identified with different water end-use patterns. </p> <p>•     This has implications for the development of targeted strategies for effective demand management and water use prediction to optimise planning and operations of water networks.</p> <p>•     The Behavioural End Use Stochastic Simulator (BESS) that utilises differences in behaviour and water using appliances to provide end-use predictions was found to be highly accurate (~5-10% errors) when calibrated with local end-use measurements. </p> <p>•     This implies BESS can provide reliable water use predictions that incorporate changes in behaviour and household characteristics. BESS was used to attribute water-use reduction during the 2007-2009 drought and provide predictions of demand management scenarios (uptake of water efficient appliances) in the future (2025 and 2050). </p> <p><b>Drivers of Outdoor Use and Peak Demands </b></p> <p>The key drivers of outdoor water use and peak demand were analyzed by combining the three years of smart water measurements with climate and household characteristics (garden size/irrigation type etc). Key findings are: </p> <p>•    Potential impacts of future climate change on peak demands.</p> <p>•    Identification of the key drivers of outdoor water use and its implications for water prediction and demand management strategies. </p> <p>•    Identification of the key drivers of peak water and its implications for peak demand prediction and peak demand reduction strategies. An important finding being that a small proportion of the households with certain characteristics contribute a large amount to the peak demand. </p> <p>The majority of these findings emerged from the “Identifying the Key Drivers of Household Water Use” component of the Goyder Institute for Water Research Optimal Water Resource Mix (OWRM) for Greater Adelaide project of which SA Water was a key stakeholder.</p

Insights from Smart Waters: Potential to Mitigate Impact of Heatwaves on Peak Demands

Presentation given at Water Research Australia workshop, "Smart metering and Liveability" on Thursday 14th June.<br><br>The key points are:<div>1. Climate change will increase peak demands in the future due to increased occurrence of longer heatwaves. </div><div>2. Majority of peak demands are caused by a small proportion of households, which we know the profile of.</div><div>3. Targeted management strategies on this small proportion of households can be used to reduce peak demands.</div><div><br></div><div><br><div><div><br></div><div><br></div></div></div

Household water use statistics from Adelaide Household Water Use Study 2013

his collection contains indoor end-use statistics for 140 households in metropolitan Adelaide and the associated demographics and appliance characteristics of the households. The end-use statistics were determined through flow trace analysis of a two week period of high resolution (10s) water usage data representative of winter use. The end-use statistics include the mean and standard deviation for the volume per person per day for each end-use and the relevant characteristics of the end-use: - Shower: Duration (mins), Frequency (events/person/day), Flow rate (L/min), Efficiency (star rating) - Toilet: Flush volume (L), Frequency (events/person/day), Efficiency (e.g. 3L/6L Dual) - Washing Machine: Volume per load (L), Frequency (events/household/week), Type (Front or Top loader) - Dishwasher: Volume per load (L), Frequency (events/household/week) - Tap: Duration (seconds), Frequency (events/person/day), Flow rate (L/min) - Bath: Volume per bath (L), Frequency (events/household/week) The demographics and household characteristics include: - Household occupancy - Age of occupants - Income - Perceived water conservation level This data was collected as part of the research program of the Goyder Institute for Water Research's Optimal Water Mix for Greater Adelaide project

Identifying Key Drivers of Household Water Use in South Australia: Practical Implications

This study identified the key drivers of household water use in a South Australia. This was undertaken by analysis of a unique database of high resolution water use measurements and surveys on household demographics, behaviour and attitudes of a representative group of 150 households in metropolitan Adelaide. High resolution monitoring was undertaken between March 2013 to February 2014. Flow trace analysis determined the individual indoor end-uses (shower, toilets etc) for a two week period in winter 2013. Key drivers for indoor end use were: (1) High variability in end-uses between households and householders themselves do not provide reliable estimate of their own end-use proportions. Householders need more information to identify water saving opportunities (2) Water efficient appliance uptake is approx. 50% with further potential savings of 19L/p/day (15% of indoor). As efficient washing machines are the largest contributor increasing their uptake will enhance water savings. (3) Distinct households usage types (related to income/age/attitude – e.g. the “pensioner” effect) with different water usage patterns and water saving opportunities were identified. This requires a targeted approach for demand management. Analysis of drivers for seasonal water use  (40% of total household use) identified that it increased with increasing property area (+25%), decreased with decreasing income (-20%) and increased with increase age (+11%). Analysis of peak day demands showed a consistent pattern that a small proportion (20%) of households made large contribution (50%) to the total demand on peak demand days. This presents an opportunity to reduce water infrastructure costs by developing targeted strategies to reduce the peak. Predictive modelling illustrated the Behavioural End Use Stochastic Simulator (BESS) provided reliable predictions of end-uses using local end-use information. Using BESS predictions 50% of the water use reduction during the 2007-2009 drought was attributed to uptake of water efficient appliances. Using BESS predictions demand management (uptake of water efficient appliances) was estimated to reduce residential water use by 7% in the short-term, reducing to 4% in the longer term due to “demand hardening”

Potential scope and impact of a transboundary model of nurse practitioners in aged care\ud \ud

Aged care is a growing issue in Australia and other countries. There are significant barriers to meeting the health needs of this population. Current services have gaps between care and lack communication and integration between care providers. Research was conducted in the Australian Capital Territory to investigate the potential role of the aged care nurse practitioner in health service delivery in aged care settings. A multimethod case study design was utilised, with three student nurse practitioners (SNP) providing care to aged care clients across three sectors of health service delivery (residential aged care facilities, general medical practices and acute care). Data collection consisted of in-depth interviews and journal entries of the SNP, as well as focus groups and surveys of multidisciplinary staff and patients over the age of 65 years in the settings frequented by the SNP. The aged care SNP were found to cross professional and organisational boundaries, cross intra- as well as interorganisational boundaries and to contribute to more seamless patient care as members of a multidisciplinary aged care team. The aged care nurse practitioner role consequently has the potential to function in a networked rather than a hierarchical manner, and this could be a key element in addressing gaps in care across care locales and between disciplines.\ud \u

Indigenous Research and Broader Issues in the Academy

The Rudd Labour Government rode to power in Australia on the education promise of 'an education revolution'. The term 'education revolution' carries all the obligatory marketing metaphors that an aspirant government might want recognised by the general public on the eve government came to power however in revolutionary terms it fades into insignificance in comparison to the real revolution in Australian education. This revolution simply put is to elevate Indigenous Knowledge Systems, in Australian Universities. In the forty three years since the nation setting Referendum of 1967 a generation has made a beach head on the educational landscape. Now a further generation who having made it into the field of higher degrees yearn for the ways and means to authentically marshal Indigenous knowledge? The Institute of Koorie Education at Deakin has for over twenty years not only witnessed the transition but is also a leader in the field. With the appointment of two Chairs of Indigenous Knowledge Systems to build on to its already established research profile the Institute moved towards what is the 'real revolution' in education – the elevation of Indigenous Knowledge as a legitimate knowledge system. This paper lays out the Institute of Koorie Education‘s Research Plan and the basis of an argument put to the academy that will be the driver for this pursuit