Novel Pan-Coronavirus 3CL Protease Inhibitor MK-7845: Biological and Pharmacological Profiling.

Severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) continues to be a global threat due to its ability to evolve and generate new subvariants, leading to new waves of infection. Additionally, other coronaviruses like Middle East respiratory syndrome coronavirus (MERS-CoV, formerly known as hCoV-EMC), which first emerged in 2012, persist and continue to present a threat of severe illness to humans. The continued identification of novel coronaviruses, coupled with the potential for genetic recombination between different strains, raises the possibility of new coronavirus clades of global concern emerging. As a result, there is a pressing need for pan-CoV therapeutic drugs and vaccines. After the extensive optimization of an HCV protease inhibitor screening hit, a novel 3CLPro inhibitor (MK-7845) was discovered and subsequently profiled. MK-7845 exhibited nanomolar in vitro potency with broad spectrum activity against a panel of clinical SARS-CoV-2 subvariants and MERS-CoV. Furthermore, when administered orally, MK-7845 demonstrated a notable reduction in viral burdens by >6 log orders in the lungs of transgenic mice infected with SARS-CoV-2 (K18-hACE2 mice) and MERS-CoV (K18-hDDP4 mice).

Structured bubbling in vibrated gas-fluidized beds of binary granular particles: experiments and simulations.

Mixing and segregation of granular particles on the basis of size and density from vertical vibration or upward gas flow is critical to a wide range of industrial, agricultural and natural processes. Recently, combined vibration and gas flow under certain conditions has been shown to create periodically repeating structured bubbling patterns within a fluidized bed of spherical, monodisperse particles. Here, we demonstrate with experiments and simulations that structured bubbling can form in binary mixtures of particles with different size and density, but with similar minimum fluidization velocities. Structured bubbling leads to particles mixing regardless of initial particle configuration, while exciting particles with only gas flow produces smaller unstructured bubbles which act to segregate particles. Discrete particle simulations match the experimental results qualitatively and, in some regards quantitatively, while continuum particle simulations do not predict mixing in the case of structured bubbling, highlighting areas for future model improvement.

Invention of MK-7845, a SARS-CoV-2 3CL Protease Inhibitor Employing a Novel Difluorinated Glutamine Mimic.

As SARS-CoV-2 continues to circulate, antiviral treatments are needed to complement vaccines. The virus's main protease, 3CLPro, is an attractive drug target in part because it recognizes a unique cleavage site, which features a glutamine residue at the P1 position and is not utilized by human proteases. Herein, we report the invention of MK-7845, a novel reversible covalent 3CLPro inhibitor. While most covalent inhibitors of SARS-CoV-2 3CLPro reported to date contain an amide as a Gln mimic at P1, MK-7845 bears a difluorobutyl substituent at this position. SAR analysis and X-ray crystallographic studies indicate that this group interacts with His163, the same residue that forms a hydrogen bond with the amide substituents typically found at P1. In addition to promising in vivo efficacy and an acceptable projected human dose with unboosted pharmacokinetics, MK-7845 exhibits favorable properties for both solubility and absorption that may be attributable to the unusual difluorobutyl substituent.

Orally available nucleoside analog UMM-766 provides protection in a murine model of orthopox disease.

Although smallpox has been eradicated, other orthopoxviruses continue to be a public health concern as exemplified by the ongoing Mpox (formerly monkeypox) global outbreak. While medical countermeasures (MCMs) previously approved by the Food and Drug Administration for the treatment of smallpox have been adopted for Mpox, previously described vulnerabilities coupled with the questionable benefit of at least one of the therapeutics during the 2022 Mpox outbreak reinforce the need for identifying and developing other MCMs against orthopoxviruses. Here, we screened a panel of Merck proprietary small molecules and identified a novel nucleoside inhibitor with potent broad-spectrum antiviral activity against multiple orthopoxviruses. Efficacy testing of a 7-day dosing regimen of the orally administered nucleoside in a murine model of severe orthopoxvirus infection yielded a dose-dependent increase in survival. Treated animals had greatly reduced lesions in the lung and nasal cavity, particularly in the 10 µg/mL dosing group. Viral levels were also markedly lower in the UMM-766-treated animals. This work demonstrates that this nucleoside analog has anti-orthopoxvirus efficacy and can protect against severe disease in a murine orthopox model.IMPORTANCEThe recent monkeypox virus pandemic demonstrates that members of the orthopoxvirus, which also includes variola virus, which causes smallpox, remain a public health issue. While currently FDA-approved treatment options exist, risks that resistant strains of orthopoxviruses may arise are a great concern. Thus, continued exploration of anti-poxvirus treatments is warranted. Here, we developed a template for a high-throughput screening assay to identify anti-poxvirus small-molecule drugs. By screening available drug libraries, we identified a compound that inhibited orthopoxvirus replication in cell culture. We then showed that this drug can protect animals against severe disease. Our findings here support the use of existing drug libraries to identify orthopoxvirus-targeting drugs that may serve as human-safe products to thwart future outbreaks.

Faraday wave instability analog in vibrated gas-fluidized granular particles.

Granular materials are critical to many natural and industrial processes, yet the chaotic flow behavior makes granular dynamics difficult to understand, model, and control, causing difficulties for natural disaster mitigation as well as scale-up and optimization of industrial devices. Hydrodynamic instabilities in externally excited grains often resemble those in fluids, but have different underlying mechanisms, and these instabilities provide a pathway to understand geological flow patterns and control granular flows in industry. Granular particles subject to vibration have been shown to exhibit Faraday waves analogous to those in fluids; however, waves can only form at high vibration strengths and in shallow layers. Here, we demonstrate that combined gas flow and vibration induces granular waves without these limitations to enable structured, controllable granular flows at larger scale with lower energy consumption for potential industrial processes. Continuum simulations reveal that drag force under gas flow creates more coordinated particle motions to allow waves in taller layers as seen in liquids, bridging the gap between waves produced in conventional fluids and granular particles subject to vibration alone.

Evaluating Spray Drying and Co-Precipitation as Manufacturing Processes for Amorphous Solid Dispersions of a Low Tg API.

Amorphous solid dispersions feature prominently in the approach to mitigate low bioavailability of poorly water-soluble small molecules, particularly in the early development space focusing on toxicity evaluations and clinical studies in normal healthy volunteers, where high exposures are needed to establish safety margins. Spray drying has been the go-to processing route for a number of reasons, including ubiquitous availability of equipment, the ability to accommodate small scale deliveries, and established processes for delivering single phase amorphous material. Active pharmaceutical ingredients (APIs) with low glass transition temperatures (Tg) can pose challenges to this approach. This study addresses multiple routes towards overcoming issues encountered with a low Tg (∼ 12 °C) API during manufacture of a spray dry intermediate (SDI). Even once formulated as an amorphous solid dispersion (ASD) with HPMCAS-LG, the Tg of the ASD was sufficiently low to require the use of non-ideal solvents, posing safety concerns and ultimately resulting in low yields with frequent process interruptions to resolve product build-up. To resolve challenges with spray drying the HPMCAS-L SDI, higher Tg polymers were assessed during spray drying, and an alternative antisolvent precipitation-based process was evaluated to generate co-precipitated amorphous dispersions (cPAD) with either HPMCAS-L or the additional higher Tg polymers. Both approaches were found to be viable alternatives to achieve single phase ASDs while demonstrating comparable in vitro and in vivo bioperformance compared to the SDI. The results of this effort offer valuable considerations for future early-stage activities for ASDs with low Tg APIs.

Do Misconceptions About Health-Related Quality of Life Affect General Population Valuations of Health States?

OBJECTIVES: Healthcare resource allocation decisions are often informed by the expected gains in patients' quality-adjusted life-years. Misconceptions about ill-health's consequences for quality of life (QOL) may however affect evaluations of health states by the general population and hence affect resource allocation decisions informed by quality-adjusted life-years. We examine whether people selectively misestimate the QOL consequences of moderate anxiety or depression compared with other dimensions of health, and we test whether informing people of actual changes in QOL associated with health states changes appraisals of their relative undesirability. METHODS: UK general population participants (N = 1259; in 2017) expressed preferences over moderate problems: anxiety or depression, self-care, and pain or discomfort. A randomized control trial design was used whereby a control group was given a functional description of each health state, and 2 intervention groups were additionally given information on the actual differences in either life satisfaction (LS) or day affect (DA) associated with experiencing each health state. RESULTS: The LS (DA) group reported a higher preference for avoiding living with moderate anxiety or depression, being 13.4% (13.9%) more likely to choose it as most undesirable. CONCLUSION: Informing people of the change in LS or DA associated with health states before they appraise them is a feasible way to obtain informed preferences.

The Invention of WM382, a Highly Potent PMIX/X Dual Inhibitor toward the Treatment of Malaria.

Drug resistance to first-line antimalarials-including artemisinin-is increasing, resulting in a critical need for the discovery of new agents with novel mechanisms of action. In collaboration with the Walter and Eliza Hall Institute and with funding from the Wellcome Trust, a phenotypic screen of Merck's aspartyl protease inhibitor library identified a series of plasmepsin X (PMX) hits that were more potent than chloroquine. Inspired by a PMX homology model, efforts to optimize the potency resulted in the discovery of leads that, in addition to potently inhibiting PMX, also inhibit another essential aspartic protease, plasmepsin IX (PMIX). Further potency and pharmacokinetic profile optimization efforts culminated in the discovery of WM382, a very potent dual PMIX/X inhibitor with robust in vivo efficacy at multiple stages of the malaria parasite life cycle and an excellent resistance profile.

Activity of Tricyclic Pyrrolopyrimidine Gyrase B Inhibitor against Mycobacterium abscessus.

Tricyclic pyrrolopyrimidines (TPPs) are a new class of antibacterials inhibiting the ATPase of DNA gyrase. TPP8, a representative of this class, is active against Mycobacterium abscessus in vitro. Spontaneous TPP8 resistance mutations mapped to the ATPase domain of M. abscessus DNA gyrase, and the compound inhibited DNA supercoiling activity of recombinant M. abscessus enzyme. Further profiling of TPP8 in macrophage and mouse infection studies demonstrated proof-of-concept activity against M. abscessus ex vivo and in vivo.

A Rayleigh-Bénard convection instability analog in vibrated gas-fluidized granular particles.

Granular particles subject to both vertical gas flow and vertical vibration are shown experimentally to exhibit structured convection cells in a densely packed yet fluidized state without gas voids traveling through the particles. Continuum gas-granular simulations reproduce the phenomenon and demonstrate that the convection occurs due to buoyant force arising from a positive vertical gradient in bulk solid density competing with viscous force created by interparticle friction. Simulations further show that convection structures persist in a controllable manner when increasing system width.

Hierarchical Particle Approach for Co-Precipitated Amorphous Solid Dispersions for Use in Preclinical In Vivo Studies.

Amorphous solid dispersions (ASD) have become a well-established strategy to improve exposure for compounds with insufficient aqueous solubility. Of methods to generate ASDs, spray drying is a leading route due to its relative simplicity, availability of equipment, and commercial scale capacity. However, the broader industry adoption of spray drying has revealed potential limitations, including the inability to process compounds with low solubility in volatile solvents, inconsistent molecular uniformity of spray dried amorphous dispersions, variable physical properties across batches and scales, and challenges containing potent compounds. In contrast, generating ASDs via co-precipitation to yield co-precipitated amorphous dispersions (cPAD) offers solutions to many of those challenges and has been shown to achieve ASDs comparable to those manufactured via spray drying. This manuscript applies co-precipitation for early safety studies, developing a streamlined process to achieve material suitable for dosing as a suspension in conventional toxicity studies. Development targets involved achieving a rapid, safely contained process for generating ASDs with high recovery yields. Furthermore, a hierarchical particle approach was used to generate composite particles where the cPAD material is incorporated in a matrix of water-soluble excipients to allow for rapid re-dispersibility in the safety study vehicle to achieve a uniform suspension for consistent dosing. Adopting such an approach yielded a co-precipitated amorphous dispersion with comparable stability, thermal properties, and in vivo pharmacokinetics to spray dried amorphous materials of the same composition.

Dynamically structured bubbling in vibrated gas-fluidized granular materials.

The dynamics of granular materials are critical to many natural and industrial processes; granular motion is often strikingly similar to flow in conventional liquids. Food, pharmaceutical, and clean energy processes utilize bubbling fluidized beds, systems in which gas is flowed upward through granular particles, suspending the particles in a liquid-like state through which gas voids or bubbles rise. Here, we demonstrate that vibrating these systems at a resonant frequency can transform the normally chaotic motion of these bubbles into a dynamically structured configuration, creating reproducible, controlled motion of particles and gas. The resonant frequency is independent of particle properties and system size, and a simple harmonic oscillator model captures this frequency. Discrete particle simulations show that bubble structuring forms because of rapid, local transitions between solid-like and fluid-like behavior in the grains induced by vibration. Existing continuum models for gas-solid flows struggle to capture these fluid-solid transitions and thus cannot predict the bubble structuring. We propose a constitutive relationship for solids stress that predicts fluid-solid transitions and hence captures the experimental structured bubbling patterns. Similar structuring has been observed by oscillating gas flow in bubbling fluidized beds. We show that vibrating bubbling fluidized beds can produce a more ordered structure, particularly as system size is increased. The scalable structure and continuum model proposed here provide the potential to address major issues with scale-up and optimal operation, which currently limit the use of bubbling fluidized beds in existing and emerging technologies.

Inequality and Social Rank: Income Increases Buy More Life Satisfaction in More Equal Countries.

How do income and income inequality combine to influence subjective well-being? We examined the relation between income and life satisfaction in different societies, and found large effects of income inequality within a society on the relationship between individuals' incomes and their life satisfaction. The income-satisfaction gradient is steeper in countries with more equal income distributions, such that the positive effect of a 10% increase in income on life satisfaction is more than twice as large in a country with low income inequality as it is in a country with high income inequality. These findings are predicted by an income rank hypothesis according to which life satisfaction is derived from social rank. A fixed increment in income confers a greater increment in social position in a more equal society. Income inequality may influence people's preferences, such that in unequal countries people's life satisfaction is determined more strongly by their income.

A novel method for preparing stabilized amorphous solid dispersion drug formulations using acoustic fusion.

A diverse set of drug and polymer combinations have been effectively evaluated utilizing a newly developed method called acoustic fusion to form amorphous solid dispersions (ASD) on the mg-scale, indicating that this approach is a general procedure that can be applied for ASD drug formulations. We have demonstrated the effectiveness of this acoustic fusion process by generating amorphous solid dispersions of various BCS class 2 and 4 drug candidates, including torcetrapib, itraconazole, and lopinavir, with a variety of polymer systems, including HPMCAS (L, M, and H), copovidone, Soluplus®, PEG1500, Vitamin-E TPGS, Kolliphor EL, and Eudragit, etc. Formulations of these ASD drug products demonstrated significantly elevated solubility of the drug substance compared to the solubility of the crystalline form of the drug. Acoustic fusion products using the model drug torcetrapib in either HPMCAS-LF, copovidone + Vitamin-E TPGS, or Soluplus®, exhibited enhanced supersaturation solubility in aqueous buffer in vitro compared to the drug in crystalline form, indicating that the acoustic fusion process resulted in an amorphous solid dispersion state similar to those formed in spray drying (SD) or hot melt extrusion (HME) processes. In vivo dosing of formulations of the acoustic fusion products in a rat pharmacokinetic study at a dose level of 10 mg/kg resulted in an improvement in exposures of approximately 8-fold by AUC(0-24) in comparison to a conventional suspension formulation of the drug material in crystalline form, thus validating the efficiency of this novel acoustic fusion approach for elevating the bioperformance in preclinical studies.

Opportunities for Characterizing Geological Flows Using Magnetic Resonance Imaging.

Geological flows-from mudslides to volcanic eruptions-are often opaque and consist of multiple interacting phases. Scaled laboratory geological experiments using analog materials have often been limited to optical imaging of flow exteriors or ex situ measurements. Geological flows often include internal phase transitions and chemical reactions that are difficult to image externally. Thus, many physical mechanisms underlying geological flows remain unknown, hindering model development. We propose using magnetic resonance imaging (MRI) to enhance geosciences via non-invasive, in situ measurements of 3D flows. MRI is currently used to characterize the interior dynamics of multiphase flows, distinguishing between different chemical species as well as gas, liquid, and solid phases, while quantitatively measuring concentration, velocity, and diffusion fields. This perspective describes the potential of MRI techniques to image dynamics within scaled geological flow experiments and the potential of technique development for geological samples to be transferred to other disciplines utilizing MRI.

Dual Plasmepsin-Targeting Antimalarial Agents Disrupt Multiple Stages of the Malaria Parasite Life Cycle.

Artemisin combination therapy (ACT) is the main treatment option for malaria, which is caused by the intracellular parasite Plasmodium. However, increased resistance to ACT highlights the importance of finding new drugs. Recently, the aspartic proteases Plasmepsin IX and X (PMIX and PMX) were identified as promising drug targets. In this study, we describe dual inhibitors of PMIX and PMX, including WM382, that block multiple stages of the Plasmodium life cycle. We demonstrate that PMX is a master modulator of merozoite invasion and direct maturation of proteins required for invasion, parasite development, and egress. Oral administration of WM382 cured mice of P. berghei and prevented blood infection from the liver. In addition, WM382 was efficacious against P. falciparum asexual infection in humanized mice and prevented transmission to mosquitoes. Selection of resistant P. falciparum in vitro was not achievable. Together, these show that dual PMIX and PMX inhibitors are promising candidates for malaria treatment and prevention.

Valuing the Q in QALYs: Does providing patients' ratings affect population values?

OBJECTIVE: Quality-adjusted life years (QALYs) are used to measure the health benefits associated with treatments. QALYs are derived from objective mortality data weighted by assessments made by the general population of the impact on health-related quality of life associated with particular health states. In this study, a simple change is introduced to improve the validity of QALYs by giving raters information about how people living in the health states rate the health states. METHOD: Participants from the general population (N = 155) judged 3 health states using a standard valuation technique after being randomly allocated to 1 of 2 groups. The intervention group was given patients' mean ratings of their own health states from worst to best imaginable health (0-100 scale) before providing their valuations, while the control group was given this information only after providing their valuations. The participants in both groups also indicated whether patients' mean ratings were higher, broadly similar, or lower than they previously expected. RESULTS: When the mean ratings given by patients were higher (lower) than expected, participants in the intervention group provided significantly higher (lower) valuations than participants in the control group. These findings show that participants adjust their valuations of a health state in the direction of the appraisals of those experiencing that state. CONCLUSION: Insofar as policymakers are committed to valuing health states using valuations given by people from the general population, it is desirable to elicit more informed values by providing people with information on how patients rate those states. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Gravitational instabilities in binary granular materials.

The motion and mixing of granular media are observed in several contexts in nature, often displaying striking similarities to liquids. Granular dynamics occur in geological phenomena and also enable technologies ranging from pharmaceuticals production to carbon capture. Here, we report the discovery of a family of gravitational instabilities in granular particle mixtures subject to vertical vibration and upward gas flow, including a Rayleigh-Taylor (RT)-like instability in which lighter grains rise through heavier grains in the form of "fingers" and "granular bubbles." We demonstrate that this RT-like instability arises due to a competition between upward drag force increased locally by gas channeling and downward contact forces, and thus the physical mechanism is entirely different from that found in liquids. This gas channeling mechanism also generates other gravitational instabilities: the rise of a granular bubble which leaves a trail of particles behind it and the cascading branching of a descending granular droplet. These instabilities suggest opportunities for patterning within granular mixtures.

The Great Recession and subjective well-being: How did the life satisfaction of people living in the United Kingdom change following the financial crisis?

The financial crisis of 2007/08 precipitated a severe global economic downturn, typically referred to as the Great Recession. However, in the United Kingdom this period has been marked by limited change in national indicators of subjective well-being. We assessed the life satisfaction change in response to the Great Recession in a sample of British adults (N = 8,661). We first show that on average the life satisfaction change across the sample was limited. However, average effects may mask substantial amounts of heterogeneity in the data. We therefore explore beyond this average effect to determine whether there were disproportionate changes (losses and gains) in life satisfaction in key sub-groups of the population. We found that individuals experiencing unemployment, who lost income, were sick or disabled, experienced the greatest well-being reductions. Contrastingly the life satisfaction of many individuals did not greatly change following the Great Recession and for some it may have even improved. Our work highlights vulnerable groups that may need additional help during recession periods and also cautions against the over reliance on average measures of well-being.

Central bank interest rate decisions, household indebtedness, and psychiatric morbidity and distress: Evidence from the UK.

BACKGROUND: Central banks set economy-wide interest rates to meet exclusively economic objectives. There is a strong link between indebtedness and psychiatric morbidity at the individual level, with interest rates being an important factor determining ability to repay debt. However, no prior research has explored whether central bank interest rate changes directly influence mental health, nor whether this varies by levels of indebtedness. METHODS: We use British data (N = 93,255) to explore whether the Bank of England base-rate affected how perceived burden of non-mortgage debt (low, medium, and high) influenced psychiatric morbidity. Psychiatric morbidity was measured using the General Health Questionnaire (GHQ-12). Our primary outcome measure was a binary indicator of "psychiatric caseness" (>3 on a 0-12 scale). We also used the GHQ-12 as a continuous measure of distress. RESULTS: When interest rates are high (low) there is an increased (decreased) risk of psychiatric morbidity only among those with a high debt burden (b = 0.026, p =  0.02). This result was robust to alternative explanations. Thus a 1 percentage point base-rate increase is associated with a 2.6% increase that someone with a high debt burden will experience psychiatric morbidity. LIMITATIONS: Our study uses subjective indicators of debt burden. We were unable to determine the mechanism behind our effect. CONCLUSIONS: Changes in central bank interest rates to meet economic objectives pose a threat to mental health. Mental health support is needed for those in debt and central banks may need to consider how their decisions influence population mental health.