The coronavirus disease 2019 (COVID-19) pandemic is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a recently emerged human coronavirus. COVID-19 vaccines have proven to ...be successful in protecting the vaccinated from infection, reducing the severity of disease, and deterring the transmission of infection. However, COVID-19 vaccination faces many challenges, such as the decline in vaccine-induced immunity over time, and the decrease in potency against some SARS-CoV-2 variants including the recently emerged Omicron variant, resulting in breakthrough infections. The challenges that COVID-19 vaccination is facing highlight the importance of the discovery of antivirals to serve as another means to tackle the pandemic. To date, neutralizing antibodies that block viral entry by targeting the viral spike protein make up the largest class of antivirals that has received US FDA emergency use authorization (EUA) for COVID-19 treatment. In addition to the spike protein, other key targets for the discovery of direct-acting antivirals include viral enzymes that are essential for SARS-CoV-2 replication, such as RNA-dependent RNA polymerase and proteases, as judged by US FDA approval for remdesivir, and EUA for Paxlovid (nirmatrelvir + ritonavir) for treating COVID-19 infections. This review presents an overview of the current status and future direction of antiviral drug discovery for treating SARS-CoV-2 infections, covering important antiviral targets such as the viral spike protein, non-structural protein (nsp) 3 papain-like protease, nsp5 main protease, and the nsp12/nsp7/nsp8 RNA-dependent RNA polymerase complex.
Human activities may impact animal habitat and resource use, potentially influencing contemporary evolution in animals. In the United Kingdom, COVID-19 lockdown restrictions resulted in sudden, ...drastic alterations to human activity. We hypothesized that short-term daily and long-term seasonal changes in human mobility might result in changes in bird habitat use, depending on the mobility type (home, parks and grocery) and extent of change. Using Google human mobility data and 872 850 bird observations, we determined that during lockdown, human mobility changes resulted in altered habitat use in 80% (20/25) of our focal bird species. When humans spent more time at home, over half of affected species had lower counts, perhaps resulting from the disturbance of birds in garden habitats. Bird counts of some species (e.g. rooks and gulls) increased over the short term as humans spent more time at parks, possibly due to human-sourced food resources (e.g. picnic refuse), while counts of other species (e.g. tits and sparrows) decreased. All affected species increased counts when humans spent less time at grocery services. Avian species rapidly adjusted to the novel environmental conditions and demonstrated behavioural plasticity, but with diverse responses, reflecting the different interactions and pressures caused by human activity.
A severe marine heat wave (MHW) persisted in the California Current ecosystem from 2014 through 2016. The MHW featured record-high sea surface temperatures in 2015, with 2014 to 2016 being the ...warmest 3 yr period on record. Our decade-long (2010-2019) breeding and diet monitoring of the rhinoceros auklet Cerorhinca monocerata , a burrow-nesting seabird, at significant breeding colonies on Destruction Island (California Current) and Protection Island (Salish Sea) allowed us to compare reproductive and dietary responses to this MHW. Although the colonies are relatively close to each other, and their reproductive output is, on average, similar, the auklets’ responses to the MHW differed. At Destruction Island, burrow occupancy rates were lower during the MHW (0.54 ± 0.02 vs. 0.61 ± 0.02 mean ± SE in non-MHW years), suggesting that birds skipped breeding, but fledging success rates did not differ (0.85 ± 0.02 vs. 0.89 ± 0.03). At Protection Island, burrow occupancy remained at non-MHW levels (0.72 ± 0.02 vs. 0.69 ± 0.02), but reproductive success declined (0.71 ± 0.03 vs. 0.82 ± 0.02). Chick provisioning also showed different patterns. The energy (kJ) per bill load at Destruction Island showed no clear MHW effect, while at Protection Island, it was reduced. At the same time, bill-load prey item count rose at Protection Island, indicating increased foraging effort and/or a reduction in diet quality. Our results further suggest rhinoceros auklets may be more resilient than other seabird species to major climate perturbations. However, with MHWs predicted to become more frequent and severe, the auklets’ ability to maintain these levels of breeding success will be tested.
Conservation of seabirds in remote polar regions requires accurate information on the location of breeding sites, which is often limited by logistical constraints of surveying large areas. On the ...Antarctic Peninsula, many seabird colonies are visited briefly but regularly by commercial cruise vessels, a platform from which we were able to collect presence/absence data on the entire community of seabirds. We used a multistate occupancy model, accounting for limited detection during surveys, to estimate the probability of presence and breeding of all 16 species native to the area. Our results provide a much clearer view than that was previously available of how avian diversity is distributed across the region’s network of multi-species colonies and reveals species-specific differences in the effect of sea-ice concentration and site fidelity on breeding probability. Several breeding sites host an unusually large number of breeding species, but these known richness hotspots are scattered throughout the region and we were unable to identify any clear gradients in species richness that might explain why some sites are so species rich. While accounting for detection failure accelerates the pace of reliable inference on species occupancy, we find that as many as ten years of repeated visits are often required to fully catalog the seabird richness at bare rock sites along the Antarctic Peninsula. This work highlights the challenges of identifying high priority sites for special protection or management and the importance for continued surveys, even at nominally well-studied locations.
The COVID-19 pandemic resulted in extraordinary declines in human mobility, which, in turn, may affect wildlife. Using records of more than 4.3 million birds observed by volunteers from March to May ...2017–2020 across Canada and the United States, we found that counts of 66 (80%) of 82 focal bird species changed in pandemic-altered areas, usually increasing in comparison to prepandemic abundances in urban habitat, near major roads and airports, and in counties where lockdowns were more pronounced or occurred at the same time as peak bird migration. Our results indicate that human activity affects many of North America’s birds and suggest that we could make urban spaces more attractive to birds by reducing traffic and mitigating the disturbance from human transportation after we emerge from the pandemic.
Many productive ocean ecosystems are also highly variable, resulting in complex trophic interactions. We analyzed interannual patterns in the diet of a seabird, the common murreUria aalge, in a ...region of high oceanographic productivity, the northern California Current, to investigate how these top predators adjust their chick provisioning to cope with environmental variability. Murres relied chiefly on Pacific herringClupea harengus pallasiand surf smeltHypomesus pretiosusto provision chicks, although they regularly returned 8 other fish taxa. Provisioning success was measured by the energy return rate to chicks, which in turn was disarticulated into energy per meal (quality) and meal delivery rate (quantity). Parents exhibited ‘compensation’ during 2 years in which smaller, low quality prey were returned more quickly than in years with normal (i.e. ‘good’) provisioning. Despite the increased delivery rate, energy return rates were still lower in ‘compensation’ vs. ‘good’ years. The lowest energy return rates occurred in 3 ‘poor’ years, during which ocean productivity was also depressed. Our results suggest that murres in this system have the ability to shift provisioning strategies to deal with some variability in prey resources, but not when limited by exceptionally poor environmental conditions.
Biological invasions of aquatic systems disrupt ecological communities, and cause major changes in diversity and ecosystem function. The Laurentian Great Lakes of North America have been dramatically ...altered by such invasions, especially zebra (Dreissena polymorpha) and quagga (D. rostriformis bugensis) mussels. Responses to mussel invasions have included increased water clarity, and decreased chlorophyll and phytoplankton abundance. Although not all systems have responded similarly, in general, mussels have changed nutrient dynamics and physical habitat conditions. Therefore examination of different impacts can help us further understand mechanisms that underlie ecosystem responses to biological invasions. To aid our understanding of ecosystem impacts, we sampled established locations along a well-studied trophic gradient in Green Bay, Lake Michigan, after the 1993 zebra mussel invasion. A strong trophic gradient remained during the period sampled after the mussel invasion (2000-2012). However, mean summer chlorophyll increased and other measures of phytoplankton biomass (microscope and electronic cell counting) did not change significantly. Multivariate analyses of phytoplankton community structure demonstrate a significant community shift after the invasion. Cyanobacteria increased in dominance, with Microcystis becoming the major summer taxon in lower Green Bay. Diatom diversity and abundance also increased and Chlorophyta became rare. Phytoplankton responses along the trophic gradient of Green Bay to zebra mussel invasion highlight the importance of mussel effects on nutrient dynamics and phytoplankton diversity and function.
Mass balance, metabolism, and excretion of ABT-126, an
7 neuronal acetylcholine receptor agonist, were characterized in healthy male subjects (
= 4) after a single 100-mg (100
Ci) oral dose. The ...total recovery of the administered radioactivity was 94.0% (±2.09%), with 81.5% (±10.2%) in urine and 12.4% (±9.3%) in feces. Metabolite profiling indicated that ABT-126 had been extensively metabolized, with 6.6% of the dose remaining as unchanged parent drug in urine. Parent drug accounted for 12.2% of the administered radioactivity in feces. The primary metabolic transformations of ABT-126 involved aza-adamantane
-oxidation (M1, 50.3% in urine) and aza-adamantane
-glucuronidation (M11, 19.9% in urine). M1 and M11 were also major circulating metabolites, accounting for 32.6% and 36.6% of the drug-related material in plasma, respectively. These results demonstrated that ABT-126 is eliminated primarily by hepatic metabolism, followed by urinary excretion. Enzymatic studies suggested that M1 formation is mediated primarily by human liver flavin-containing monooxygenase (FMO)3 and, to a lesser extent, by human kidney FMO1; M11 is generated mainly by human uridine 5'-diphospho-glucuronosyltransferase (UGT) 1A4, whereas UGT 2B10 also contributes to ABT-126 glucuronidation. Species-dependent formation of M11 was observed in hepatocytes; M11 was formed in human and monkey hepatocytes, but not in rat and dog hepatocytes, suggesting that monkeys constitute an appropriate model for predicting the fate of compounds undergoing significant
-glucuronidation. M1 and M11 are not expected to have clinically relevant on- or off-target pharmacologic activities. In summary, this study characterized ABT-126 metabolites in the circulation and excreta and the primary elimination pathways of ABT-126 in humans.
Mass balance, metabolism, and excretion of ABT-126, an α7 neuronal acetylcholine receptor agonist, were characterized in healthy male subjects (n = 4) after a single 100-mg (100 μCi) oral dose. The ...total recovery of the administered radioactivity was 94.0% (±2.09%), with 81.5% (±10.2%) in urine and 12.4% (±9.3%) in feces. Metabolite profiling indicated that ABT-126 had been extensively metabolized, with 6.6% of the dose remaining as unchanged parent drug in urine. Parent drug accounted for 12.2% of the administered radioactivity in feces. The primary metabolic transformations of ABT-126 involved aza-adamantane N-oxidation (M1, 50.3% in urine) and aza-adamantane N-glucuronidation (M11, 19.9% in urine). M1 and M11 were also major circulating metabolites, accounting for 32.6% and 36.6% of the drug-related material in plasma, respectively. These results demonstrated that ABT-126 is eliminated primarily by hepatic metabolism, followed by urinary excretion. Enzymatic studies suggested that M1 formation is mediated primarily by human liver flavin-containing monooxygenase (FMO)3 and, to a lesser extent, by human kidney FMO1; M11 is generated mainly by human uridine 5′-diphospho-glucuronosyltransferase (UGT) 1A4, whereas UGT 2B10 also contributes to ABT-126 glucuronidation. Species-dependent formation of M11 was observed in hepatocytes; M11 was formed in human and monkey hepatocytes, but not in rat and dog hepatocytes, suggesting that monkeys constitute an appropriate model for predicting the fate of compounds undergoing significant N-glucuronidation. M1 and M11 are not expected to have clinically relevant on- or off-target pharmacologic activities. In summary, this study characterized ABT-126 metabolites in the circulation and excreta and the primary elimination pathways of ABT-126 in humans.
Cystic fibrosis (CF) is a genetic disorder that affects multiple tissues and organs. CF is caused by mutations in the CFTR gene, resulting in insufficient or impaired cystic fibrosis transmembrane ...conductance regulator (CFTR) protein. The deletion of phenylalanine at position 508 of the protein (F508del-CFTR) is the most common mutation observed in CF patients. The most effective treatments of these patients employ two CFTR modulator classes, correctors and potentiators. CFTR correctors increase protein levels at the cell surface; CFTR potentiators enable the functional opening of CFTR channels at the cell surface. Triple-combination therapies utilize two distinct corrector molecules (C1 and C2) to further improve the overall efficacy. We identified the need to develop a C2 corrector series that had the potential to be used in conjunction with our existing C1 corrector series and provide robust clinical efficacy for CF patients. The identification of a pyrrolidine series of CFTR C2 correctors and the structure–activity relationship of this series is described. This work resulted in the discovery and selection of (2S,3R,4S,5S)-3-(tert-butyl)-4-((2-methoxy-5-(trifluoromethyl)pyridin-3-yl)methoxy)-1-((S)-tetrahydro-2H-pyran-2-carbonyl)-5-(o-tolyl)pyrrolidine-2-carboxylic acid (ABBV/GLPG-3221), which was advanced to clinical trials.
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