Mapping respiratory syncytial virus fusion protein interactions with the receptor IGF1R and the impact of alanine-scanning mutagenesis on viral infection.

Respiratory syncytial virus (RSV) has two main surface glycoproteins, the attachment glycoprotein (G) and the fusion (F) protein, which together mediate viral entry. Attachment is mediated by the RSV-G protein, while the RSV-F protein makes specific contact with the cellular insulin-like growth factor 1 receptor (IGF1R). This interaction leads to IGF1R activation and initiates a signalling cascade that calls the co-receptor, nucleolin, from the nucleus to the cell surface, where it can trigger viral fusion. We performed molecular docking analysis, which provided a potential set of 35 residues in IGF1R that may be important for interactions with RSV-F. We used alanine-scanning mutagenesis to generate IGF1R mutants and assessed their abundance and maturation, as well as the effect of mutation on RSV infection. We identified several mutations that appear to inhibit IGF1R maturation; but surprisingly, these mutations had no significant effect on RSV infection. This suggests that maturation of IGF1R may not be required for RSV infection. Additionally, we identified one residue, S788, that, when mutated, significantly reduced RSV infection. Further analysis revealed that this mutation disrupted a hydrogen bonding network that may be important for both IGF1R maturation and RSV infection.

Structure-Based Discovery of Allosteric Inhibitors Targeting a New Druggable Site in the Respiratory Syncytial Virus Polymerase.

Respiratory syncytial virus (RSV) is a major cause of severe lower respiratory infections for which effective treatment options remain limited. Herein, we employed a computational structure-based design strategy aimed at identifying potential targets for a new class of allosteric inhibitors. Our investigation led to the discovery of a previously undisclosed allosteric binding site within the RSV polymerase, the large (L) protein. This discovery was achieved through a combination of virtual screening and molecular dynamics simulations. Subsequently, we identified two inhibitors, 6a and 10b, which both exhibited promising antiviral activity in the low micromolar range. Resistance profiling revealed a distinctive pattern in how RSV evaded treatment with this class of inhibitors. This pattern strongly suggested that this class of small molecules was targeting a new binding site in the RSV L protein, aligning with the computational predictions made in our study. This study paves the way for the development of more potent inhibitors for combating RSV infections by targeting a new druggable pocket within the RdRp which does not overlap with previously known resistance sites.

The Effects of Astaxanthin on Cognitive Function and Neurodegeneration in Humans: A Critical Review.

Oxidative stress is a key contributing factor in neurodegeneration, cognitive ageing, cognitive decline, and diminished cognitive longevity. Issues stemming from oxidative stress both in relation to cognition and other areas, such as inflammation, skin health, eye health, and general recovery, have been shown to benefit greatly from antioxidant use. Astaxanthin is a potent antioxidant, which has been outlined to be beneficial for cognitive function both in vitro and in vivo. Given the aforementioned promising effects, research into astaxanthin with a focus on cognitive function has recently been extended to human tissue and human populations. The present critical review explores the effects of astaxanthin on cognitive function and neurodegeneration within human populations and samples with the aim of deciphering the merit and credibility of the research findings and subsequently their potential as a basis for therapeutic use. Implications, limitations, and areas for future research development are also discussed. Key findings include the positive impacts of astaxanthin in relation to improving cognitive function, facilitating neuroprotection, and slowing neurodegeneration within given contexts.

The domestication of SARS-CoV-2 into a seasonal infection by viral variants.

Introduction: The COVID-19 pandemic was caused by the zoonotic betacoronavirus SARS-CoV-2. SARS-CoV-2 variants have emerged due to adaptation in humans, shifting SARS-CoV-2 towards an endemic seasonal virus. We have termed this process 'virus domestication'. Methods: We analyzed aggregate COVID-19 data from a publicly funded healthcare system in Canada from March 7, 2020 to November 21, 2022. We graphed surrogate calculations of COVID-19 disease severity and SARS-CoV-2 variant plaque sizes in tissue culture. Results and Discussion: Mutations in SARS-CoV-2 adapt the virus to better infect humans and evade the host immune response, resulting in the emergence of variants with altered pathogenicity. We observed a decrease in COVID-19 disease severity surrogates after the arrival of the Delta variant, coinciding with significantly smaller plaque sizes. Overall, we suggest that SARS-CoV-2 has become more infectious and less virulent through viral domestication. Our findings highlight the importance of SARS-CoV-2 vaccination and help inform public policy on the highest probability outcomes during viral pandemics.