Biology subjects

Binder, T.

Publications and source records attributed to Binder, T..

3 recordsLinked to original sources

bioRxiv2026

A rational design strategy and validation for protease-resistant fusion-inhibitor antiviral peptides

Peptide-based fusion inhibitors are promising pharmaceuticals in the fight against enveloped viruses relying on membrane fusion for host infection. However, peptide therapeutic applications have long been hindered by their poor stability in vivo. Here, we discovered that peptide inhibitors with the wildtype sequence of the heptad repeat 2 (HR2) domain of the SARS-CoV-2 spike protein are efficiently cleaved by Transmembrane Protease, Serine 2 (TMPRSS2), a key protease involved in the SARS-CoV-2 virus-cell fusion pathway. We then identified the corresponding cleavage sites and designed three protease-resistant peptides using ranking based on deep mutational scanning and natural occurrence. The three candidates all exhibit inhibitory activity in a cell-cell fusion assay. A high-resolution cryo-EM structure of the top candidate, HR2-NHN, bound to its HR1 target reveals the molecular basis for its potent activity. The top candidate of the cell-based screening assay significantly improved efficacy relative to the wildtype peptide when administered 12 h before infection in both an authentic virus-cell infection assay and a mouse assay. More broadly, our results suggest that the design strategies for protease-resistant peptides could be applied to a broad spectrum of other enveloped viruses and pave the way for the development of safe, prophylactic antivirals that can be administered before exposure.

microbiology↗

bioRxiv2024

Saturated fatty acid-Coenzyme A supplementation restores neuronal energy levels and protein homeostasis in hereditary spastic paraplegia

Mitochondrial ATP production is fuelled by a fatty acid flux generated by phospholipase and triglyceride lipases in metabolically demanding tissues such as heart and liver, while the brain has long been believed to use almost solely glucose for energy. Phospholipase A1 enzyme DDHD2 is a major triglyceride lipase in the brain, and the loss of DDHD2 function results in a saturated free fatty acid (sFFA) imbalance and lipid droplet (LD) accumulation in the brain. The LD accumulation in neurons has been enigmatic as LDs are mainly considered to serve as a fuel storage. Here, we demonstrate that the loss of DDHD2 results in a mitochondrial respiratory dysfunction that leads to a significant decrease in ATP production and acetyl coenzyme A levels in neurons, even when the glycolytic breakdown of glycose occurs normally. Loss of DDHD2 also leads to a presynaptic defect as well as an imbalance in the global protein homeostasis in the neurons. These defects were rescued by external supplementation of the sFFA myristic acid coupled with its cofactor coenzyme A (Myr-CoA), indicating sFFA fuelling for neuronal {beta}-oxidation. We have thus discovered that the sFFAs released by the activity of DDHD2 play a central role in providing energy to fuel synaptic function. One Sentence SummaryFree fatty acids released by DDHD2 activity play a central role in maintaining neuronal energy levels and synaptic function.

neuroscience↗

bioRxiv2020

Sex-specific gut microbiota modulation of aversive conditioning and basolateral amygdala dendritic spine density

Gut microbiota influence numerous aspects of host biology, including brain structure and function. Growing evidence implicates gut microbiota in aversive conditioning and anxiety-related behaviors, but research has focused almost exclusively on males. To investigate sex-specific effects of gut dysbiosis on aversive learning and memory, adult female and male C57BL/6N mice were orally administered a moderate dose of non-absorbable antimicrobial medications (ATMs; neomycin, bacitracin, pimaricin) or a control over 10 days. Changes in gut microbiome composition were analyzed by 16S rRNA sequencing. Open field behavior, cued aversive learning, context recall, and cued recall were assessed. Following behavioral testing, the morphology of basolateral amygdala (BLA) principal neuron dendrites and spines was characterized. Results revealed that ATMs induced distinct but overlapping patterns of gut dysbiosis across sex, with stronger effects in females. There were also sex-specific effects on behavior and neuroanatomy. Treated males but not females exhibited altered locomotor and anxiety-like behavior in the novel open field test. Treated females but not males showed impairments in aversive memory acquisition and cued recall. Context recall remained intact in both sexes, as did dendritic structure of BLA principal neurons. However, ATMs exerted sex-specific effects on spine density. A second experiment was conducted to isolate gut perturbation to cued recall. Results revealed no effect of ATMs on recall of a previously consolidated fear memory, suggesting that gut dysbiosis preferentially impacts aversive learning. These data shed new light on how gut microbiota interact with sex to influence aversive conditioning, anxiety-like behavior, and BLA dendritic spine architecture. SignificanceGut microbiota can influence brain function and behavior, including trauma and anxiety-related disorders. Although these disorders disproportionately affect women, preclinical research has focused almost exclusively on male rodent models. We investigated the impact of antimicrobial administration on gut microbiome structure, aversive conditioning, open field behavior, and basolateral amygdala principal neuron morphology in female and male mice. Results showed that treatment exerted wide-ranging effects, many of which were sex-specific. Our findings underscore the importance of studying sex differences and support a role for microbial modulation of aversive learning, anxiety-like behavior, and amygdala spine patterning.

neuroscience↗