Biology subjects

Georgiou, K.

Publications and source records attributed to Georgiou, K..

6 recordsLinked to original sources

bioRxiv2026

A brain-penetrant P2X7R antagonist mitigates Alzheimer's disease pathology

The ATP-gated P2X7 receptor (P2X7R) activates inflammatory signaling pathways in the central nervous system. In particular, P2X7Rs drive chronic glia-mediated neuroinflammation, which is increasingly recognized as a key contributor to Alzheimers disease, a neurodegenerative disorder that lacks effective disease-modifying therapies. Here we identify a potent and selective negative allosteric modulator of P2X7Rs with therapeutic potential. We synthesize a series of small molecules based on a polycyclic scaffold and confirm blood-brain barrier penetration by testing a radiolabeled analogue using positron emission tomography imaging. Through a structure-guided medicinal chemistry campaign centered on our scaffold, we identify four promising P2X7R antagonists. Of these, UB-ALT-P2 exhibits the most favorable safety profile, high oral bioavailability and robust brain penetration. High-resolution cryo-EM structures of UB-ALT-P2 bound to human, mouse, and rat P2X7Rs reveal a conserved antagonist binding mode with steric features that favor prolonged binding to human receptors. In the 5xFAD mouse model of AD, oral UB-ALT-P2 blunts weight loss, improves short- and long-term memory, reduces amyloid-{beta} plaque burden, lowers hyperphosphorylated tau, and diminishes oxidative and inflammatory markers. These results establish UB-ALT-P2 as a potent and safe P2X7R antagonist that can mitigate core AD pathologies, providing a compelling foundation for further development.

neuroscience↗

bioRxiv2025

Exploring polycyclic scaffolds as adamantane replacements in M2 channel inhibitors of Influenza A virus

The increasing resistance of influenza A viruses to adamantane-based antivirals underscores the need for new inhibitors targeting both wild-type (WT) and mutant M2 ion channels. Here, we report the synthesis and biological evaluation of polycyclic cage amines designed to replace the adamantane scaffold as M2 inhibitors. These include ring-contracted and ring-expanded analogues, evaluated both as primary amines and as aryl-/heteroaryl-substituted derivatives. Most of the polycyclic amines inhibited the WT M2 channel as demonstrated by electrophysiological assays. Among them, compound 10, a 3,4,8,9-tetramethyltetracyclo[4.4.0.03..0.]decan-1-amine, emerged as a triple blocker active against M2 WT, M2 L27F, and M2 V27A channels. In contrast, compound 6c, a noradamantane-isoxazole derivative, showed selective inhibition of the S31N mutant. Although no antiviral activity was observed against influenza A virus in infected cell assays, both compounds 6c and 10 displayed significant antiviral activity against human coronavirus 229E. Furthermore, compound 10 demonstrated favourable pharmacokinetic properties. MD simulations show that noradamantane 6c binds inside the M2 S31N pore, with its ammonium forming H-bonds to Asn31 and the isoxazole positioned near Val27, restricting water entry. In contrast, larger polycyclic amines likely cannot access the pore due to steric hindrance.

pharmacology and toxicology↗

bioRxiv2025

Continental-scale relationships of fine root and soil carbon stocks hold in grasslands but not forests

Increasing root carbon inputs into soils has been proposed as a solution to increasing soil organic carbon (SOC). However, while fine root carbon (FRC) inputs can increase SOC accrual in soils, FRC can also enhance SOC loss by stimulating microbial respiration and cause a net loss of SOC through priming. It remains unclear how SOC varies as a function of FRC at broad spatial scales and across ecosystems and depths. Here, we tested the relationship of SOC and FRC using data from 43 sites across the US National Ecological Observatory Network (NEON). We found that total stocks of SOC and FRC in the top 2 meters of soil were positively related with an across-ecosystem slope of 7 {+/-} 3 kg SOC m-2 per kg FRC m-2. However, grassland sites primarily drove this relationship. Grasslands had 15 {+/-} 2 kg SOC m-2 per kg FRC m-2, which is double the across-ecosystem slope. We used deviations from the standardized 1:1 relationship between FRC and SOC to infer whether ecosystems were net priming (indicated by observed SOC being lower than the 1:1 line) or SOC accruing (higher SOC than the 1:1 line). Grassland soils and especially their deep soil layers (>30 cm) showed primarily SOC accrual with increasing fine root abundance. Meanwhile, forest soils had high variability in whether increasing fine roots were associated with net SOC priming or accrual across both shallow and deeper soil layers. We found that in grasslands, FRC inputs are strongly related to SOC accrual, especially at depth and at sites with high moisture and clay content. In contrast, SOC-FRC relationships in forests remain difficult to characterize. Nevertheless, deep grassland soils may serve as optimal environments in which increasing FRC could lead to meaningful increases in SOC stocks.

ecology↗

bioRxiv2025

UB-MBX-46 is a potent and selective antagonist of the human P2X7 receptor developed by structure-based drug design

The P2X7 receptor is an ATP-gated ion channel that activates inflammatory pathways involved in diseases such as cancer, atherosclerosis, and neurodegeneration. However, despite the potential benefits of blocking overactive signaling, no P2X7 receptor antagonists have been approved for clinical use. Interspecies variation among existing antagonists has proven challenging, in part due to the dearth of molecular information on different receptor orthologs. Here, to identify distinct molecular features in the human receptor, we determine high-resolution cryo-EM structures of the full-length wild-type human P2X7 receptor in apo closed and ATP-bound open state conformations and draw comparisons with new and existing structures of other orthologs. We also report a cryo-EM structure of the human receptor in complex with an adamantane-based inhibitor, which we leverage, in conjunction with functional data and molecular dynamics simulations, to design a potent and selective antagonist with a unique polycyclic scaffold. Functional and structural analysis reveal how this optimized ligand, UB-MBX-46, interacts with the classical allosteric pocket of the human P2X7 receptor with picomolar potency and high selectivity, revealing its significant therapeutic potential.

biochemistry↗

bioRxiv2023

Contribution of carbon inputs to soil carbon accumulation cannot be neglected

In a recently published paper (1), the authors report that microbial carbon use efficiency (CUE) is the primary determinant of global soil organic carbon (SOC) storage and that the relative impact of plant carbon inputs on SOC is minor. While soil microbes undoubtedly play an important role in soil organic carbon cycling, we are concerned about the robustness of the approach taken by Tao et al. (1) and highlight potential biases in their analyses that may lead to misleading, model-dependent results.

ecology↗

bioRxiv2020

LAP2alpha maintains a mobile and low assembly state of A-type lamins in the nuclear interior

Lamins form stable filaments at the nuclear periphery in metazoans. Unlike B-type lamins, lamins A and C localize also in the nuclear interior, where they interact with lamin-associated polypeptide 2 alpha (LAP2). We show that lamin A in the nuclear interior is formed from newly expressed pre-lamin A during processing and from soluble mitotic mature lamins in a LAP2-independent manner. Binding of LAP2 to lamins A/C in the nuclear interior during interphase inhibits formation of higher order structures of lamin A/C in vitro and in vivo, keeping lamin A/C in a mobile low assembly state independent of lamin A/C S22 phosphorylation. Loss of LAP2 causes formation of larger, less mobile and biochemically stable lamin A/C structures in the nuclear interior, which reduce the mobility of chromatin. We propose that LAP2 is essential to maintain a mobile lamin A/C pool in the nuclear interior, which is required for proper nuclear functions.

cell biology↗