Biology subjects

Turcu, A. L.

Publications and source records attributed to Turcu, A. L..

3 recordsLinked to original sources

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

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↗

bioRxiv2024

Memantine Inhibits Calcium-Permeable AMPA Receptors

Memantine is an US Food and Drug Administration (FDA) approved drug that selectively inhibits NMDA-subtype ionotropic glutamate receptors (NMDARs) for treatment of dementia and Alzheimers. NMDARs enable calcium influx into neurons and are critical for normal brain function. However, increasing evidence shows that calcium influx in neurological diseases is augmented by calcium-permeable AMPA-subtype ionotropic glutamate receptors (AMPARs). Here, we demonstrate that these calcium-permeable AMPARs (CP-AMPARs) are inhibited by memantine. Electrophysiology unveils that memantine inhibition of CP-AMPARs is dependent on their calcium permeability and the presence of their neuronal auxiliary subunit transmembrane AMPAR regulatory proteins (TARPs). Through cryo-electron microscopy we elucidate that memantine blocks CP-AMPAR ion channels in a unique mechanism of action from NMDARs. Furthermore, we demonstrate that memantine reverses a gain of function AMPAR mutation found in a patient with a neurodevelopmental disorder and inhibits CP-AMPARs in nerve injury. Our findings alter the paradigm for the memantine mechanism of action and provide a blueprint for therapeutic approaches targeting CP-AMPARs.

biophysics↗