The receptor-binding domain (RBD) of the severe acute respiratory syndrome coronavirus 2s pike (S) protein playsacentral role in mediating the first step of virus infection to cause disease:v irus binding to angiotensin-converting enzyme 2( ACE2) receptors on human host cells.T herefore, S/RBD is an ideal target for blocking and neutralization therapies to prevent and treat coronavirus disease 2019 (COVID-19). Using at arget-based selection approach, we developed oligonucleotide aptamers containing ac onserved sequence motif that specifically targets S/RBD.S ynthetic aptamers had high binding affinity for S/RBD-coated virus mimics (K D % 7nM) and also blocked interaction of S/RBD with ACE2 receptors (IC 50 % 5nM). Importantly,a ptamers were able to neutralizeSprotein-expressing viral particles and prevent host cell infection, suggesting apromising COVID-19 therapys trategy.

The endocannabinoid 2-arachidonoylglycerol (2-AG) mediates activity-dependent depression of excitatory neurotransmission at central synapses; however, the molecular regulation of 2-AG synthesis is not well understood. Here we identify a novel functional interaction between the 2-AG synthetic enzyme diacylglycerol lipase-α (DGLα) and calcium/calmodulin dependent protein kinase II (CaMKII). Activated CaMKII interacts with the C-terminal domain of DGLα, phosphorylates two serine residues, and inhibits DGLα activity. Moreover, CaMKII inhibition augments short-term retrograde eCB signaling at striatal glutamatergic synapses. Consistent with an inhibitory role for CaMKII in synaptic 2-AG synthesis, in vivo genetic inhibition of CaMKII increases striatal DGL activity and basal 2-AG levels. Moreover, blockade of 2-AG breakdown using concentrations of JZL-184 that have no significant effect in wild type mice produces a hypo-locomotor response in mice with reduced CaMKII activity. These findings provide novel mechanistic insight into the molecular regulation of striatal eCB signaling with implications for physiological control of motor function.

The association of the receptor binding domain (RBD) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein with human angiotensin-converting enzyme 2 (hACE2) represents the first required step for cellular entry. SARS-CoV-2 has continued to evolve with the emergence of several novel variants, and amino acid changes in the RBD have been implicated with increased fitness and potential for immune evasion. Reliably predicting the effect of amino acid changes on the ability of the RBD to interact more strongly with the hACE2 can help assess the implications for public health and the potential for spillover and adaptation into other animals. Here, we introduce a two-step framework that first relies on 48 independent 4-ns molecular dynamics (MD) trajectories of RBD−hACE2 variants to collect binding energy terms decomposed into Coulombic, covalent, van der Waals, lipophilic, generalized Born solvation, hydrogen bonding, π−π packing, and self-contact correction terms. The second step implements a neural network to classify and quantitatively predict binding affinity changes using the decomposed energy terms as descriptors. The computational base achieves a validation accuracy of 82.8% for classifying single–amino acid substitution variants of the RBD as worsening or improving binding affinity for hACE2 and a correlation coefficient of 0.73 between predicted and experimentally calculated changes in binding affinities. Both metrics are calculated using a fivefold cross-validation test. Our method thus sets up a framework for screening binding affinity changes caused by unknown single– and multiple–amino acid changes offering a valuable tool to predict host adaptation of SARS-CoV-2 variants toward tighter hACE2 binding.

The receptor-binding domain (RBD) of the severe acute respiratory syndrome coronavirus 2s pike (S) protein playsacentral role in mediating the first step of virus infection to cause disease:v irus binding to angiotensin-converting enzyme 2( ACE2) receptors on human host cells.T herefore, S/RBD is an ideal target for blocking and neutralization therapies to prevent and treat coronavirus disease 2019 (COVID-19). Using at arget-based selection approach, we developed oligonucleotide aptamers containing ac onserved sequence motif that specifically targets S/RBD.S ynthetic aptamers had high binding affinity for S/RBD-coated virus mimics (K D % 7nM) and also blocked interaction of S/RBD with ACE2 receptors (IC 50 % 5nM). Importantly,a ptamers were able to neutralizeSprotein-expressing viral particles and prevent host cell infection, suggesting apromising COVID-19 therapys trategy.

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