Biology subjects

Nazarova, A. L.

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

3 recordsLinked to original sources

bioRxiv2025

Development of Potent, Selective cPLA2 Inhibitors for Targeting Neuroinflammation in Alzheimer's Disease and Other Neurodegenerative Disorders

Chronic neuroinflammation plays a key role in the progression of Alzheimers disease (AD), and the cytosolic calcium-dependent phospholipase A2 (cPLA2) enzyme is a critical mediator of inflammatory lipid signaling pathways. Here we investigate the therapeutic potential of novel cPLA2 inhibitors in modulating neuroinflammation in AD. By leveraging the giga-scale V-SYNTHES 2.0 virtual screening in on-demand chemical space and conducting two rounds of optimization for potency and selectivity, we have identified BRI-50460, achieving an IC50 of 0.88 nM in cellular assays of cPLA2 activity. In vivo studies revealed favorable brain-to-plasma ratios, highlighting the ability of BRI-50460 to penetrate the central nervous system, potentially modulating neuroinflammatory pathways and restoring lipid homeostasis. In cultured astrocytes and neurons derived from human induced pluripotent stem cells, BRI-50460 mitigates the effects of amyloid beta 42 oligomers on cPLA2 activation, tau hyperphosphorylation, and synaptic and dendritic reduction. Our results suggest that small molecule inhibitors of the cPLA2 enzyme can modulate the downstream inflammatory lipid signaling pathways, offering a promising therapeutic strategy for AD and other neurodegenerative diseases.

neuroscience↗

bioRxiv2024

An opioid efficacy switch for reversible optical control of peripheral analgesia

The mu-opioid receptor (MOR) is a major target for the treatment of pain. However, opioids are prone to side effects which limit their effectiveness as analgesics and can lead to opioid use disorders or, even, lethal overdose. The systemic administration of opioid agonists makes it both very difficult to decipher their underlying circuit mechanisms of action and to limit drug action to specific receptor subpopulations to isolate therapeutic effects from adverse side effects. Here we design, synthesize, and characterize a reversibly photoswitchable morphinan agonist termed "azo-morphine-3" (AM-3) which interconverts from low to high efficacy in response to different wavelengths of light to enable optical control of MOR signaling. Cryo-EM structures of the low efficacy "trans" and high efficacy "cis" states of AM-3 bound to the MOR reveal distinct binding modes of the photoswitchable azobenzene moiety, each inducing unique structural dynamics, providing insight into the molecular basis of agonist efficacy. In mice, AM-3 drives reversible and repeatable optical control of anti-nociception with a reduced side effect profile owing to its restriction to the periphery and its ability to be locally activated at the site of pain.

pharmacology and toxicology↗

bioRxiv2024

Angiotensin-(1-5) is a Potent Endogenous Angiotensin AT2-Receptor Agonist

BackgroundThe renin-angiotensin system involves many more enzymes, receptors and biologically active peptides than originally thought. With this study, we investigated whether angiotensin-(1-5) [Ang-(1-5)], a 5-amino acid fragment of angiotensin II, has biological activity, and through which receptor it elicits effects. MethodsThe effect of Ang-(1-5) (1{micro}M) on nitric oxide release was measured by DAF-FM staining in human aortic endothelial cells (HAEC), or Chinese Hamster Ovary (CHO) cells stably transfected with the angiotensin AT2-receptor (AT2R) or the receptor Mas. A potential vasodilatory effect of Ang-(1-5) was tested in mouse mesenteric and human renal arteries by wire myography; the effect on blood pressure was evaluated in normotensive C57BL/6 mice by Millar catheter. These experiments were performed in the presence or absence of a range of antagonists or inhibitors or in AT2R-knockout mice. Binding of Ang-(1-5) to the AT2R was confirmed and the preferred conformations determined by in silico docking simulations. The signaling network of Ang-(1-5) was mapped by quantitative phosphoproteomics. ResultsKey findings included: (1) Ang-(1-5) induced activation of eNOS by changes in phosphorylation at Ser1177eNOS and Tyr657eNOS and thereby (2) increased NO release from HAEC and AT2R-transfected CHO cells, but not from Mas-transfected or non-transfected CHO cells. (3) Ang-(1-5) induced relaxation of preconstricted mouse mesenteric and human renal arteries and (4) lowered blood pressure in normotensive mice - effects which were respectively absent in arteries from AT2R-KO or in PD123319-treated mice and which were more potent than effects of the established AT2R-agonist C21. (5) According to in silico modelling, Ang-(1-5) binds to the AT2R in two preferred conformations, one differing substantially from where the first five amino acids within angiotensin II bind to the AT2R. (6) Ang-(1-5) modifies signaling pathways in a protective RAS-typical way and with relevance for endothelial cell physiology and disease. ConclusionsAng-(1-5) is a potent, endogenous AT2R-agonist.

pharmacology and toxicology↗