Spectrum of antiviral activity of 4-aminopyrimidine -oxides against a broad panel of tick-borne encephalitis virus strains.

Tick-borne encephalitis is an important human arbovirus neuroinfection spread across the Northern Eurasia. Inhibitors of tick-borne encephalitis virus (TBEV) strain Absettarov, presumably targeting E protein -octyl-β-d-glucoside (β-OG) pocket, were reported earlier. In this work, these inhibitors were tested against seven strains representing three main TBEV subtypes.

Ivermectin inhibits HSP27 and potentiates efficacy of oncogene targeting in tumor models.

HSP27 is highly expressed in, and supports oncogene addiction of, many cancers. HSP27 phosphorylation is a limiting step for activation of this protein and a target for inhibition, but its highly disordered structure challenges rational structure-guided drug discovery. We performed multistep biochemical, structural, and computational experiments to define a spherical 24-monomer complex composed of 12 HSP27 dimers with a phosphorylation pocket flanked by serine residues between their N-terminal domains.

Tick-borne flavivirus reproduction inhibitors based on isoxazole core linked with adamantane.

Infections caused by flaviviruses pose a huge threat for public health all over the world. The search for therapeutically relevant compounds targeting tick-borne flaviviruses requires the exploration of novel chemotypes. In the present work a large series of novel polyfunctionalized isoxazole derivatives bearing substituents with various steric and electronic effects was obtained by our unique versatile synthetic procedure and their antiviral activity against tick-borne encephalitis, Omsk hemorrhagic fever, and Powassan viruses was studied in vitro.

Computer-Aided Discovery of Small Molecule Inhibitors of Transcriptional Activity of TLX (NR2E1) Nuclear Receptor.

Orphan nuclear receptor TLX (NR2E1) plays a critical role in the regulation of neural stem cells (NSC) as well as in the development of NSC-derived brain tumors. In the last years, new data have emerged implicating TLX in prostate and breast cancer. Therefore, inhibitors of TLX transcriptional activity may have a significant impact on the treatment of several critical malignancies.

Synthesis and assessment of 4-aminotetrahydroquinazoline derivatives as tick-borne encephalitis virus reproduction inhibitors.

Tick-borne encephalitis virus (TBEV) belonging to Flavivirus genus causes severe infection in humans. The search for therapeutically relevant compounds targeting TBEV requires the exploration of novel chemotypes. A versatile synthesis of previously unknown 4-aminopyrimidines and 4-aminopyrimidine N-oxides based on a fluorosubstituted heterocyclic core is described.

Interaction of Flaviviruses with Reproduction Inhibitors Binding in β-OG Pocket: Insights from Molecular Dynamics Simulations.

Flaviviral diseases, including dengue fever, West Nile fever, yellow fever, tick-borne encephalitis, Omsk haemorrhagic fever, and Powassan encephalitis, threaten human health all over the world. Lack of effective antivirals targeting replication cycle of flaviviruses makes the search of such compounds a challenging task. Recently we have identified a reproduction inhibitor effective against tick-borne encephalitis virus and Powassan virus (POWV) (ACS Med.

Inhibitors of tick-borne flavivirus reproduction from structure-based virtual screening.

Flaviviruses form a large family of enveloped viruses affecting millions of people over the world. To date, no specific therapy was suggested for the infected people, making the treatment exclusively symptomatic. Several attempts were performed earlier for the design of fusion inhibitors for mosquito-borne flaviviruses, whereas for the tick-borne flaviviruses such design had not been performed.