PAMAM-calix-dendrimers: Synthesis and Thiacalixarene Conformation Effect on DNA Binding.

A convenient method for the synthesis of the first generation PAMAM dendrimers based on the thiacalix[4]arene has been developed for the first time. Three new PAMAM-calix-dendrimers with the macrocyclic core in cone, partial cone, and 1,3-alternate conformations were obtained with high yields. The interaction of the obtained compounds with salmon sperm DNA resulted in the formation of the associates of the size up to 200 nm, as shown by the UV-Vis spectroscopy, DLS, and TEM. It was demonstrated by the CD method that the structure of the DNA did not undergo significant changes upon binding. The PAMAM-calix-dendrimer based on the macrocycle in cone conformation stabilized DNA and prevented its degradation.

The neutralization effect of montelukast on SARS-CoV-2 is shown by multiscale in silico simulations and combined in vitro studies.

Small molecule inhibitors have previously been investigated in different studies as possible therapeutics in the treatment of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). In the current drug repurposing study, we identified the leukotriene (D4) receptor antagonist montelukast as a novel agent that simultaneously targets two important drug targets of SARS-CoV-2. We initially demonstrated the dual inhibition profile of montelukast through multiscale molecular modeling studies. Next, we characterized its effect on both targets by different in vitro experiments including the enzyme (main protease) inhibition-based assay, surface plasmon resonance (SPR) spectroscopy, pseudovirus neutralization on HEK293T/hACE2+TMPRSS2, and virus neutralization assay using xCELLigence MP real-time cell analyzer. Our integrated in silico and in vitro results confirmed the dual potential effect of montelukast both on the main protease enzyme inhibition and virus entry into the host cell (spike/ACE2). The virus neutralization assay results showed that SARS-CoV-2 virus activity was delayed with montelukast for 20 h on the infected cells. The rapid use of new small molecules in the pandemic is very important today. Montelukast, whose pharmacokinetic and pharmacodynamic properties are very well characterized and has been widely used in the treatment of asthma since 1998, should urgently be completed in clinical phase studies and, if its effect is proved in clinical phase studies, it should be used against coronavirus disease 2019 (COVID-19).

Potential Novel Thioether-Amide or Guanidine-Linker Class of SARS-CoV-2 Virus RNA-Dependent RNA Polymerase Inhibitors Identified by High-Throughput Virtual Screening Coupled to Free-Energy Calculations.

SARS-CoV-2, or severe acute respiratory syndrome coronavirus 2, represents a new pathogen from the family of Coronaviridae that caused a global pandemic of COVID-19 disease. In the absence of effective antiviral drugs, research of novel therapeutic targets such as SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) becomes essential. This viral protein is without a human counterpart and thus represents a unique prospective drug target. However, in vitro biological evaluation testing on RdRp remains difficult and is not widely available. Therefore, we prepared a database of commercial small-molecule compounds and performed an in silico high-throughput virtual screening on the active site of the SARS-CoV-2 RdRp using ensemble docking. We identified a novel thioether-amide or guanidine-linker class of potential RdRp inhibitors and calculated favorable binding free energies of representative hits by molecular dynamics simulations coupled with Linear Interaction Energy calculations. This innovative procedure maximized the respective phase-space sampling and yielded non-covalent inhibitors representing small optimizable molecules that are synthetically readily accessible, commercially available as well as suitable for further biological evaluation and mode of action studies.

GSH-ZnS Nanoparticles Exhibit High-Efficiency and Broad-Spectrum Antiviral Activities via Multistep Inhibition Mechanisms.

Despite the good biocompatibility and antibacterial activity of zinc sulfide nanoparticles (ZnS NPs), whether they possess antiviral activity is still unclear. Here, GSH-modified ZnS NPs (GSH-ZnS NPs) were synthesized and their significant antiviral activity was demonstrated using the Arteriviridae family RNA virus, porcine reproductive and respiratory syndrome virus (PRRSV), as a model. Mechanistically, GSH-ZnS NPs were shown to reduce PRRSV-induced ROS production to prevent PRRSV multiplication, with no activating effect on the interferon (IFN) signal pathway, the first defense line against virus infection. Furthermore, isobaric tags for relative and absolute quantification (iTRAQ)-based quantitative proteomic analysis of GSH-ZnS NP-treated cells revealed the involvement of numerous crucial proteins in virus proliferation, with vitronectin (VTN) being confirmed as an efficient PRRSV antagonist here. Furthermore, GSH-ZnS NPs were found to have potent antiviral effects on the Herpesviridae family DNA virus, pseudorabies virus (PRV), the Coronaviridae family positive-sense RNA virus, porcine epidemic diarrhea virus (PEDV), and the Rhabdoviridae family negative-stranded RNA virus, vesicular stomatitis virus (VSV), indicating their broad-spectrum antiviral activity against viruses from different families with various genome types. Overall, GSH-ZnS NP is a prospective candidate for the development of antiviral nanomaterials and may serve as a model for investigation of potential host restriction factors in combination with proteomics.