PROTAC-attractive site as a new target for suppressing P-glycoprotein activity.

P-glycoprotein (P-gp) plays an important role in the rapid release of various small molecule substances from the cell. In turn, inhibition of this efflux transporter is an attractive strategy for both overcoming chemoresistance and facilitating oral absorption of drugs or CNS drug delivery. In this work, we adopt an approach typical for PROteolysis Targeting Chimera (PROTAC), which is based on the artificial drawing together of the target protein to E3 ubiquitin ligase, to P-gp.

Rational Design Problematics of Peptide Nucleic Acids as SARS-CoV-2 Inhibitors.

The use of viral protein inhibitors has shown to be insufficiently effective in the case of highly variable SARS-CoV-2. In this work, we examined the possibility of designing agents that bind to a highly conserved region of coronavirus (+)RNA. We demonstrated that while the design of antisense RNAs is based on the complementary interaction of nitrogenous bases, it is possible to use semirigid docking methods in the case of unnatural peptide nucleic acids.

A Visual Compendium of Principal Modifications within the Nucleic Acid Sugar Phosphate Backbone.

Nucleic acid chemistry is a huge research area that has received new impetus due to the recent explosive success of oligonucleotide therapy. In order for an oligonucleotide to become clinically effective, its monomeric parts are subjected to modifications. Although a large number of redesigned natural nucleic acids have been proposed in recent years, the vast majority of them are combinations of simple modifications proposed over the past 50 years.

Ubiquitin recruiting chimera: more than just a PROTAC.

Ubiquitinylation of protein substrates results in various but distinct biological consequences, among which ubiquitin-mediated degradation is most well studied for its therapeutic application. Accordingly, artificially targeted ubiquitin-dependent degradation of various proteins has evolved into the therapeutically relevant PROTAC technology. This tethered ubiquitinylation of various targets coupled with a broad assortment of modifying E3 ubiquitin ligases has been made possible by rational design of bi-specific chimeric molecules that bring these proteins in proximity.