Triazavirine supramolecular complexes as modifiers of the peptide oligomeric structure

Abstract

In this study we present molecular dynamics simulations of the antiviral drug triazavirine, that affects formation of amyloid-like fibrils of the model peptide (SI). According to our simulations, triazavirine is able to form linear supramolecular structures which can act as shields and prevent interactions between SI monomers. This model, as validated by simulations, provides an adequate explanation of triazavirine's mechanism of action as it pertains to SI peptide fibril formation.

A double-edged sword: supramolecular complexes of triazavirine display multicenter binding effects which influence aggregate formation

“…2 In the course of studies on TZV activity using model peptides by our colleague, Dr. Olga Alexandrovna Mirgorodskaya, an observation was made that the drug stimulates the precipitation of the peptide from solution. Because this observed TZV effect was contrary to what we previously documented when studying its effects on a peptide comprising an ionic self-complementary motif [5], [6], we decided to analyze the effect in detail. The formation of strong hydrogen bonds between arginine and TZV (mentioned in [5]) could explain aggregation of the generally hydrophobic peptide by a mechanism in which there is shielding of the electrostatic repulsion between arginines.…”

“…The simulation results showed that in the presence of self-organizing supramolecular chains of TZV, the pairwise distance between the centers of mass of the MLT molecules decreases (Figure 3a). It should be noted that some TZV molecules are strongly connected with MLT ( Figure 3b 8 It should be noted that in our earlier work [6], the antiaggregation effect of TZV chains on SI peptide (GDIRIDIRIDIRG) is also due to the interaction of TZV with positively charged a.a.r. The distances from the a.a.r.…”

“…The mixtures were centrifuged and the activity of MLT in supernatants was studied on erythrocytes isolated from healthy volunteers (Figure 1, f). 6 The membranolytic activity of MLT in the presence of TZV changed nearly instantaneously and only when TZV exceeded MLT by 30 or more fold (1:30, 1:60). Moreover, at ratios from 1:1 to 1:5, a small increase in the membranolytic activity of MLT was observed, while TZV itself did not act as a membrane protective agent at any of the concentrations tested.…”

COVID-19 Therapeutic Options Under Investigation

“…Despite the lack of any pre-clinical efficacy data and the absence of the drug target in SARS-CoV-2, clinical trials are underway in China to evaluate its effectiveness for moderate to severe COVID-19 pneumonia. Triazavirin, a guanine nucleotide analog, is currently being assessed in a multicenter randomized clinical trial despite that available data is limited to its antiviral activity against influenza viruses ( Kiselev et al., 2012 ; Shvetsov et al., 2018 ).…”

Study on SARS‐CoV‐2 inhibition of some potential drugs using molecular docking simulation

“…[6] Clevudine, also known under the trade names Levovir and Revovir, is an antiviral drug for hepatitis B treatment in South Korea and the Philippines. Triazavirin has been proved performing high efficacy towards influenza A and B, including the highly developed H 5 N 1 strain [7][8][9][10] in Russia. Because of the structural similarities between SARS-CoV-2 and H 5 N 1 , health officials are conducting studies on Triazavirin as a potential drug candidate to combat SARS-CoV-2.…”