(+)-Usnic Acid and Its Derivatives as Inhibitors of a Wide Spectrum of SARS-CoV-2 Viruses

Abstract

In order to test the antiviral activity, a series of usnic acid derivatives were synthesized, including new, previously undescribed compounds. The activity of the derivatives against three strains of SARS-CoV-2 virus was studied. To understand the mechanism of antiviral action, the inhibitory activity of the main protease of SARS-CoV-2 virus was studied using the developed model as well as the antiviral activity against the pseudoviral system with glycoprotein S of SARS-CoV-2 virus on its surface. It was shown that usnic acid exhibits activity against three strains of SARS-CoV-2 virus: Wuhan, Delta, and Omicron. Compounds 10 and 13 also showed high activity against the three strains. The performed biological studies and molecular modeling allowed us to assume that the derivatives of usnic acid bind in the N-terminal domain of the surface glycoprotein S at the binding site of the hemoglobin decay metabolite.

Usnic acid based thiazole-hydrazones as multi-targeting inhibitors of a wide spectrum of SARS-CoV-2 viruses

“…Testing on an infectious virus allows us to understand whether the compound has activity against the specified virus, but it does not give an understanding of the mechanism of this agent action. Since the data obtained using infectious virus did not correlate directly with those obtained for the main viral protease 3CLPro and we 24 and other researchers 47 have previously shown that usnic acid derivatives can be the effective inhibitors of entry; our further efforts were focused on studying the biological properties of compounds using the pseudovirus system.…”

“…The N-terminal domain of the S-protein was considered as a potential biological target. It was shown 24 that a number of usnic acid derivatives could bind to the biliverdin site. 51 The choice of such a binding site was justified by a detailed study of the structure and function of the SARS-CoV-2 surface glycoprotein, as well as by a comparison of the pharmacophore profiles of the binding site and ligands.…”

“…In our previous study, (+)-usnic acid and its derivatives 2 and 3 obtained by minor modifications were shown to be active in the micromolar concentration range against three coronavirus variants (Wuhan, Delta, Omicron). 24 In that research, derivatives 2 and 3 (Fig. 2) were obtained and studied as inhibitors of SARS-CoV-2 virus of three strains.…”

Triterpenic Acid Amides as Potential Inhibitors of the SARS-CoV-2 Main Protease

“…Effective protease inhibitors were detected using this surrogate test system [18]. In addition, this surrogate model enabled us to elucidate the mechanism of antiviral action of effective SARS-CoV-2 inhibitors, based on natural usnic acid [19]. The inhibitory activity of the synthesized conjugates against the SARS-CoV-2 Mpro was studied in vitro using the previously developed FRET-based enzyme assay (Table 3).…”

Safety in Rats of a Novel Nasal Spray Formulation for the Prevention of Airborne Viral Infections

“…UA and remdesivir (a product recently approved for the treatment of COVID-19) showed a similar activity in a SARS-CoV-2 binding assay [ 44 ]. Finally, an in vitro study performed on Vero E6 cells showed a significant activity of UA against three different strains of SARS-CoV-2, namely Wuhan, Delta, and Omicron [ 45 ].…”