Amicoumacin analogs for specific SARS-CoV 2 targeting

ABSTRACT

The pandemics of SARS-CoV 2 dramatically influenced the field of virology challenging for new antiviral drugs with alternative modes of actions. Translation machinery represents an attractive target for new antivirals. In this study, the antibiotic amicoumacin (Ami) was used for the development of a prodrug against SARS-CoV 2. Naturally, Ami is produced by probiotic Bacillus pumilus strains mediating their antimicrobial activity. Ami is a particularly potent translational inhibitor both in proand eukaryotes. We hypothesize that delivery of inactivated Ami prodrug to infected cells will result in the release of the active molecule by cleaving the precursor by the Mpro protease resulting in the inhibition of translation. However, Ami is rapidly hydrolyzed into inactive products under physiological conditions. A panel of Ami derivatives was synthesized to obtain stable Ami analogs. A panel of Ami analogs demonstrated increased stability in aqueous solutions while retaining antibiotic activity. The introduction of substituted amides and hydrazides increased the stability of the Ami molecule in aqueous solution, while the reasonable antibiotic activity was retained. Ami analogs provide a promising tool for translation machinery targeting and drug development.