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Amicoumacin-based prodrug development approach

V. Shmygarev, A. Yu Prokopenko,S. S. Terekhov,M. Yu Zakharova,M. A. Dubinnyi,I. Smirnov, S. S. Yampolsky, A. S. Isarkova

BULLETIN OF RUSSIAN STATE MEDICAL UNIVERSITY(2022)

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Abstract
Coronavirus disease COVID-19, caused by the SARS-CoV-2 virus, is highly contagious and has a severe morbidity. Providing care to patients with COVID-19 requires the development of new types of antiviral drugs. The aim of this work is to develop a prodrug for the treatment of coronavirus disease using the antibiotic Amicoumacin A (Ami), the mechanism of action of which is based on translation inhibition. Enzymatic hydrolysis of an inactivated prodrug by the SARS-CoV-2 main protease can lead to the release of the active Ami molecule and, as a consequence, the suppression of protein biosynthesis in infected cells. To test the proposed hypothesis, a five-stage synthesis of an inactivated analogue of Amicoumacin A was carried out. Its in vitro testing with the SARS-CoV-2 recombinant protease MPro showed a low percentage of hydrolysis. Further optimization of the peptide fragment of the inactivated analog recognized by the SARS-CoV-2 MPro protease may lead to an increase in proteolysis and the release of Amicoumacin A.
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Key words
translation, translation inhibitor, antiviral agents, prodrugs, inactivated amicoumacin derivatives
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