2022 / 06

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DOI: 10.24075/brsmu.2022.073

ORIGINAL RESEARCH

Amicoumacin-based prodrug development approach

Shmygarev VI1, Prokopenko YuA1, Terekhov SS1, Zakharova MYu1, Dubinny MA1, Smirnov IV1, Yampolsky IV1,2, Tsarkova AS1,2
About authors

1 Shemyakin and Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow, Russia

2 Pirogov Russian National Research Medical University, Moscow, Russia

Correspondence should be addressed: Alexandra Sergeevna Tsarkova
st. Miklukho-Maklaya, 16/10, Moscow, 117997, Russia; moc.liamg@avokrastla

About paper

Funding: the work was supported by the grant № 075-15-2021-1049 from the Ministry of Science and Higher Education of the Russian Federation.

Contribution of the authors: Yu. A. Prokopenko — development and isolation of Amikoumacin; V. I. Shmygarev — complete synthesis of an inactivated analog of Amikoumacin A; S. S. Terekhov, M. Yu. Zakharova — in vitro experiments with MPro protease; M. A. Dubinny — NMR spectroscopy and data analysis; A. S. Tsarkova — literature analysis, data processing, article writing; I. V. Yampolsky, I. V. Smirnov - general project management.

Compliance with ethical standards: the work was carried out in compliance with the principles of the Declaration of Helsinki of the World Medical Association.

Received: 2022-11-15 Accepted: 2022-12-18 Published online: 2022-12-30
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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.

Keywords: antiviral drugs, translation, translation inhibitor, prodrugs, inactivated amicoumacin derivatives

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