Abstract
A molecular umbrella composed of two O-sulfated cholic acid residues was applied for the construction of conjugates with cispentacin, containing a “trimethyl lock” (TML) or o-dithiobenzylcarbamoyl moiety as a cleavable linker. Three out of five conjugates demonstrated antifungal in vitro activity against C. albicans and C. glabrata but not against C. krusei, with MIC90 values in the 0.22–0.99 mM range and were not hemolytic. Antifungal activity of the most active conjugate 24c, containing the TML–pimelate linker, was comparable to that of intact cispentacin. A structural analogue of 24c, containing the Nap-NH2 fluorescent probe, was accumulated in Candida cells, and TML-containing conjugates were cleaved in cell-free extract of C. albicans cells. These results suggest that a molecular umbrella can be successfully applied as a nanocarrier for the construction of cleavable antifungal conjugates.
Highlights
In the present SARS COVID-19 pandemic period, it is obvious that in the field of infectious diseases, special attention is focused on progress in the prevention of viral infections and antiviral chemotherapy
A basic rationale in this work was application of the molecular umbrella scaffold for the construction of conjugates with an inhibitor of intracellular fungal enzyme
The simplest diwalled molecular umbrella was chosen as an optimal carrier, since it had been previously shown as the most effective umbrella component of conjugates with an antifungal antibiotic Amphotericin B, where its presence resulted in decreased mammalian toxicity [10]
Summary
In the present SARS COVID-19 pandemic period, it is obvious that in the field of infectious diseases, special attention is focused on progress in the prevention of viral infections and antiviral chemotherapy. One cannot underestimate the fact that microbial resistance to antibiotics has emerged, and its spread worldwide has resulted in another significant threat to public health [1] This challenge is valid in the case of infections caused by human pathogenic fungi. One of the most promising strategies for overcoming this problem is the use of molecular carriers to ensure the delivery of enzymatic inhibitors to the intracellular target site [5], which is known as the “Trojan horse strategy” This approach is based on idea of conjugation of an active substance with a macromolecular or low molecular weight organic carrier penetrating the cell membrane [6]. Rationally designed cleavable conjugates of the diwalled molecular umbrella with cispentacin, an inhibitor of Ile-tRNAIle synthetase, have been tested as antifungal agents
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