期刊
ACS CHEMICAL BIOLOGY
卷 17, 期 12, 页码 3515-3526出版社
AMER CHEMICAL SOC
DOI: 10.1021/acschembio.2c00708
关键词
-
资金
- [UAR2607]
This study synthesized multivalent compounds that can inhibit lung infections caused by fungal and bacterial pathogens by adhesion to glycoconjugates. The compounds showed strong inhibitory activity and aggregating mechanism, reducing the adhesion of pathogens to lung epithelial cells.
Fungal and bacterial pathogens causing lung infections often use lectins to mediate adhesion to glycoconjugates at the surface of host tissues. Given the rapid emergence of resistance to the treatments in current use, beta-propeller lectins such as FleA from Aspergillus fumigatus, SapL1 from Scedosporium apiospermum, and BambL from Burkholderia ambifaria have become appealing targets for the design of anti-adhesive agents. In search of novel and cheap anti-infectious agents, we synthesized multivalent compounds that can display up to 20 units of fucose, the natural ligand. We obtained nanomolar inhibitors that are several orders of magnitude stronger than their monovalent analogue according to several biophysical techniques (i.e., fluorescence polarization, isothermal titration calorimetry, and bio-layer interferometry). The reason for high affinity might be attributed to a strong aggregating mechanism, which was examined by analytical ultracentrifugation. Notably, the fucosylated inhibitors reduced the adhesion of A. fumigatus spores to lung epithelial cells when administered 1 h before or after the infection of human lung epithelial cells. For this reason, we propose them as promising anti-adhesive drugs for the prevention and treatment of aspergillosis and related microbial lung infections.
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