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Macrocyclic Mechanism‐Based Inhibitor for Neuraminidases
Author(s) -
Kai Hirokazu,
Hinou Hiroshi,
Naruchi Kentaro,
Matsushita Takahiko,
Nishimura ShinIchiro
Publication year - 2013
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201200859
Subject(s) - aglycone , neuraminidase , chemistry , stereochemistry , sialic acid , moiety , glycoside , neuraminidase inhibitor , linker , biochemistry , enzyme , medicine , disease , covid-19 , pathology , computer science , infectious disease (medical specialty) , operating system
A macrocyclic mechanism‐based inhibitor for neuraminidases (NAs) bearing a 2‐difluoromethylphenyl aglycone and a linker between the aglycone and C‐9 positions of sialic acid was synthesized and evaluated. The macrocyclic structure was designed to keep the aglycone moiety in the active site of the neuraminidase after cleavage of the glycoside bond. When Vibrio chorelae neuraminidase (VCNA) was treated with a similar acyclic derivative in the presence of detergent, the irreversible inhibition property was disabled. In contrast, this macrocyclic compound acted as an irreversible inhibitor for VCNA in the presence of detergent. Inhibition assay for various NAs using this macrocyclic compound revealed that the irreversible inhibition property depends on the k cat of the neuraminidase treated. NAs having small k cat values, such as Influenza viruses, Clostridium, Trypanosoma cruzi , and Human , were also inhibited irreversibly. However, Salmonella typhimurium NA, which has an extremely high k cat , was not affected irreversibly by the inhibitor. Interestingly, in contrast to common k cat inhibitors, the irreversibility of inhibition by this macrocyclic compound is inversely proportional to the k cat of the target neuraminidase.