期刊
BIOORGANIC CHEMISTRY
卷 115, 期 -, 页码 -出版社
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bioorg.2021.105185
关键词
Methionine aminopeptidase; Selective inhibition; Azaindole; Hydroxamic acid; Helicobacter pylori
资金
- Science and Engineering Research Board (SERB), India [EMR/2015/000461, CRG/2019/006013, ECR/2016/000288]
- DBT (Department of Biotechnology), India
- DST (Department of Science and Technology), India
The study analyzed MetAP sequences, identified a pattern of variation in the S1 pocket, and designed 17 selective inhibitors. These inhibitors selectively inhibited H. pylori MetAP compared to the human counterpart, with structural studies providing the molecular basis for the selectivity.
Methionine aminopeptidases (MetAPs) are an important class of enzymes that work co-translationally for the removal of initiator methionine. Chemical inhibition or gene knockdown is lethal to the microbes suggesting that they can be used as antibiotic targets. However, sequence and structural similarity between the microbial and host MetAPs has been a challenge in the identification of selective inhibitors. In this study, we have analyzed several thousands of MetAP sequences and established a pattern of variation in the S1 pocket of the enzyme. Based on this knowledge, we have designed a library of 17 azaindole based hydroxamic acid derivatives which selectively inhibited the MetAP from H. pylori compared to the human counterpart. Structural studies provided the molecular basis for the selectivity.
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