Rational Design and Synthesis of D-galactosyl Lysophospholipids as Selective Substrates and non-ATP-competitive Inhibitors of Phosphatidylinositol Phosphate Kinases.
Chemistry
; : e202202083, 2022 Nov 24.
Article
in English
| MEDLINE | ID: covidwho-2235996
ABSTRACT
Phosphatidylinositol phosphate kinases (PIPKs) produce lipid signaling molecules and have been attracting increasing attention as drug targets for cancer, neurodegenerative diseases, and viral infection. Given the potential cross-inhibition of kinases and other ATP-utilizing enzymes by ATP-competitive inhibitors, targeting the unique lipid substrate binding site represents a superior strategy for PIPK inhibition. Here, by taking advantage of the nearly identical stereochemistry between myo-inositol and D-galactose, we designed and synthesized a panel of D-galactosyl lysophospholipids, one of which was found to be a selective substrate of phosphatidylinositol 4-phosphate 5-kinase. Derivatization of this compound led to the discovery of a human PIKfyve inhibitor with an apparent IC50 of 6.2â
µM, which significantly potentiated the inhibitory effect of Apilimod, an ATP-competitive PIKfyve inhibitor under clinical trials against SARS-CoV-2 infection and amyotrophic lateral sclerosis. Our results provide the proof of concept that D-galactose-based phosphoinositide mimetics can be developed into artificial substrates and new inhibitors of PIPKs.
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Type of study:
Prognostic study
/
Randomized controlled trials
Language:
English
Journal:
Chemistry
Journal subject:
Chemistry
Year:
2022
Document Type:
Article
Affiliation country:
Chem.202202083
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