Selective Inhibitors of Human Neuraminidase 3.
Tianlin GuoPhilipp DätwylerEkaterina DeminaMichele R RichardsPeng GeChunxia ZouRuixiang ZhengAnne FougeratAlexey V PshezhetskyBeat ErnstChristopher W CairoPublished in: Journal of medicinal chemistry (2018)
Human neuraminidases (NEU) are associated with human diseases including cancer, atherosclerosis, and diabetes. To obtain small molecule inhibitors as research tools for the study of their biological functions, we designed a library of 2-deoxy-2,3-didehydro- N-acetylneuraminic acid (DANA) analogues with modifications at C4 and C9 positions. This library allowed us to discover selective inhibitors targeting the human NEU3 isoenzyme. Our most selective inhibitor for NEU3 has a Ki of 320 ± 40 nM and a 15-fold selectivity over other human neuraminidase isoenzymes. This inhibitor blocks glycolipid processing by NEU3 in vitro. To improve their pharmacokinetic properties, various esters of the best inhibitors were synthesized and evaluated. Finally, we confirmed that our best compounds exhibited selective inhibition of NEU orthologues from murine brain.
Keyphrases
- endothelial cells
- small molecule
- induced pluripotent stem cells
- type diabetes
- cardiovascular disease
- pluripotent stem cells
- squamous cell carcinoma
- multiple sclerosis
- lymph node
- radiation therapy
- young adults
- cancer therapy
- metabolic syndrome
- lymph node metastasis
- insulin resistance
- molecular docking
- glycemic control
- cerebral ischemia
- papillary thyroid
- protein protein
- locally advanced