162536-41-6Relevant articles and documents
Design of Substrate Transmembrane Mimetics as Structural Probes for ?3-Secretase
Bhattarai, Sanjay,Devkota, Sujan,Douglas, Justin T.,Meneely, Kathleen M.,Wolfe, Michael S.,Xing, Minli
, p. 3351 - 3355 (2020)
?3-Secretase is a membrane-embedded aspartyl protease complex central in biology and medicine. How this enzyme recognizes transmembrane substrates and catalyzes hydrolysis in the lipid bilayer is unclear. Inhibitors that mimic the entire substrate transmembrane domain and engage the active site should provide important tools for structural biology, yielding insight into substrate gating and trapping the protease in the active state. Here, we report transmembrane peptidomimetic inhibitors of the ?3-secretase complex that contain an N-terminal helical peptide region that engages a substrate docking exosite and a C-terminal transition-state analog moiety targeted to the active site. Both regions are required for stoichiometric inhibition of ?3-secretase. Moreover, enzyme inhibition kinetics and photoaffinity probe displacement experiments demonstrate that both the docking exosite and the active site are engaged by the bipartite inhibitors. The solution conformations of these potent transmembrane-mimetic inhibitors are similar to those of bound natural substrates, suggesting these probes are preorganized for high-affinity binding and should allow visualization of the active ?3-secretase complex, poised for intramembrane proteolysis, by cryo-electron microscopy.
The pseudo-symmetric n-benzyl hydroxyethylamine core in a new series of heteroarylcarboxyamide hiv-1 pr inhibitors: Synthesis, molecular modeling and biological evaluation
D’orsi, Rosarita,Funicello, Maria,Laurita, Teresa,Lupattelli, Paolo,Berti, Federico,Chiummiento, Lucia
, (2021/10/30)
Here, we report the synthesis, enzyme inhibition and structure–activity relationship studies of a new potent class of HIV-1 protease inhibitors, which contain a pseudo-symmetric hydroxyethylamine core and heteroarylcarboxyamide moieties. The simple synthetic pathway furnished nine compounds in a few steps with high yields. The compounds were designed taking into account our previous results on other series of inhibitors with different substituents at P’ and P” and different ways of linking them to the inhibitor core. Potent inhibitory activity was obtained with nanomolar IC50 values measured with a standard fluorimetric test in 100 mM MES buffer, pH 5.5, containing 400 mM NaCl, 1 mM EDTA, 1 mM DTT and 1 mg/mL BSA. Compounds 9a–c, containing the indole ring in P1, exhibited an HIV-1 protease inhibitory activity more powerful than darunavir in the same assay. To obtain molecular insight into the binding properties of these compounds, docking analysis was performed, and their binding properties were also compared.
NOVEL 9H-FLUORENE DERIVATIVES OR THEIR PHARMACEUTICALLY ACCEPTABLE SALTS
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Page/Page column 9-12, (2021/12/07)
A group of novel 9H-fluorcnc derivatives suitable for the preparation of active substances for the treatment of Alzheimer's disease, in particular as multifunctional inhibitors of the BuChE and BACE1 enzymes and beta-amyloid aggregation.
