39570-63-3Relevant articles and documents
Design of Transmembrane Mimetic Structural Probes to Trap Different Stages of γ-Secretase-Substrate Interaction
Bhattarai, Sanjay,Devkota, Sujan,Wolfe, Michael S.
, p. 15367 - 15378 (2021/11/01)
The transmembrane domain (TMD) of the amyloid precursor protein of Alzheimer's disease is cut processively by γ-secretase through endoproteolysis and tricarboxypeptidase "trimming". We recently developed a prototype substrate TMD mimetic for structural analysis - composed of a helical peptide inhibitor linked to a transition-state analogue - that simultaneously engages a substrate exosite and the active site and is pre-organized to trap the carboxypeptidase transition state. Here, we developed variants of this prototype designed to allow visualization of transition states for endoproteolysis, TMD helix unwinding, and lateral gating of the substrate, identifying potent inhibitors for each class. These TMD mimetics exhibited non-competitive inhibition and occupy both the exosite and the active site, as demonstrated by inhibitor cross-competition experiments and photoaffinity probe binding assays. The new probes should be important structural tools for trapping different stages of substrate recognition and processing via ongoing cryo-electron microscopy with γ-secretase, ultimately aiding rational drug design.
Structure-Guided Optimization of Dipeptidyl Inhibitors of Norovirus 3CL Protease
Rathnayake, Athri D.,Kim, Yunjeong,Dampalla, Chamandi S.,Nguyen, Harry Nhat,Jesri, Abdul-Rahman M.,Kashipathy, Maithri M.,Lushington, Gerald H.,Battaile, Kevin P.,Lovell, Scott,Chang, Kyeong-Ok,Groutas, William C.
, p. 11945 - 11963 (2020/11/26)
Acute gastroenteritis caused by noroviruses has a major impact on public health worldwide in terms of morbidity, mortality, and economic burden. The disease impacts most severely immunocompromised patients, the elderly, and children. The current lack of approved vaccines and small-molecule therapeutics for the treatment and prophylaxis of norovirus infections underscores the need for the development of norovirus-specific drugs. The studies described herein entail the use of the gem-dimethyl moiety as a means of improving the pharmacological activity and physicochemical properties of a dipeptidyl series of transition state inhibitors of norovirus 3CL protease, an enzyme essential for viral replication. Several compounds were found to be potent inhibitors of the enzyme in biochemical and cell-based assays. The pharmacological activity and cellular permeability of the inhibitors were found to be sensitive to the location of the gem-dimethyl group.
Piperidine carbamate peptidomimetic inhibitors of the serine proteases HGFA, matriptase and hepsin
Damalanka, Vishnu C.,Wildman, Scott A.,Janetka, James W.
, p. 1646 - 1655 (2019/09/30)
Matriptase and hepsin are type II transmembrane serine proteases (TTSPs). Along with related S1 trypsin like serine protease HGFA (hepatocyte growth factor activator), their unregulated proteolytic activity has been associated with cancer including tumor progression and metastasis. These three proteases have two substrates in common, hepatocyte growth factor (HGF) and macrophage stimulating protein (MSP), the ligands for MET and recepteur d'origine nantais (RON) receptor tyrosine kinases. Mechanism-based tetrapeptide and benzamidine inhibitors of these proteases have been shown to block HGF/MET and MSP/RON cancer cell signaling. Herein, we have rationally designed a new class of peptidomimetic hybrid small molecule piperidine carbamate dipeptide inhibitors comparable in potency to much larger tetrapeptides. We have identified multiple compounds which have potent activity against matriptase and hepsin and with excellent selectivity over the off-target serine proteases factor Xa and thrombin.
