89991-12-8Relevant articles and documents
Self-Masked Aldehyde Inhibitors: A Novel Strategy for Inhibiting Cysteine Proteases
Li, Linfeng,Chenna, Bala C.,Yang, Kai S.,Cole, Taylor R.,Goodall, Zachary T.,Giardini, Miriam,Moghadamchargari, Zahra,Hernandez, Elizabeth A.,Gomez, Jana,Calvet, Claudia M.,Bernatchez, Jean A.,Mellott, Drake M.,Zhu, Jiyun,Rademacher, Andrew,Thomas, Diane,Blankenship, Lauren R.,Drelich, Aleksandra,Laganowsky, Arthur,Tseng, Chien-Te K.,Liu, Wenshe R.,Wand, A. Joshua,Cruz-Reyes, Jorge,Siqueira-Neto, Jair L.,Meek, Thomas D.
, p. 11267 - 11287 (2021/08/16)
Cysteine proteases comprise an important class of drug targets, especially for infectious diseases such as Chagas disease (cruzain) and COVID-19 (3CL protease, cathepsin L). Peptide aldehydes have proven to be potent inhibitors for all of these proteases. However, the intrinsic, high electrophilicity of the aldehyde group is associated with safety concerns and metabolic instability, limiting the use of aldehyde inhibitors as drugs. We have developed a novel class of self-masked aldehyde inhibitors (SMAIs) for cruzain, the major cysteine protease of the causative agent of Chagas disease - Trypanosoma cruzi. These SMAIs exerted potent, reversible inhibition of cruzain (Ki? = 18-350 nM) while apparently protecting the free aldehyde in cell-based assays. We synthesized prodrugs of the SMAIs that could potentially improve their pharmacokinetic properties. We also elucidated the kinetic and chemical mechanism of SMAIs and applied this strategy to the design of anti-SARS-CoV-2 inhibitors.
Synthesis and structure activity relationships of novel non-peptidic metallo-aminopeptidase inhibitors
Albrecht, Sebastien,Defoin, Albert,Salomon, Emmanuel,Tarnus, Celine,Wetterholm, Anders,Haeggstroem, Jasper Z.
, p. 7241 - 7257 (2007/10/03)
Racemic derivatives of 3-amino-2-tetralone were synthesised and evaluated for their ability to inhibit metallo-aminopeptidase activities. New compounds substituted in position 2 by methyl ketone, substituted oximes or hydroxamic acids as well as heterocyclic derivatives were evaluated against representative members of zinc-dependent aminopeptidases: leucine aminopeptidase (E.C. 3.4.11.1), aminopeptidase-N (E.C. 3.4.11.2), Aeromonas proteolytica aminopeptidase (E.C. 3.4.11.10), and the aminopeptidase activity of leukotriene A4 hydrolase (E.C. 3.3.2.6). Several compounds showed Ki values in the low micromolar range against the 'one-zinc' aminopeptidases, while most of them were rather poor inhibitors of the 'two-zinc' enzymes. This interesting selectivity profile may guide the design of new, specific inhibitors of target mammalian aminopeptidases with one active site zinc.
