170852-98-9Relevant academic research and scientific papers
Evaluation of a non-prime site substituent and warheads combined with a decahydroisoquinolin scaffold as a SARS 3CL protease inhibitor
Ohnishi, Kouji,Hattori, Yasunao,Kobayashi, Kazuya,Akaji, Kenichi
, p. 425 - 435 (2019)
A non-prime site substituent and warheads combined with a decahydroisoquinolin scaffold was evaluated as a novel inhibitor for severe acute respiratory syndrome (SARS) chymotrypsin-like protease (3CLpro). The decahydroisoquinolin scaffold has b
Structure-based design, synthesis, and evaluation of peptide-mimetic SARS 3CL protease inhibitors
Akaji, Kenichi,Konno, Hiroyuki,Mitsui, Hironori,Teruya, Kenta,Shimamoto, Yasuhiro,Hattori, Yasunao,Ozaki, Takeshi,Kusunoki, Masami,Sanjoh, Akira
experimental part, p. 7962 - 7973 (2012/03/26)
The design and evaluation of low molecular weight peptide-based severe acute respiratory syndrome (SARS) chymotrypsin-like protease (3CL) protease inhibitors are described. A substrate-based peptide aldehyde was selected as a starting compound, and optimum side-chain structures were determined, based on a comparison of inhibitory activities with Michael type inhibitors. For the efficient screening of peptide aldehydes containing a specific C-terminal residue, a new approach employing thioacetal to aldehyde conversion mediated by N-bromosuccinimide was devised. Structural optimization was carried out based on X-ray crystallographic analyses of the R188I SARS 3CL protease in a complex with each inhibitor to provide a tetrapeptide aldehyde with an IC50 value of 98 nM. The resulting compound carried no substrate sequence, except for a P3 site directed toward the outside of the protease. X-ray crystallography provided insights into the protein-ligand interactions.
Incorporation of a bioactive reverse-turn heterocycle into a peptide template using solid-phase synthesis to probe melanocortin receptor selectivity and ligand conformations by 2D 1H NMR
Singh, Anamika,Wilczynski, Andrzej,Holder, Jerry R.,Witek, Rachel M.,Dirain, Marvin L.,Xiang, Zhimin,Edison, Arthur S.,Haskell-Luevano, Carrie
experimental part, p. 1379 - 1390 (2011/05/12)
By use of a solid-phase synthetic approach, a bioactive reverse turn heterocycle was incorporated into a cyclic peptide template to probe melanocortin receptor potency and ligand structural conformations. The five melanocortin receptor isoforms (MC1R-MC5R) are G-protein-coupled receptors (GPCRs) that are regulated by endogenous agonists and antagonists. This pathway is involved in pigmentation, weight, and energy homeostasis. Herein, we report novel analogues of the chimeric AGRP-melanocortin peptide template integrated with a small molecule moiety to probe the structural and functional consequences of the core His-Phe-Arg-Trp peptide domain using a reverse-turn heterocycle. A series of six compounds are reported that result in inactive to full agonists with nanomolar potency. Biophysical structural analysis [2D 1H NMR and computer-assisted molecular modeling (CAMM)] were performed on selected analogues, resulting in the identification that these peptide-small molecule hybrids possessed increased flexibility and fewer discrete conformational families compared to the reference peptide and result in a novel template for further structure-function studies.
