272123-01-0Relevant articles and documents
Cyclohexyl-octahydro-pyrrolo[1,2-a]pyrazine-Based Inhibitors of Human N-Myristoyltransferase-1
French, Kevin J.,Zhuang, Yan,Schrecengost, Randy S.,Copper, Jean E.,Xia, Zuping,Smith, Charles D.
, p. 340 - 347 (2004)
N-Myristoyltransferase (NMT) is an emerging therapeutic target that catalyzes the attachment of myristate to the N terminus of an acceptor protein. We have developed a medium-throughput assay for screening potential small molecule inhibitors of human NMT-1 consisting of recombinant enzyme, biotinylated peptide substrate, and [3H]myristoyl-CoA. Approximately 16,000 diverse compounds have been evaluated, and significant inhibition of NMT was found with 0.8% of the compounds. From these hits, we have identified the cyclohexyl-octahydro-pyrrolo[1,2-a]pyrazine (COPP) chemotype as inhibitory toward human NMT-1. Thirty-two compounds containing this substructure inhibited NMT-1, with IC50 values ranging from 6 μM to millimolar concentrations, and a quantitative structure-activity relationship equation (r2 = 0.72) was derived for the series. The most potent inhibitor (24, containing 9-ethyl-9H-carbazole) demonstrated competitive inhibition for the peptide-binding site of NMT-1 and noncompetitive inhibition for the myristoyl-CoA site. Computational docking studies using the crystal structure of the highly homologous yeast NMT confirmed that 24 binds with excellent complementarity to the peptide-binding site of the enzyme. To evaluate the ability of 24 to inhibit NMT activity in intact cells, monkey CV-1 cells expressing an N-myristoylated green fluorescent protein (GFP) fusion protein were treated with a known NMT inhibitor or with 24. Each compound caused the redistribution of GFP from the plasma membrane to the cytosol. Furthermore, 24 inhibits cancer cell proliferation at doses similar to those that inhibit protein myristoylation. Overall, these studies establish an efficient assay for screening for inhibitors of human NMT and identify a novel family of inhibitors that compete at the peptide-binding site and have activity in intact cells.
Translation of Mycobacterium Survival Strategy to Develop a Lipo-peptide based Fusion Inhibitor**
Sardar, Avijit,Lahiri, Aritraa,Kamble, Mithila,Mallick, Amirul I.,Tarafdar, Pradip K.
, p. 6101 - 6106 (2021/02/01)
The entry of enveloped virus requires the fusion of viral and host cell membranes. An effective fusion inhibitor aiming at impeding such membrane fusion may emerge as a broad-spectrum antiviral agent against a wide range of viral infections. Mycobacterium survives inside the phagosome by inhibiting phagosome–lysosome fusion with the help of a coat protein coronin 1. Structural analysis of coronin 1 and other WD40-repeat protein suggest that the trp-asp (WD) sequence is placed at distorted β-meander motif (more exposed) in coronin 1. The unique structural feature of coronin 1 was explored to identify a simple lipo-peptide sequence (myr-WD), which effectively inhibits membrane fusion by modulating the interfacial order, water penetration, and surface potential. The mycobacterium inspired lipo-dipeptide was successfully tested to combat type 1 influenza virus (H1N1) and murine coronavirus infections as a potential broad-spectrum antiviral agent.
A tripeptide-based self-shrinking hydrogel for waste-water treatment: Removal of toxic organic dyes and lead (Pb2+) ions
Basak, Shibaji,Nandi, Nibedita,Paul, Subir,Hamley, Ian W.,Banerjee, Arindam
supporting information, p. 5910 - 5913 (2017/07/11)
A triphenylalanine-based superhydrogel shows automatic syneresis (self-compressing properties) with time and this self-shrinking behavior has been successfully utilized to remove toxic lead ions and organic dyes from waste-water efficiently with the abili
