- Characterization of Specific N-α-Acetyltransferase 50 (Naa50) Inhibitors Identified Using a DNA Encoded Library
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Two novel compounds were identified as Naa50 binders/inhibitors using DNA-encoded technology screening. Biophysical and biochemical data as well as cocrystal structures were obtained for both compounds (3a and 4a) to understand their mechanism of action. These data were also used to rationalize the binding affinity differences observed between the two compounds and a MLGP peptide-containing substrate. Cellular target engagement experiments further confirm the Naa50 binding of 4a and demonstrate its selectivity toward related enzymes (Naa10 and Naa60). Additional analogs of inhibitor 4a were also evaluated to study the binding mode observed in the cocrystal structures.
- Bingham, Patrick,Burke, Benjamin J.,Chen, Qiuxia,Cheng, Xuemin,Deng, Ya-Li,Dou, Dengfeng,Feng, Junli,Gallego, Gary M.,Gehring, Michael R.,Grant, Stephan K.,Greasley, Samantha,Harris, Anthony R.,Kung, Pei-Pei,Maegley, Karen A.,Meier, Jordan,Meng, Xiaoyun,Montano, Jose L.,Morgan, Barry A.,Naughton, Brigitte S.,Palde, Prakash B.,Paul, Thomas A.,Richardson, Paul,Sakata, Sylvie,Shaginian, Alex,Sonnenburg, William K.,Stewart, Albert E.,Subramanyam, Chakrapani,Timofeevski, Sergei,Wan, Jinqiao,Yan, Wen
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supporting information
p. 1175 - 1184
(2020/07/04)
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- Antibacterial and anti-TB tat-peptidomimetics with improved efficacy and half-life
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Non-natural antimicrobial peptides are ideal as next-generation antibiotics because of their ability to circumvent the problems of drug resistance and in vivo instability. We report novel all-α- and α,γ-mixed Tat peptide analogues as potential antibacterial and anti-TB agents. These peptides have broad spectrum antibacterial activities against Gram-positive (MICs 0.61 ± 0.03 to 1.35 ± 0.21 μM with the peptide γTatM4) and Gram-negative (MICs 0.71 ± 0.005 to 1.26 ± 0.02 μM with γTatM4) bacteria and are also effective against active and dormant forms of Mycobacterium tuberculosis, including strains that are resistant to rifampicin and isoniazid. The introduction of the non-natural amino acids of the study in the Tat peptide analogues results in increased resistance to degradation by proteolysis, significantly increasing their half-life. The peptides appear to inhibit bacteria by a membrane disruption mechanism, and have only a low cytotoxic effect on mammalian cells.
- Bhosle, Govind S.,Nawale, Laxman,Yeware, Amar M.,Sarkar, Dhiman,Fernandes, Moneesha
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supporting information
p. 358 - 369
(2018/05/22)
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- Superior HIV-1 TAR Binders with Conformationally Constrained R52 Arginine Mimics in the Tat(48–57) Peptide
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We report a 100-fold increase in binding affinity of the Tat(48–57) peptide to HIV-1 transcriptional activator-responsive element (TAR) RNA by replacing Arg52, an essential and critical residue for Tat's specific binding, with (2S,4S)-4-guanidinoproline. The resulting αTat1M peptide is a far superior binder than γTat1M, a peptide containing another conformationally constrained arginine mimic, (2S,4S)-4-amino-N-(3-guanidinopropyl)proline, or even the control Tat peptide (CtrlTat) itself. Our observations are supported by circular dichroism (CD), isothermal titration calorimetry (ITC), gel electrophoresis and UV spectroscopy studies. Molecular dynamics simulations suggest increased interactions between the more compact αTat1M and TAR RNA, relative to CtrlTat. The CD signature of the RNA itself remains largely unchanged upon binding of the peptides. The Tat mimetics further have better cell uptake properties than the control Tat peptide, thus increasing their potential application as specific TAR-binding molecules.
- Bhosle, Govind S.,Kharche, Shalmali,Kumar, Santosh,Sengupta, Durba,Maiti, Souvik,Fernandes, Moneesha
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supporting information
p. 220 - 226
(2018/01/22)
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- Discovery of subnanomolar arginine-glycine-aspartate-based αvβ3/αvβ5 integrin binders embedding 4-aminoproline residues
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The embodiment of 4-aminoproline residues (Amp) into the arginine-glycine-aspartate (RGD) sequence led to the discovery of a novel class of high-affinity αvβ3/αvβ 5 integrin binders [IC50h(αvβ 3) 0.03-5.12 nM; IC50h(αvβ 5) 0.88-154 nM]. A total of eight cyclopeptides of type cyclo-[-Arg-Gly-Asp-Amp-], 5-12, were assembled by a standard solid-phase peptide synthesis protocol that involved the C2-carboxyl and C4-amino functionalities of the proline scaffolds, leaving the Nα- nuclear site untouched. Functionalization of this vacant proline site with either alkyl or acyl substituents proved feasible, with significant benefit to the integrin binding capabilities of the ligands. Notably, six out of eight cyclopeptide inhibitors, 5-7 and 9-11, showed moderate yet significant selectivity toward the αvβ3 receptor. The three-dimensional structure in water was determined by NMR techniques and molecular dynamics calculations. Docking studies to the X-ray crystal structure of the extracellular segment of integrin αvβ3 complexed with reference compound 1 were also performed on selected analogues to highlight the structural features required for potent ligand binding affinity.
- Zanardi, Franca,Burreddu, Paola,Rassu, Gloria,Auzzas, Luciana,Battistini, Lucia,Curti, Claudio,Sartori, Andrea,Nicastro, Giuseppe,Menchi, Gloria,Cini, Nicoletta,Bottonocetti, Anna,Raspanti, Silvia,Casiraghi, Giovanni
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p. 1771 - 1782
(2008/09/21)
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- ANTIVIRAL COMPOUNDS
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The invention is related to phosphorus substituted anti-viral inhibitory compounds, compositions containing such compounds, and therapeutic methods that include the administration of such compounds, as well as to processes and intermediates useful for preparing such compounds.
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Page/Page column 352-353
(2008/06/13)
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