- Targeted covalent inhibitors of MDM2 using electrophile-bearing stapled peptides
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Herein, we describe the development of a novel staple with an electrophilic warhead to enable the generation of stapled peptide covalent inhibitors of the p53-MDM2 protein-protein interaction (PPI). The peptide developed showed complete and selective covalent binding resulting in potent inhibition of p53-MDM2 PPI.
- Charoenpattarapreeda, Jiraborrirak,Tan, Yaw Sing,Iegre, Jessica,Walsh, Stephen J.,Fowler, Elaine,Eapen, Rohan S.,Wu, Yuteng,Sore, Hannah F.,Verma, Chandra S.,Itzhaki, Laura,Spring, David R.
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supporting information
p. 7914 - 7917
(2019/07/12)
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- Arginine-linked neomycin B dimers: Synthesis, rRNA binding, and resistance enzyme activity
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The nucleotides comprising the ribosomal decoding center are highly conserved, as they are important for maintaining translational fidelity. The bacterial A-site has a small base variation as compared with the human analogue, allowing aminoglycoside (AG) antibiotics to selectively bind within this region of the ribosome and negatively affect microbial protein synthesis. Here, by using a fluorescence displacement screening assay, we demonstrate that neomycin B (NEO) dimers connected by l-arginine-containing linkers of varying length and composition bind with higher affinity to model A-site RNAs compared to NEO, with IC50 values ranging from ~40-70 nM, and that a certain range of linker lengths demonstrates a clear preference for the bacterial A-site RNA over the human analogue. Furthermore, AG-modifying enzymes (AMEs), such as AG O-phosphotransferases, which are responsible for conferring antibiotic resistance in many types of infectious bacteria, demonstrate markedly reduced activity against several of the l-arginine-linked NEO dimers in vitro. The antimicrobial activity of these dimers against several bacterial strains is weaker than that of the parent NEO.
- Jin, Yi,Watkins, Derrick,Degtyareva, Natalya N.,Green, Keith D.,Spano, Meredith N.,Garneau-Tsodikova, Sylvie,Arya, Dev P.
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supporting information
p. 164 - 169
(2016/01/30)
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- Helical pitch of m-phenylene ethynylene foldamers by double spin labeling
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To investigate the helical conformation of oligo(m-phenylene ethynylene)s, a pair of TEMPO spin labels were appended to the backbone. The two TEMPO radicals were separated by the four, five, and six repeating units. ESR spectra of the labeled oligomers were measured in chloroform and in ethyl acetate solvents in which the oligomers are disordered and folded, respectively. The measurement and analysis of ESR spectra revealed that six repeating units make one helical turn. Copyright
- Matsuda, Kenji,Stone, Matthew T.,Moore, Jeffrey S.
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p. 11836 - 11837
(2007/10/03)
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- m-Diethynylbenzene macrocycles: Syntheses and self-association behavior in solution
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m-Diethynylbenzene macrocycles (DBMs), buta-1,3-diyne-bridged [4n]metacyclophanes, have been synthesized and their self-association behaviors in solution were investigated, Cyclic tetramers, hexamers, and octamers of DBMs having exo-annular octyl, hexadecyl, and 3,6,9-trioxadecyl ester groups were prepared by intermolecular oxidative coupling of dimer units or intramolecular cyclization of the corresponding open-chain oligomers. The aggregation properties were investigated by two methods, the 1H NMR spectra and the vapor pressure osmometry (VPO). Although some discrepancies were observed between the association constants obtained from the two methods, the qualitative view was consistent with each other. The analysis of self-aggregation by VPO revealed unique aggregation behavior of DBMs in acetone and toluene, which was not elucidated by the NMR method. Namely, the association constants for infinite association are several times larger than the dimerization constant, suggesting that the aggregation is enhanced by the formation of dimers (a nucleation mechanism). In polar solvents, DBMs aggregate more strongly than in chloroform due to the solvophobic interactions between the macrocyclic framework and the solvents. Moreover, DBMs self-associate in aromatic solvents such as toluene and o-xylene more readily than in chloroform. In particular, the hexameric DBM having a large macrocyclic cavity exhibits extremely large association constants in aromatic solvents. By comparing the aggregation properties of DBMs with the corresponding acyclic oligomers, the effect of the macrocyclic structure on the aggregation propensity was clarified. Finally, it turned out that DBMs tend to aggregate more readily than the corresponding phenylacetylene macrocycles, acetylene-bridged [2n]metacyclophanes, owing to the withdrawal of the electron density from the aromatic rings by the butadiyne linkages which facilitates π-π stacking interactions.
- Tobe, Yoshito,Utsumi, Naoto,Kawabata, Kazuya,Nagano, Atsushi,Adachi, Kiyomi,Araki, Shunji,Sonoda, Motohiro,Hirose, Keiji,Naemura, Koichiro
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p. 5350 - 5364
(2007/10/03)
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