Oligomers and peptidomimetics consisting of methyl 3-amino-2,3-dideoxyhexopyranosiduronic acids

Sikorska, Emilia; Tuwalska, Dorota; Karpowicz, Przemysław; Jankowska, Elżbieta; Nowacki, Andrzej; Liberek, Beata

doi:10.1016/j.tet.2015.02.009

Cited by 2 publications

(1 citation statement)

References 38 publications

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“…It remains to be established whether the introduction of β-turns via the Tic-Oic moiety has a unique influence on the inhibitory properties of Tat1 peptide or it could be recapitulated with other turn inducers. Our preliminary exploration of the chemical space indicates that other turn inducers can to some extent substitute for Tic-Oic [ 66 ]. The structure of the region 4–6 is important for inhibition of the 20S proteasome.…”

Section: Discussionmentioning

confidence: 99%

Interplay between Structure and Charge as a Key to Allosteric Modulation of Human 20S Proteasome by the Basic Fragment of HIV-1 Tat Protein

et al. 2015

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The proteasome is a giant protease responsible for degradation of the majority of cytosolic proteins. Competitive inhibitors of the proteasome are used against aggressive blood cancers. However, broadening the use of proteasome-targeting drugs requires new mechanistic approaches to the enzyme’s inhibition. In our previous studies we described Tat1 peptide, an allosteric inhibitor of the proteasome derived from a fragment of the basic domain of HIV-Tat1 protein. Here, we attempted to dissect the structural determinants of the proteasome inhibition by Tat1. Single- and multiple- alanine walking scans were performed. Tat1 analogs with stabilized beta-turn conformation at positions 4–5 and 8–9, pointed out by the molecular dynamics modeling and the alanine scan, were synthesized. Structure of Tat1 analogs were analyzed by circular dichroism, Fourier transform infrared and nuclear magnetic resonance spectroscopy studies, supplemented by molecular dynamics simulations. Biological activity tests and structural studies revealed that high flexibility and exposed positive charge are hallmarks of Tat1 peptide. Interestingly, stabilization of a beta-turn at the 8–9 position was necessary to significantly improve the inhibitory potency.

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Section: Discussionmentioning

confidence: 99%

Interplay between Structure and Charge as a Key to Allosteric Modulation of Human 20S Proteasome by the Basic Fragment of HIV-1 Tat Protein

et al. 2015

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From glucose to enantiopure morpholino β-amino acid: a new tool for stabilizing γ-turns in peptides

et al. 2019

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A new cyclic enantiopure b-amino acid, named b-Morph, containing the morpholino ring, was obtained in gram scale starting from a-D-glucopyranose enantiopure material, focusing on the "environmental sustainability" concept. A series of ultrashort model peptides containing b-Morph were prepared. b-Morph was found able to induce an inverse g-turn in Leu-Val containing sequences. Key element for the g-turn formation might be the oxygen atom of morpholino ring that could drive the spatial orientation of NH of amino acid i+1, through an unusual hydrogen bond. This datum was confirmed by QTAIM calculations. Interestingly, when two b-Morph-Leu-Val repeats are present in the peptide, two g-turns can be formed, as supported by NMR experiments and aMD and H-REMD calculations. Introduction g-Turns is a very short motif able to reverse the main chain of a peptide/protein. It is stabilized by the formation of a hydrogen bond between the C=O of residue i and the NH of residue i+2 forming a pseudo-seven-membered ring. Depending on the f and y angles, two different type of turns can be designed defined as inverse [φ (-75°); y (+65°)] and classical φ (+75°); y (-65°)] g-turns. In the first one, the R substituent of the a-amino acid lies in the equatorial position, while in the second one in axial position. Inverse g-turns are generally located at a position of reversal in chain direction (180°) and often within b-strands associated to b-sheets. On the other hand, classical g-turns are less common in proteins, and in most cases, they lie at the loop end of a β-hairpin. 1 A new cyclic enantiopure b-amino acid, named b-Morph, containing the morpholino ring, was obtained in gram scale starting from a-D-glucopyranose enantiopure material, focusing on the "environmental sustainability" concept. A series of ultrashort model peptides containing b-Morph were prepared. b-Morph was found able to induce an inverse g-turn in Leu-Val containing sequences. Key element for the g-turn formation might be the oxygen atom of morpholino ring that could drive the spatial orientation of NH of amino acid i+1, through an unusual hydrogen bond. This datum was confirmed by QTAIM calculations. Interestingly, when two b-Morph-Leu-Val repeats are present in the peptide, two g-turns can be formed, as supported by NMR experiments and aMD and H-REMD calculations.

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Oligomers and peptidomimetics consisting of methyl 3-amino-2,3-dideoxyhexopyranosiduronic acids

Cited by 2 publications

References 38 publications

Interplay between Structure and Charge as a Key to Allosteric Modulation of Human 20S Proteasome by the Basic Fragment of HIV-1 Tat Protein

Interplay between Structure and Charge as a Key to Allosteric Modulation of Human 20S Proteasome by the Basic Fragment of HIV-1 Tat Protein

From glucose to enantiopure morpholino β-amino acid: a new tool for stabilizing γ-turns in peptides

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