scholarly journals Macrocyclization of an all-d linear α-helical peptide imparts cellular permeability

2020 ◽  
Vol 11 (21) ◽  
pp. 5577-5591 ◽  
Author(s):  
Srinivasaraghavan Kannan ◽  
Pietro G. A. Aronica ◽  
Simon Ng ◽  
Dawn Thean Gek Lian ◽  
Yuri Frosi ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Protein Protein Interactions ◽  
Intracellular Protein ◽  
Helical Peptide ◽  
Cellular Permeability ◽  
Targeted Inhibitors

Peptide-based molecules hold great potential as targeted inhibitors of intracellular protein–protein interactions (PPIs).

scholarly journals Optimal Anchoring of a Urea-based Foldamer Inhibitor of ASF1 Histone Chaperone Through Backbone Plasticity

2020 ◽  
Author(s):  
Johanne Mbianda ◽  
May Bakail ◽  
Christophe André ◽  
Gwenaëlle Moal ◽  
Marie E. Perrin ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Histone Chaperone ◽  
Protein Protein Interactions ◽  
Protein Surface ◽  
Chromatin Dynamics ◽  
Correct Orientation ◽  
Surface Recognition ◽  
Binding Interface ◽  
Helical Peptide ◽  
Α Helix

<p><b>Sequence-specific oligomers with predictable folding patterns, i.e. foldamers provide new opportunities to mimic α-helical peptides and design inhibitors of protein-protein interactions. One major hurdle of this strategy is to retain the correct orientation of key side chains involved in protein surface recognition. Here, we show that the structural plasticity of a foldamer backbone may significantly contribute to the required spatial adjustment for optimal interaction with the protein surface. By using oligoureas as α-helix mimics, we designed a foldamer/peptide hybrid inhibitor of histone chaperone ASF1, a key regulator of chromatin dynamics. The crystal structure of its complex with ASF1 reveals a striking plasticity of the urea backbone, which adapts to the ASF1 surface to maintain the same binding interface. One additional benefit of generating ASF1 ligands with non-peptide oligourea segments is the resistance to proteolysis in human plasma which was highly improved compared to the cognate α-helical peptide. </b></p>

Assessing the cellular toxicity of peptide inhibitors of intracellular protein-protein interactions by microinjection

2021 ◽  
Vol 29 ◽  
pp. 115906
Author(s):  
Sanjeevini Babu Reddiar ◽  
Hareth Al-Wassiti ◽  
Colin W. Pouton ◽  
Cameron J. Nowell ◽  
Macgregor A. Matthews ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Peptide Inhibitors ◽  
Protein Protein Interactions ◽  
Intracellular Protein ◽  
Cellular Toxicity

Uncoupling the Folding-Function Paradigm of Lytic Peptides to Deliver Impermeable Inhibitors of Intracellular Protein–Protein Interactions

2020 ◽  
Vol 142 (47) ◽  
pp. 19950-19955
Author(s):  
Stephen E. Miller ◽  
Kohei Tsuji ◽  
Rachel P.M. Abrams ◽  
Terrence R. Burke ◽  
Joel P. Schneider
Keyword(s):  
Protein Interactions ◽  
Protein Protein Interactions ◽  
Intracellular Protein ◽  
Lytic Peptides

A Cyclized Helix-Loop-Helix Peptide as a Molecular Scaffold for the Design of Inhibitors of Intracellular Protein-Protein Interactions by Epitope and Arginine Grafting

2016 ◽  
Vol 128 (36) ◽  
pp. 10770-10773 ◽  
Author(s):  
Daisuke Fujiwara ◽  
Hidekazu Kitada ◽  
Masahiro Oguri ◽  
Toshio Nishihara ◽  
Masataka Michigami ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Protein Protein Interactions ◽  
Intracellular Protein ◽  
Molecular Scaffold ◽  
Helix Loop Helix

scholarly journals Discovery of cell active macrocyclic peptides with on-target inhibition of KRAS signaling

2021 ◽  
Author(s):  
Shuhui Lim ◽  
Nicolas Boyer ◽  
Nicole Boo ◽  
Chunhui Huang ◽  
Gireedhar Venkatachalam ◽  
...  
Keyword(s):  
Small Molecules ◽  
Protein Interactions ◽  
Therapeutic Targets ◽  
Protein Protein Interactions ◽  
Intracellular Protein ◽  
Macrocyclic Peptides

Macrocyclic peptides have the potential to address intracellular protein-protein interactions (PPIs) of high value therapeutic targets that have proven largely intractable to small molecules. Here, we report broadly applicable lessons...

scholarly journals Important Considerations Related to Permeability of Peptides

2021 ◽  
Vol 75 (6) ◽  
pp. 522-524
Author(s):  
Thomas E. Vorherr
Keyword(s):  
Protein Interactions ◽  
Oral Bioavailability ◽  
Intracellular Delivery ◽  
Oral Route ◽  
Assay Development ◽  
Alternative Methods ◽  
Protein Protein Interactions ◽  
Intracellular Protein ◽  
To Come ◽  
Peptide Uptake

This review on intracellular delivery and oral bioavailability of peptides reflects a number of principal investigations at Novartis. Our studies were aimed at either understanding features enabling peptides to interfere with intracellular protein–protein interactions, or to achieve a more patient-friendly delivery by the oral route. In the light of these objectives, we have also spent some effort on assay development to come up with alternative methods for monitoring cellular peptide uptake. This summary of our insights is intended to help in the assessment and development of peptide therapeutics requiring membrane transition

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