Computational Design of a β-Peptide That Targets Transmembrane Helices

Shandler, Scott J.; Korendovych, Ivan V.; Moore, David T.; Smith-Dupont, Kathryn B.; Streu, Craig; Litvinov, Rustem I.; Billings, Paul C.; Gai, Feng; Bennett, Joel S.; DeGrado, William F.

doi:10.1021/ja204215f

Cited by 54 publications

(39 citation statements)

References 30 publications

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“…This was the first example of the targeting of transmembrane helices [116]. Further b-peptides were synthetized which interacted with the integrin a IIb b 3 and activated it in vitro [117]. In a similar way, glucagon-like peptide-1 analog a/b-peptides were designed with high activity and proteolytic stability.…”

Section: B-peptidesmentioning

confidence: 99%

An overview of peptide and peptoid foldamers in medicinal chemistry

Mándity¹,

Fülöp²

2015

Expert Opinion on Drug Discovery

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Various new foldamers have been created with a range of structures and biological applications. Membrane-acting antibacterial foldamers have been introduced. A general property of these structures is their amphiphilic nature. The amphiphilicity can be stationary or induced by the membrane binding. Cell-penetrating foldamers have been described which serve as cargo molecules, and foldamers have been used as autophagy inducers. Anti-Alzheimer compounds too have been created and the greatest breakthrough was attained via the modification of protein-protein interactions. This can serve as the chemical and pharmaceutical basis for the relevance of foldamers in the future.

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Section: B-peptidesmentioning

confidence: 99%

An overview of peptide and peptoid foldamers in medicinal chemistry

Mándity¹,

Fülöp²

2015

Expert Opinion on Drug Discovery

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“…The success of this approach was due in part to exploiting known TMD–TMD PPI motifs, as the interaction face between the anti-TMD peptide and target TMD helices resembled a glycine zipper motif. The CHAMP methodology was later extended to a β-peptide foldamer targeting integrins (β-CHAMP), which allowed the DeGrado group (136) to target the Gx 3 G motif on the α IIb TMD by first positioning a poly(homoglycine) sequence to find the optimal backbone, using a grid search and the CHARM force field, and then optimizing van der Waals contacts with the target TMD.…”

Section: Approaches To Targeting Membrane Protein Interactionsmentioning

confidence: 99%

Drugging Membrane Protein Interactions

Yin¹,

Flynn

2016

Annu. Rev. Biomed. Eng.

285

240

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The majority of therapeutics target membrane proteins, accessible on the surface of cells, to alter cellular signaling. Cells use membrane proteins to transduce signals into cells, transport ions and molecules, bind the cell to a surface or substrate, and catalyze reactions. Newly devised technologies allow us to drug conventionally “undruggable” regions of membrane proteins, enabling modulation of protein–protein, protein–lipid, and protein–nucleic acid interactions. In this review, we survey the state of the art in high-throughput screening and rational design in drug discovery, and we evaluate the advances in biological understanding and technological capacity that will drive pharmacotherapy forward against unorthodox membrane protein targets.

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“…While existing integrin modulators work by stabilizing the inactive conformation of the ecto-domains, there has been recent interest in pharmacological targeting of transmembrane structure (Shandler et al, 2011). However, transmembrane domains pose a particular challenge for conventional solution NMR due to the large molecular weight of the bilayer required to maintain the protein in the correct conformation.…”

Section: Expression and Labelingmentioning

confidence: 99%