Selective and Potent Proteomimetic Inhibitors of Intracellular Protein–Protein Interactions

Barnard, Anna; Long, Kérya; Martin, Heather L.; Miles, Jennifer A.; Edwards, Thomas A.; Tomlinson, Darren C.; Macdonald, Andrew; Wilson, Andrew J.

doi:10.1002/anie.201410810

Cited by 89 publications

(72 citation statements)

References 61 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…This is the first report of fine-tuning of the PPI selectivity by means of stereochemistry [136]. Furthermore, in cellulo active oligomers were characterized [137].…”

Section: Aromatic Oligoamidesmentioning

confidence: 79%

An overview of peptide and peptoid foldamers in medicinal chemistry

Mándity¹,

Fülöp²

2015

Expert Opinion on Drug Discovery

View full text Add to dashboard Cite

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.

show abstract

“…This is the first report of fine-tuning of the PPI selectivity by means of stereochemistry [136]. Furthermore, in cellulo active oligomers were characterized [137].…”

Section: Aromatic Oligoamidesmentioning

confidence: 79%

An overview of peptide and peptoid foldamers in medicinal chemistry

Mándity¹,

Fülöp²

2015

Expert Opinion on Drug Discovery

View full text Add to dashboard Cite

show abstract

“…Our observations regarding Bcl-x L vs. Mcl-1 selectivity complement other recent reports of comparable selectivity in within different ligand families. 41,42 …”

Section: Discussionmentioning

confidence: 99%

Residue-Based Preorganization of BH3-Derived α/β-Peptides: Modulating Affinity, Selectivity and Proteolytic Susceptibility in α-Helix Mimics

et al. 2015

View full text Add to dashboard Cite

We report progress toward a general strategy for mimicking the recognition properties of specific α-helices within natural proteins through the use of oligomers that are less susceptible than conventional peptides to proteolysis. The oligomers contain both α- and β-amino acid residues, with the density of the β subunits low enough that an α-helix-like conformation can be formed but high enough to interfere with protease activity. Previous studies with a different protein-recognition system suggested ring-constrained β residues can be superior to flexible β residues in terms of maximizing α/β-peptide affinity for a targeted protein surface. Here, we use mimicry of the 18-residue Bim BH3 domain to expand the scope of this strategy. Two significant advances have been achieved. First, we have developed and validated a new ring-constrained β residue that bears an acidic side chain, which complements previously known analogues that are either hydrophobic or basic. Second, we have discovered that placing cyclic β residues at sites that make direct contact with partner proteins can lead to substantial discrimination between structurally homologous binding partners, the proteins Bcl-xL and Mcl-1. Overall, this study helps to establish that α/β-peptides containing ring-preorganized β residues can reliably provide proteolytically resistant ligands for proteins that naturally evolved to recognize α-helical partners.

show abstract

“…However, current research is also faced with several challenges. 186 Case study 1: a comprehensive small molecule library of secondary structure mimetics as PPI inhibitors. Diverse space that corresponds to PPI ''hot-spots'' is necessary for the discovery of small-molecule inhibitors.…”

Section: Design Of Small Molecule Mimetics Of the Secondary Structurementioning

confidence: 99%

State-of-the-art strategies for targeting protein–protein interactions by small-molecule inhibitors

et al. 2015

View full text Add to dashboard Cite

Targeting protein-protein interactions (PPIs) has emerged as a viable approach in modern drug discovery. However, the identification of small molecules enabling us to effectively interrupt their interactions presents significant challenges. In the recent past, significant advances have been made in the development of new biological and chemical strategies to facilitate the discovery process of small-molecule PPI inhibitors. This review aims to highlight the state-of-the-art technologies and the achievements made recently in this field. The "hot spots" of PPIs have been proved to be critical for small molecules to bind. Three strategies including screening, designing, and synthetic approaches have been explored for discovering PPI inhibitors by targeting the "hot spots". Although the classic high throughput screening approach can be used, fragment screening, fragment-based drug design and newly improved virtual screening are demonstrated to be more effective in the discovery of PPI inhibitors. In addition to screening approaches, design strategies including anchor-based and small molecule mimetics of secondary structures involved in PPIs have become powerful tools as well. Finally, constructing new chemically spaced libraries with high diversity and complexity is becoming an important area of interest for PPI inhibitors. The successful cases from the recent five year studies are used to illustrate how these approaches are implemented to uncover and optimize small molecule PPI inhibitors and notably some of them have become promising therapeutics.

show abstract

Selective and Potent Proteomimetic Inhibitors of Intracellular Protein–Protein Interactions

Cited by 89 publications

References 61 publications

An overview of peptide and peptoid foldamers in medicinal chemistry

An overview of peptide and peptoid foldamers in medicinal chemistry

Residue-Based Preorganization of BH3-Derived α/β-Peptides: Modulating Affinity, Selectivity and Proteolytic Susceptibility in α-Helix Mimics

State-of-the-art strategies for targeting protein–protein interactions by small-molecule inhibitors

Contact Info

Product

Resources

About