α-Helix mimetics as inhibitors of protein–protein interactions

2008 ◽  
Vol 36 (6) ◽  
pp. 1414-1417 ◽  
Author(s):  
Ishu Saraogi ◽  
Andrew D. Hamilton
Keyword(s):  
Protein Interactions ◽  
First Generation ◽  
Side Chain ◽  
Protein Protein Interactions ◽  
Substitution Pattern ◽  
Pathological Conditions ◽  
Synthetic Accessibility ◽  
Helix Mimetics ◽  
Viable Approach ◽  
Α Helix

The inhibition of protein–protein interactions using small molecules is a viable approach for the treatment of a range of pathological conditions that result from a malfunctioning of these interactions. Our strategy for the design of such agents involves the mimicry of side-chain residues on one face of the α-helix; these residues frequently play a key role in mediating protein–protein interactions. The first-generation terphenyl scaffold, with a 3,2′,2″-substitution pattern, is able to successfully mimic key helix residues and disrupt therapeutically relevant interactions, including the Bcl-XL–Bak and the p53–hDM2 (human double minute 2) interactions that are implicated in cancer. The second- and third-generation scaffolds have resulted in greater synthetic accessibility and more drug-like character in these molecules.

Using halo (het) arylboronic species to achieve synthesis of foldamers as protein–protein interaction disruptors

2012 ◽  
Vol 84 (11) ◽  
pp. 2467-2478 ◽  
Author(s):  
Anne Sophie Voisin-Chiret ◽  
Sylvain Rault
Keyword(s):  
Protein Interactions ◽  
Cell Biology ◽  
First Generation ◽  
In Silico Analysis ◽  
Side Chain ◽  
Protein Protein Interactions ◽  
Protein Protein Interaction ◽  
Common Motif ◽  
Difficult Procedure ◽  
Α Helix

Protein–protein interactions (PPIs) play a central role in all biological processes and have been the focus of intense investigations from structural molecular biology to cell biology for the majority of the last two decades and, more recently, are emerging as important targets for pharmaceuticals. A common motif found at the interface of PPIs is the α-helix, and apart from the peptidic structures, numerous nonpeptidic small molecules have been developed to mimic α-helices. The first-generation terphenyl scaffold is able to successfully mimic key helix residues and disrupt relevant interactions, including Bcl-xL-Bak interactions that are implicated in apoptosis mechanism. These scaffolds were designed and evaluated in silico. Analysis revealed that substituents on aromatic scaffolds can efficiently mimic side-chain surfaces. Unfortunately, the literature describes a long and difficult procedure to access these aromatic-based scaffolds. The search for new simpler methodology is the aim of the research of our medicinal chemistry team. On the basis of structural requirements, we developed a program concerning the synthesis of new oligo(het)aryl scaffolds produced by iterative couplings of boronic species (garlanding) in which substituents on rings project functionality in spatial orientations that mimic residues of an α-helix.

scholarly journals Heterocyclic α-helix mimetics for targeting protein–protein interactions

2007 ◽  
Vol 17 (16) ◽  
pp. 4641-4645 ◽  
Author(s):  
Shannon M. Biros ◽  
Lionel Moisan ◽  
Enrique Mann ◽  
Alexandre Carella ◽  
Dayong Zhai ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Protein Protein Interactions ◽  
Helix Mimetics ◽  
Α Helix

scholarly journals α-Helix stabilization by co-operative side chain charge-reinforced interactions to phosphoserine in a basic kinase-substrate motif

2021 ◽  
Author(s):  
Matthew Batchelor ◽  
Robert S Dawber ◽  
Andrew J Wilson ◽  
Richard Bayliss
Keyword(s):  
Protein Interactions ◽  
Molecular Mechanisms ◽  
Side Chain ◽  
Protein Protein Interactions ◽  
Cellular Functions ◽  
Kinase Substrate ◽  
Human Proteins ◽  
Recognition Motifs ◽  
Α Helix ◽  
General Method

How cellular functions are regulated through protein phosphorylation events that promote or inhibit protein-protein interactions (PPIs) is key to understanding regulatory molecular mechanisms. Whilst phosphorylation can orthosterically or allosterically influence protein recognition, phospho-driven changes in the conformation of recognition motifs are less well explored. We recently discovered that clathrin heavy chain recognises phosphorylated TACC3 through a helical motif that, in the unphosphorylated protein, is disordered. However, it was unclear whether and how phosphorylation could stabilize a helix in a broader context. In the current manuscript, we address this challenge using poly-Ala based model peptides and a suite of circular dichroism and nuclear magnetic resonance spectroscopies. We show that phosphorylation of a Ser residue stabilizes the α-helix in the context of an Arg(i - 3)pSeri Lys(i + 4) triad through charge-reinforced side chain interactions with positive co-operativity, whilst phosphorylation of Thr induces an opposing response. This is significant as it may represent a general method for control of PPIs by phosphorylation; basic kinase-substrate motifs are common with 55 human protein kinases recognising an Arg at a position -3 from the phosphorylated Ser, whilst the Arg(i - 3)pSeri Lys(i + 4) is a motif found in over 2000 human proteins.

Converting One-Face α-Helix Mimetics into Amphiphilic α-Helix Mimetics as Potent Inhibitors of Protein–Protein Interactions

2015 ◽  
Vol 18 (1) ◽  
pp. 36-42 ◽  
Author(s):  
Ji Hoon Lee ◽  
Misook Oh ◽  
Hyun Soo Kim ◽  
Huisun Lee ◽  
Wonpil Im ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Protein Protein Interactions ◽  
Helix Mimetics ◽  
Α Helix

scholarly journals Novel Pyrrolopyrimidine-Based α-Helix Mimetics: Cell-Permeable Inhibitors of Protein−Protein Interactions

2011 ◽  
Vol 133 (4) ◽  
pp. 676-679 ◽  
Author(s):  
Ji Hoon Lee ◽  
Qi Zhang ◽  
Sunhwan Jo ◽  
Sergio C. Chai ◽  
Misook Oh ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Protein Protein Interactions ◽  
Helix Mimetics ◽  
Α Helix
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