Peptide-based inhibitors of protein–protein interactions: biophysical, structural and cellular consequences of introducing a constraint

Wang, Hongshuang; Dawber, Robert S.; Zhang, Peiyu; Walko, Martin; Wilson, Andrew J.; Wang, Xiaohui

doi:10.1039/d1sc00165e

Cited by 70 publications

(76 citation statements)

References 125 publications

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“…While the native tertiary structure as well as the stability of the full-length protein is based on the sum of interactions determined by its constituting amino acids (e.g., hydrophobic effects, polarities, charges, stabilizing disulphide bridges, etc. ), the structure and shape of isolated peptides is rather flexible and thus might not closely reproduce the actual interaction interface of both full-length proteins as present in vivo [37]. Prior to the performed peptide-protein docking simulations, the secondary structures of all analyzed peptides have been predicted by the PSIPRED algorithm [28].…”

Section: Discussionmentioning

confidence: 99%

CK1δ-Derived Peptides as Novel Tools Inhibiting the Interactions between CK1δ and APP695 to Modulate the Pathogenic Metabolism of APP

Roth

Gärtner

Mayer

et al. 2021

IJMS

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Alzheimer’s disease (AD) is the major cause of dementia, and affected individuals suffer from severe cognitive, mental, and functional impairment. Histologically, AD brains are basically characterized by the presence of amyloid plaques and neurofibrillary tangles. Previous reports demonstrated that protein kinase CK1δ influences the metabolism of amyloid precursor protein (APP) by inducing the generation of amyloid-β (Aβ), finally contributing to the formation of amyloid plaques and neuronal cell death. We therefore considered CK1δ as a promising therapeutic target and suggested an innovative strategy for the treatment of AD based on peptide therapeutics specifically modulating the interaction between CK1δ and APP. Initially, CK1δ-derived peptides manipulating the interactions between CK1δ and APP695 were identified by interaction and phosphorylation analysis in vitro. Selected peptides subsequently proved their potential to penetrate cells without inducing cytotoxic effects. Finally, for at least two of the tested CK1δ-derived peptides, a reduction in Aβ levels and amyloid plaque formation could be successfully demonstrated in a complex cell culture model for AD. Consequently, the presented results provide new insights into the interactions of CK1δ and APP695 while also serving as a promising starting point for further development of novel and highly innovative pharmacological tools for the treatment of AD.

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Section: Discussionmentioning

confidence: 99%

CK1δ-Derived Peptides as Novel Tools Inhibiting the Interactions between CK1δ and APP695 to Modulate the Pathogenic Metabolism of APP

Roth

Gärtner

Mayer

et al. 2021

IJMS

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“…The design principles of interface peptides and the repertoire of technical solutions are detailed in recent reviews [ 44 , 45 , 46 , 47 , 48 , 49 , 50 ]. Optimization of the linear peptides is usually required to increase the binding affinity to the target protein, overcome a number of pharmacodynamic (pharmacokinetic) limitations and unfavorable physicochemical properties that reduce the in vivo efficacy.…”

Section: Current Approaches To the Design Of Interfacial Peptidesmentioning

confidence: 99%

Interfacial Peptides as Affinity Modulating Agents of Protein-Protein Interactions

2022

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The identification of disease-related protein-protein interactions (PPIs) creates objective conditions for their pharmacological modulation. The contact area (interfaces) of the vast majority of PPIs has some features, such as geometrical and biochemical complementarities, “hot spots”, as well as an extremely low mutation rate that give us key knowledge to influence these PPIs. Exogenous regulation of PPIs is aimed at both inhibiting the assembly and/or destabilization of protein complexes. Often, the design of such modulators is associated with some specific problems in targeted delivery, cell penetration and proteolytic stability, as well as selective binding to cellular targets. Recent progress in interfacial peptide design has been achieved in solving all these difficulties and has provided a good efficiency in preclinical models (in vitro and in vivo). The most promising peptide-containing therapeutic formulations are under investigation in clinical trials. In this review, we update the current state-of-the-art in the field of interfacial peptides as potent modulators of a number of disease-related PPIs. Over the past years, the scientific interest has been focused on following clinically significant heterodimeric PPIs MDM2/p53, PD-1/PD-L1, HIF/HIF, NRF2/KEAP1, RbAp48/MTA1, HSP90/CDC37, BIRC5/CRM1, BIRC5/XIAP, YAP/TAZ–TEAD, TWEAK/FN14, Bcl-2/Bax, YY1/AKT, CD40/CD40L and MINT2/APP.

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“…The determinants of α-helix stability are key in understanding the formation and strength of α-helix mediated protein-protein interactions (PPIs), 1 and therefore in enabling peptide drugdiscovery. 2,3 Prior studies established helix propensities of individual amino acids, 4,5 the role of helix capping 6,7 and effects of interaction between side chains, [8][9][10][11] however the role of phosphorylation is less well explored. Downloaded from http://portlandpress.com/biochemj/article-pdf/doi/10.1042/BCJ20210812/929569/bcj-2021-0812.pdf by guest on 07 March 2022 for analytical characterization data).…”

Section: Introductionmentioning

confidence: 99%

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

Batchelor

Dawber

Wilson

et al. 2022

Biochemical Journal

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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)pSeriLys(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)Seri Lys(i + 4) is a motif found in over 2000 human proteins.

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Peptide-based inhibitors of protein–protein interactions: biophysical, structural and cellular consequences of introducing a constraint

Abstract: This review summarizes the influence of inserting constraints on biophysical, conformational, structural and cellular behaviour for peptides targeting α-helix mediated protein–protein interactions.

Cited by 70 publications

References 125 publications

CK1δ-Derived Peptides as Novel Tools Inhibiting the Interactions between CK1δ and APP695 to Modulate the Pathogenic Metabolism of APP

CK1δ-Derived Peptides as Novel Tools Inhibiting the Interactions between CK1δ and APP695 to Modulate the Pathogenic Metabolism of APP

Interfacial Peptides as Affinity Modulating Agents of Protein-Protein Interactions

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

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