Strategies to Develop Inhibitors of Motif-Mediated Protein-Protein Interactions as Drug Leads

Corbi‐Verge, Carles; Garton, Michael; Nim, Satra; Kim, Philip M.

doi:10.1146/annurev-pharmtox-010716-104805

Cited by 35 publications

(31 citation statements)

References 155 publications

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“…6,8,12,13 Representing a cutting-edge breakthrough in drug discovery, allosteric PPI modulators are widely accepted as a possible complement and alternative to orthosteric PPI ligands due to their potential for improved physiochemical and pharmacological properties. Several allosteric PPI modulators have already reached the clinic, such as paclitaxel (19) and its derivatives targeting αand β-tubulin. 6,8,193,195,[206][207][208][209][210][211][212][213] Nevertheless, problems such as suboptimal pharmacokinetic properties still exist.…”

Section: Discussionmentioning

confidence: 99%

“…Despite these challenges, a small fraction of PPIs has been successfully tailored by orthosteric PPI ligands. Many excellent reviews have been written on the discovery of orthosteric PPI ligands, 6,8,[11][12][13][14][15][16][17][18][19][20][21] which have provided complete and thorough mechanistic insights into their mechanisms, so we will not describe the repertoire of orthosteric PPI ligands any further here.…”

mentioning

confidence: 99%

“…Although many reviews have been published on the topic of PPI modulators, [6][7][8]13,15,18,19,21 the majority of them mainly focused on orthosteric PPI ligands. Furthermore, compared with the action modes of orthosteric PPI modulators, the mechanisms underlying the allosteric regulation towards PPIs are more complicated, and a comprehensive review on this topic is still lacking.…”

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confidence: 99%

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Emerging roles of allosteric modulators in the regulation of protein‐protein interactions (PPIs): A new paradigm for PPI drug discovery

Zhang

2019

Medicinal Research Reviews

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Protein‐protein interactions (PPIs) are closely implicated in various types of cellular activities and are thus pivotal to health and disease states. Given their fundamental roles in a wide range of biological processes, the modulation of PPIs has enormous potential in drug discovery. However, owing to the general properties of large, flat, and featureless interfaces of PPIs, previous attempts have demonstrated that the generation of therapeutic agents targeting PPI interfaces is challenging, rendering them almost “undruggable” for decades. To date, rapid progress in chemical and structural biology techniques has promoted the exploitation of allostery as a novel approach in drug discovery. By attaching to allosteric sites that are topologically and spatially distinct from PPI interfaces, allosteric modulators can achieve improved physiochemical properties. Thus, allosteric modulators may represent an alternative strategy to target intractable PPIs and have attracted intense pharmaceutical interest. In this review, we first briefly introduce the characteristics of PPIs and then present different approaches for investigating PPIs, as well as the latest methods for modulating PPIs. Importantly, we comprehensively review the recent progress in the development of allosteric modulators to inhibit or stabilize PPIs. Finally, we conclude with future perspectives on the discovery of allosteric PPI modulators, especially the application of computational methods to aid in allosteric PPI drug discovery.

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Section: Discussionmentioning

confidence: 99%

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Emerging roles of allosteric modulators in the regulation of protein‐protein interactions (PPIs): A new paradigm for PPI drug discovery

Zhang

2019

Medicinal Research Reviews

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“…Usually short linear peptides are considered to be lousy drug candidates because of their fast proteolytic degradation rates and low cell permeability . Surprisingly, peptide 10 , a tetramethylrhodamine (TAMRA) labelled derivative of peptide 5 , was cell permeable and resistant to proteolysis (Figure S3–S7), which allowed us to measure the IC 50 value for NFAT inhibition of (12.7±4.2) μ m .…”

Section: Figurementioning

confidence: 96%

Screening for Selective Protein Inhibitors by Using the IANUS Peptide Array

et al. 2018

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Finding new road blacks: A peptidic inhibitor of calcineurin (CaN)-mediated nuclear factor of activated T cells (NFAT) dephosphorylation, which is developed through a template-assisted IANUS (Induced orgANisation of strUcture by matrix-assisted togethernesS) peptide array, is cell permeable and able to block the translocation of green fluorescent protein-NFAT fusion protein (GFP-NFAT) into the nucleus after stimulation.

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“…Such techniques can be used to design inhibitors of the biological interaction with a view to producing a therapeutic outcome. Peptide fragments at protein–protein interfaces can be extracted and used as peptide inhibitors of protein–protein interactions (PPIs) . Such peptides often have suboptimal binding affinity and require substantial optimization to achieve efficacy at therapeutically viable concentrations.…”

Section: Introductionmentioning

confidence: 99%

Rapid and accurate structure‐based therapeutic peptide design using GPU accelerated thermodynamic integration

Garton

Corbi‐Verge

et al. 2019

Proteins

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Peptide‐based therapeutics are an alternative to small molecule drugs as they offer superior specificity, lower toxicity, and easy synthesis. Here we present an approach that leverages the dramatic performance increase afforded by the recent arrival of GPU accelerated thermodynamic integration (TI). GPU TI facilitates very fast, highly accurate binding affinity optimization of peptides against therapeutic targets. We benchmarked TI predictions using published peptide binding optimization studies. Prediction of mutations involving charged side‐chains was found to be less accurate than for non‐charged, and use of a more complex 3‐step TI protocol was found to boost accuracy in these cases. Using the 3‐step protocol for non‐charged side‐chains either had no effect or was detrimental. We use the benchmarked pipeline to optimize a peptide binding to our recently discovered cancer target: EME1. TI calculations predict beneficial mutations using both canonical and non‐canonical amino acids. We validate these predictions using fluorescence polarization and confirm that binding affinity is increased. We further demonstrate that this increase translates to a significant reduction in pancreatic cancer cell viability.

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Strategies to Develop Inhibitors of Motif-Mediated Protein-Protein Interactions as Drug Leads

Cited by 35 publications

References 155 publications

Emerging roles of allosteric modulators in the regulation of protein‐protein interactions (PPIs): A new paradigm for PPI drug discovery

Emerging roles of allosteric modulators in the regulation of protein‐protein interactions (PPIs): A new paradigm for PPI drug discovery

Screening for Selective Protein Inhibitors by Using the IANUS Peptide Array

Rapid and accurate structure‐based therapeutic peptide design using GPU accelerated thermodynamic integration

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