All-hydrocarbon stapled peptides as Synthetic Cell-Accessible Mini-Proteins

Verdine, Gregory L.; Hilinski, Gerard J.

doi:10.1016/j.ddtec.2012.01.004

Cited by 69 publications

(68 citation statements)

References 45 publications

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“…Stapled peptides are highly promising therapeutic agents for the inhibition of PPIs, because they generally exhibit enhanced helicity, protease resistance, and biological potency [19][20][21][22]. The development of stapled peptides promises to enable access to a-helix-mediated PPI drug targets [23,24].…”

Section: Introductionmentioning

confidence: 99%

Stapled peptide design: principles and roles of computation

Tan

Lane

Verma

2016

Drug Discovery Today

101

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Section: Introductionmentioning

confidence: 99%

Stapled peptide design: principles and roles of computation

Tan

Lane

Verma

2016

Drug Discovery Today

101

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“…[19][20][21][22][23][24][27][28][29] and 62 for reviews) for the modulation a plethora of intracellular targets (i.e. Bcl2-family, 19,[22][23][24]43,47,48,58,[67][68][69][70][71]76,77,83,92,93,98 p53:MDM2/X, 42,57,65,66,72,79,81,82,87,89,94,95 MAML:Notch, 49 eIF4E, 158 ERa/ERb, 50 IRS1, 84 HIF-1:p300, 56,90 RAS:SOS, 59 Rab-GTPase, 96 b-catenin, 64,78,80 protein kinase-A, 91 RPA, 97 HIV-1 integrase, …”

Section: Stapled Peptide Modulation Of Drug Target Spacementioning

confidence: 99%

“…Most importantly, it is this abundance of compelling therapeutic opportunities corresponding to such a-helical interfaces in protein-protein drug space that has propelled the concept of a new drug modality based upon macrocyclic a-helical peptide design. 3,12,[16][17][18][19][20][21][22][23][24][25][26][27][28][29] In particular, stapled peptides have been developed as novel molecular probes within academia and, notably, Aileron Therapeutics is advancing the stapled peptides into drug development and future clinical testing.…”

Section: A-helical Interfaces In Protein-protein Drug Target Spacementioning

confidence: 99%

Macrocyclic α-Helical Peptide Drug Discovery

Sawyer

Guerlavais

Darłak

et al. 2014

Macrocycles in Drug Discovery

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Macrocyclic α-helical peptides have emerged as a promising new drug class and within the scope of hydrocarbon-stapled peptides such molecules have advanced into the clinic. The overarching concept of designing proteomimetics of an α-helical ‘ligand’ which binds its cognate ‘target’ relative to α-helical interfacing protein-protein interactions has been well-validated and expanded through numerous investigations for a plethora of therapeutic targets oftentimes referred to as “undruggable” with respect to other modalities (e.g., small-molecule or proteins). This chapter highlights the evolution of macrocyclic α-helical peptides in terms of target space, biophysical and computational chemistry, structural diversity and synthesis, drug design and chemical biology. It is noteworthy that hydrocarbon-stapled peptides have successfully risen to the summit of such drug discovery campaigns.

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“…15,27 Various computational methods have been developed to rapidly identify binding sites on protein surfaces in the last couple of decades. The earliest methods were either geometry-based or energy-based, such as POCKET 28 and GRID, 29 respectively.…”

Section: ■ Introductionmentioning

confidence: 99%

The Application of Ligand-Mapping Molecular Dynamics Simulations to the Rational Design of Peptidic Modulators of Protein–Protein Interactions

Tan

Spring

Abell

et al. 2015

J. Chem. Theory Comput.

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A computational ligand-mapping approach to detect protein surface pockets that interact with hydrophobic moieties is presented. In this method, we incorporated benzene molecules into explicit solvent molecular dynamics simulations of various protein targets. The benzene molecules successfully identified the binding locations of hydrophobic hot-spot residues and all-hydrocarbon cross-links from known peptidic ligands. They also unveiled cryptic binding sites that are occluded by side chains and the protein backbone. Our results demonstrate that ligand-mapping molecular dynamics simulations hold immense promise to guide the rational design of peptidic modulators of protein-protein interactions, including that of stapled peptides, which show promise as an exciting new class of cell-penetrating therapeutic molecules.

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All-hydrocarbon stapled peptides as Synthetic Cell-Accessible Mini-Proteins

Cited by 69 publications

References 45 publications

Stapled peptide design: principles and roles of computation

Stapled peptide design: principles and roles of computation

Macrocyclic α-Helical Peptide Drug Discovery

The Application of Ligand-Mapping Molecular Dynamics Simulations to the Rational Design of Peptidic Modulators of Protein–Protein Interactions

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