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Inhibition of nutlin-resistant HDM2 mutants by stapled peptides.

ABSTRACT: Pharmacological modulation of p53 activity is an attractive therapeutic strategy in cancers with wild-type p53. Presently in clinical trials, the small molecule Nutlin-3A competitively binds to HDM2, a key negative regulator of p53 and blocks its activity. We have described resistance mutations in HDM2 that selectively reduce affinity for Nutlin but not p53. In the present communication, we show that stapled peptides targeting the same region of HDM2 as Nutlin are refractory to these mutations, and display reduced discrimination between the wild-type and mutant HDM2s with regards to functional abrogation of interaction with p53. The larger interaction footprint afforded by stapled peptides suggests that this class of ligands may prove comparatively more resilient to acquired resistance in a clinical setting.

SUBMITTER: Wei SJ

PROVIDER: S-EPMC3835680 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Inhibition of nutlin-resistant HDM2 mutants by stapled peptides.

Wei Siau Jia SJ Joseph Thomas T Chee Sharon S Li Ling L Yurlova Larisa L Zolghadr Kourosh K Brown Christopher C Lane David D Verma Chandra C Ghadessy Farid F

PloS one 20131120 11

Pharmacological modulation of p53 activity is an attractive therapeutic strategy in cancers with wild-type p53. Presently in clinical trials, the small molecule Nutlin-3A competitively binds to HDM2, a key negative regulator of p53 and blocks its activity. We have described resistance mutations in HDM2 that selectively reduce affinity for Nutlin but not p53. In the present communication, we show that stapled peptides targeting the same region of HDM2 as Nutlin are refractory to these mutations, ...[more]

PMID: 24278380

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In vitro selection of mutant HDM2 resistant to Nutlin inhibition.

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Structure of a stapled peptide antagonist bound to nutlin-resistant Mdm2.

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Screening of Hydrocarbon-Stapled Peptides for Inhibition of Calcium-Triggered Exocytosis.

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2022-09-29 | GSE201116 | GEO

Effect of linker on the binding free energy of stapled p53/HDM2 complex.

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Conjugates of Aminoglycosides with Stapled Peptides as a Way to Target Antibiotic-Resistant Bacteria.

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Design of stapled antimicrobial peptides that are stable, nontoxic and kill antibiotic-resistant bacteria in mice.

Project description:The clinical translation of cationic α-helical antimicrobial peptides (AMPs) has been hindered by structural instability, proteolytic degradation and in vivo toxicity from nonspecific membrane lysis. Although analyses of hydrophobic content and charge distribution have informed the design of synthetic AMPs with increased potency and reduced in vitro hemolysis, nonspecific membrane toxicity in vivo continues to impede AMP drug development. Here, we analyzed a 58-member library of stapled AMPs (StAMPs) based on magainin II and applied the insights from structure-function-toxicity measurements to devise an algorithm for the design of stable, protease-resistant, potent and nontoxic StAMP prototypes. We show that a lead double-stapled StAMP named Mag(i+4)1,15(A9K,B21A,N22K,S23K) can kill multidrug-resistant Gram-negative pathogens, such as colistin-resistant Acinetobacter baumannii in a mouse peritonitis-sepsis model, without observed hemolysis or renal injury in murine toxicity studies. Inputting the amino acid sequences alone, we further generated membrane-selective StAMPs of pleurocidin, CAP18 and esculentin, highlighting the generalizability of our design platform.

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