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Chemically modified peptides targeting the PDZ domain of GIPC as a therapeutic approach for cancer.

Publication ,  Journal Article
Patra, CR; Rupasinghe, CN; Dutta, SK; Bhattacharya, S; Wang, E; Spaller, MR; Mukhopadhyay, D
Published in: ACS chemical biology
April 2012

GIPC (GAIP-interacting protein, C terminus) represents a new target class for the discovery of chemotherapeutics. While many of the current generation of anticancer agents function by directly binding to intracellular kinases or cell surface receptors, the disruption of cytosolic protein-protein interactions mediated by non-enzymatic domains is an underdeveloped avenue for inhibiting cancer growth. One such example is the PDZ domain of GIPC. Previously we developed a molecular probe, the cell-permeable octapeptide CR1023 (N-myristoyl-PSQSSSEA), which diminished proliferation of pancreatic cancer cells. We have expanded upon that discovery using a chemical modification approach and here report a series of cell-permeable, side chain-modified lipopeptides that target the GIPC PDZ domain in vitro and in vivo. These peptides exhibit significant activity against pancreatic and breast cancers, both in cellular and animal models. CR1166 (N-myristoyl-PSQSK(εN-4-bromobenzoyl)SK(εN-4-bromobenzoyl)A), bearing two halogenated aromatic units on alternate side chains, was found to be the most active compound, with pronounced down-regulation of EGFR/1GF-1R expression. We hypothesize that these organic acid-modified residues extend the productive reach of the peptide beyond the canonical binding pocket, which defines the limit of accessibility for the native proteinogenic sequences that the PDZ domain has evolved to recognize. Cell permeability is achieved with N-terminal lipidation using myristate, rather than a larger CPP (cell-penetrating peptide) sequence. This, in conjunction with optimization of targeting through side chain modification, has yielded an approach that will allow the discovery and development of next-generation cellular probes for GIPC PDZ as well as for other PDZ domains.

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Published In

ACS chemical biology

DOI

EISSN

1554-8937

ISSN

1554-8929

Publication Date

April 2012

Volume

7

Issue

4

Start / End Page

770 / 779

Related Subject Headings

  • Structure-Activity Relationship
  • PDZ Domains
  • Organic Chemistry
  • Oligopeptides
  • Neoplasms
  • Humans
  • Adaptor Proteins, Signal Transducing
  • 34 Chemical sciences
  • 31 Biological sciences
  • 06 Biological Sciences
 

Citation

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Patra, C. R., Rupasinghe, C. N., Dutta, S. K., Bhattacharya, S., Wang, E., Spaller, M. R., & Mukhopadhyay, D. (2012). Chemically modified peptides targeting the PDZ domain of GIPC as a therapeutic approach for cancer. ACS Chemical Biology, 7(4), 770–779. https://doi.org/10.1021/cb200536r
Patra, Chitta Ranjan, Chamila N. Rupasinghe, Shamit K. Dutta, Santanu Bhattacharya, Enfeng Wang, Mark R. Spaller, and Debabrata Mukhopadhyay. “Chemically modified peptides targeting the PDZ domain of GIPC as a therapeutic approach for cancer.ACS Chemical Biology 7, no. 4 (April 2012): 770–79. https://doi.org/10.1021/cb200536r.
Patra CR, Rupasinghe CN, Dutta SK, Bhattacharya S, Wang E, Spaller MR, et al. Chemically modified peptides targeting the PDZ domain of GIPC as a therapeutic approach for cancer. ACS chemical biology. 2012 Apr;7(4):770–9.
Patra, Chitta Ranjan, et al. “Chemically modified peptides targeting the PDZ domain of GIPC as a therapeutic approach for cancer.ACS Chemical Biology, vol. 7, no. 4, Apr. 2012, pp. 770–79. Epmc, doi:10.1021/cb200536r.
Patra CR, Rupasinghe CN, Dutta SK, Bhattacharya S, Wang E, Spaller MR, Mukhopadhyay D. Chemically modified peptides targeting the PDZ domain of GIPC as a therapeutic approach for cancer. ACS chemical biology. 2012 Apr;7(4):770–779.
Journal cover image

Published In

ACS chemical biology

DOI

EISSN

1554-8937

ISSN

1554-8929

Publication Date

April 2012

Volume

7

Issue

4

Start / End Page

770 / 779

Related Subject Headings

  • Structure-Activity Relationship
  • PDZ Domains
  • Organic Chemistry
  • Oligopeptides
  • Neoplasms
  • Humans
  • Adaptor Proteins, Signal Transducing
  • 34 Chemical sciences
  • 31 Biological sciences
  • 06 Biological Sciences