Tailoring peptidomimetics for targeting protein-protein interactions

Omar N. Akram, David J. DeGraff, Jonathan H. Sheehan, Wayne D. Tilley, Robert J. Matusik, Jung Mo Ahn, Ganesh V. Raj

Research output: Contribution to journalReview article

20 Citations (Scopus)

Abstract

Protein-protein interactions (PPI) are a hallmark of cellular signaling. Such interactions occur abundantly within the cellular milieu and encompass interactions involved in vital cellular processes. Understanding the various types, mechanisms, and consequences of PPIs with respect to cellular signaling and function is vital for targeted drug therapy. Various types of small-molecule drugs and targeted approaches to drug design have been developed to modulate PPIs. Peptidomimetics offer an exciting class of therapeutics as they can be designed to target specific PPIs by mimicking key recognition motifs found at critical points in the interface of PPIs (e.g., hotspots). In contrast to peptides, peptidomimetics do not possess a natural peptide backbone structure but present essential functional groups in a required three-dimensional pattern complimentary to the protein-binding pocket. This design feature overcomes many limitations of peptide therapeutics including limited stability toward peptidases, poor transport across biologic membranes, and poor target specificity. Equally important is deciphering the structural requirements and amino acid residues critical to PPIs. This review provides an up-to-date perspective of the complexity of cellular signaling and strategies for targeting PPIs in disease states, particularly in cancer, using peptidomimetics, and highlights that the rational design of agents that target PPIs is not only feasible but is of the utmost clinical importance.

Original languageEnglish (US)
Pages (from-to)967-978
Number of pages12
JournalMolecular Cancer Research
Volume12
Issue number7
DOIs
StatePublished - Jul 2014

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Peptidomimetics
Protein Transport
Peptides
Biological Transport
Proteins
Drug Design
Protein Binding
Peptide Hydrolases
Amino Acids
Drug Therapy
Membranes
Therapeutics
Pharmaceutical Preparations
Neoplasms

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Oncology
  • Cancer Research

Cite this

Akram, O. N., DeGraff, D. J., Sheehan, J. H., Tilley, W. D., Matusik, R. J., Ahn, J. M., & Raj, G. V. (2014). Tailoring peptidomimetics for targeting protein-protein interactions. Molecular Cancer Research, 12(7), 967-978. https://doi.org/10.1158/1541-7786.MCR-13-0611
Akram, Omar N. ; DeGraff, David J. ; Sheehan, Jonathan H. ; Tilley, Wayne D. ; Matusik, Robert J. ; Ahn, Jung Mo ; Raj, Ganesh V. / Tailoring peptidomimetics for targeting protein-protein interactions. In: Molecular Cancer Research. 2014 ; Vol. 12, No. 7. pp. 967-978.
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Akram, ON, DeGraff, DJ, Sheehan, JH, Tilley, WD, Matusik, RJ, Ahn, JM & Raj, GV 2014, 'Tailoring peptidomimetics for targeting protein-protein interactions', Molecular Cancer Research, vol. 12, no. 7, pp. 967-978. https://doi.org/10.1158/1541-7786.MCR-13-0611

Tailoring peptidomimetics for targeting protein-protein interactions. / Akram, Omar N.; DeGraff, David J.; Sheehan, Jonathan H.; Tilley, Wayne D.; Matusik, Robert J.; Ahn, Jung Mo; Raj, Ganesh V.

In: Molecular Cancer Research, Vol. 12, No. 7, 07.2014, p. 967-978.

Research output: Contribution to journalReview article

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T1 - Tailoring peptidomimetics for targeting protein-protein interactions

AU - Akram, Omar N.

AU - DeGraff, David J.

AU - Sheehan, Jonathan H.

AU - Tilley, Wayne D.

AU - Matusik, Robert J.

AU - Ahn, Jung Mo

AU - Raj, Ganesh V.

PY - 2014/7

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