title: Tailoring peptidomimetics for targeting protein-protein interactions.
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.
authors.affiliation: Authors' Affiliations: Department of Urology, University of Texas Southwestern Medical Center, Dallas;
authors.forename: Omar N
authors.initials: ON
authors.lastname: Akram
authors.affiliation: Penn State College of Medicine, Milton S. Hershey Medical Center, Hershey, Pennsylvania.
authors.forename: David J
authors.initials: DJ
authors.lastname: DeGraff
authors.affiliation: Department of Biochemistry (Center for Structural Biology), Vanderbilt University, Nashville, Tennessee;
authors.forename: Jonathan H
authors.initials: JH
authors.lastname: Sheehan
authors.affiliation: Dame Roma Mitchell Cancer Research Laboratories and the Adelaide Prostate, Cancer Research Centre, School of Medicine, Hanson Institute Building, University of Adelaide, Adelaide, Australia; and.
authors.forename: Wayne D
authors.initials: WD
authors.lastname: Tilley
authors.affiliation: Department of Urologic Surgery, Vanderbilt University Medical Center;
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Matusik
authors.affiliation: Department of Chemistry, University of Texas at Dallas, Richardson, Texas;
authors.forename: Jung-Mo
authors.initials: JM
authors.lastname: Ahn
authors.affiliation: Authors' Affiliations: Department of Urology, University of Texas Southwestern Medical Center, Dallas; ganesh.raj@utsouthwestern.edu.
authors.forename: Ganesh V
authors.initials: GV
authors.lastname: Raj
mesh_terms: D015195:Drug Design; D006801:Humans; D057786:Peptidomimetics / Q000378:metabolism*; D011485:Protein Binding; D025941:Protein Interaction Mapping; D017433:Protein Structure, Secondary; D015398:Signal Transduction
chemical_list: D057786:Peptidomimetics