Strategies to Develop Inhibitors of Motif-Mediated Protein-Protein Interactions as Drug Leads.
Protein-protein interactions are fundamental for virtually all functions of the cell. A large fraction of these interactions involve short peptide motifs, and there has been increased interest in targeting them using peptide-based therapeutics. Peptides benefit from being specific, relatively safe, and easy to produce. They are also easy to modify using chemical synthesis and molecular biology techniques. However, significant challenges remain regarding the use of peptides as therapeutic agents. Identification of peptide motifs is difficult, and peptides typically display low cell permeability and sensitivity to enzymatic degradation. In this review, we outline the principal high-throughput methodologies for motif discovery and describe current methods for overcoming pharmacokinetic and bioavailability limitations.
Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario M5S 3E1, Canada; email: carles.corbiverge@utoronto.ca , michael.garton@utoronto.ca , satra.nim@kimlab.org , pi@kimlab.org.
Carles
C
Corbi-Verge
Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario M5S 3E1, Canada; email: carles.corbiverge@utoronto.ca , michael.garton@utoronto.ca , satra.nim@kimlab.org , pi@kimlab.org.
Michael
M
Garton
Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario M5S 3E1, Canada; email: carles.corbiverge@utoronto.ca , michael.garton@utoronto.ca , satra.nim@kimlab.org , pi@kimlab.org.
Satra
S
Nim
Terrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario M5S 3E1, Canada; email: carles.corbiverge@utoronto.ca , michael.garton@utoronto.ca , satra.nim@kimlab.org , pi@kimlab.org.|Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 3E1, Canada.|Department of Computer Science, University of Toronto, Toronto, Ontario M5S 3E1, Canada.
Philip M
PM
Kim
D000818:Animals; D055808:Drug Discovery / Q000379:methods* / Q000639:trends; D006801:Humans; D019151:Peptide Library; D010455:Peptides / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects / Q000502:physiology; D054730:Protein Interaction Domains and Motifs / Q000187:drug effects* / Q000502:physiology
D019151:Peptide Library; D010455:Peptides
cell-penetrating peptides; cyclic peptides; d-amino acids; drug discovery; lentivirus delivery; liposomes; mRNA display; nanotubes; noncanonical amino acids; peptide arrays; peptidomimetics; phage display; ribosome display; stapled peptides; yeast display