Protein-Peptide Interactions Revolutionize Drug Development

Stretching Peptides to Generate Small Molecule β-Strand Mimics

“…Extended amino acid backbone conformations are an abundant structural motif responsible for mediating a myriad of protein–protein interactions (PPIs). Along with other secondary structures including turns and helices, extended regions present ordered backbone and side chain orientations that contribute to specific recognition of protein targets. − Common modes of binding within protein–protein interaction domains include recognition of extended β-strand and type II polyproline (PPII) helical conformations . Modulation of these interactions requires mimicry of the specific and selective interactions between proteins, often originating from the PPII rich disordered regions present in over half of eukaryotic proteins. − The development of designed peptides biased toward an extended β-strand or PPII helical conformation is relevant for solving diverse biological problems from addressing the “undruggable” population of the proteome − to modeling or disrupting peptide aggregation .…”

“…1−3 Common modes of binding within protein−protein interaction domains include recognition of extended β-strand and type II polyproline (PPII) helical conformations. 4 Modulation of these interactions requires mimicry of the specific and selective interactions between proteins, often originating from the PPII rich disordered regions present in over half of eukaryotic proteins. 5−7 The development of designed peptides biased toward an extended β-strand or PPII helical conformation is relevant for solving diverse biological problems from addressing the "undruggable" population of the proteome 8−11 to modeling or disrupting peptide aggregation.…”

Insights into the molecular mechanisms of action of bioportides: a strategy to target protein-protein interactions

“…59) highlighted the challenge of developing cell permeable agents that are relatively resistant to metabolism by intestinal, plasma and cellular proteases. Hence, the major focus of this review is the synthesis and applications of cell permeable peptides, both stabilised helical peptides and bioportides that can target PPIs and so satisfy the requirements of peptide and peptide-like drugs (Refs 23, 32, 33, 34, 59, 60).…”

“…There is also a widespread recognition that PPIs play a central role in the development of many human diseases. It is perhaps no surprise, therefore, that we are currently witnessing an increased focus on peptide therapeutics that offer distinct advantages to the targeting of intracellular proteins (Refs 31, 34, 59, 60, 97, 98). We concur that it is most likely that the molecular mode of action of many bioportides (reviewed in Ref.…”

“…From such studies it is obvious that many human proteins consist of multiple accreted domains that are relatively ancien t in evolutionary terms. Moreover, it is particularly striking that, among proteins involved in intracellular signalling networks, there are many common promiscuous domains typically involved in PPIs (Refs 22, 23, 24, 38, 60, 94, 95, 96).…”