Interface Peptide Mimetics-Rationale and Application as Therapeutic Agents

Abstract

Biomolecular recognition via protein-protein interactions (PPI) is central to the signaling events in most physiological and pathological processes. Hence PPI are considered excellent targets for drug development. In recent years there is considerable interest in the design and development of peptide based drugs as antagonists or agonists of PPI. High potency, great selectivity and better safety profile are significant advantages of peptide therapeutics. The following is a brief review of the rationale and modifications in the design of peptide mimetics of PPI interface.

Mechanisms of NF-κB p65 and strategies for therapeutic manipulation

“…A conceptually simple strategy for development of inhibitors of interprotein interactions is to take advantage of the evolutionary selection of residues for individual protein:protein interaction and design interface peptides derived from the primary sequence of one of the binding partners. 85 , 86 As stated above, phosphorylation on Ser276, Ser529, Ser536, and Ser471 induces conformational changes in p65 and facilitates its binding with other transcriptional cofactors such as p300 and PCAF. 59 Synthetic peptides encompassing these phosphorylation sites in p65 fused with a protein transduction domain have been shown to suppress NF-κB activation induced by a variety of stimuli such as LPS, interleukin-1, okadaic acid, phorbol 12-myristate 13-acetate, and cigarette smoke condensate inflammatory stimuli.…”

Nuclear factor‐kappa B: Glucocorticoid‐induced leucine zipper interface analogs suppress pathology in an Alzheimer's disease model

“…Interfaces of protein-protein interactions are considered excellent targets for developing peptide inhibitors [46] . Rapid proteolytic degradation and poor stability are considered significant shortcomings of peptides as drugs.…”

Using Peptidomimetics and Constrained Peptides as Valuable Tools for Inhibiting Protein–Protein Interactions

“…Overcoming these difficulties frequently involves one or more of the following: incorporation of non-native amino acids [ 53 ], D-amino acids [ 54 , 55 , 56 , 57 ], and β-amino acids [ 58 ]; retro-inverso peptides [ 59 ]; changing the backbone (through N -methylation [ 60 ], or the introduction of amide bond isosteres [ 61 ]); and cyclising strategies [ 62 , 63 , 64 , 65 ]. Non-native amino acids confer stability as a result of the proteolytic machinery in the cell being ill equipped to deal with unnatural amino acids [ 66 ]. Unnatural amino acids such as α-aminobutyric acid (Aib or α-methylalanine) can promote secondary structure formation (3 10 -helix), while other α,α-disubstituted amino acids, such as α-pentenylalanine, can help form an α-helix, owing to the Thorpe–Ingold effect [ 67 ].…”

“…Other backbone modifications, such as the use of foldamers, β-peptides and peptoids can additionally infer both proteolytic and metabolic stability [ 69 , 70 ]. Cyclic peptides have improved metabolic stability compared with their linear counterparts and cyclisation introduces conformational constraints that can reduce the flexibility of the peptide, allowing for a reduced entropic cost upon binding, thus increasing binding affinity [ 66 , 71 ]. A few of the above peptide modifications will be discussed further in the following Sections.…”