Designing Peptidomimetics

Abstract

The concept of a peptidomimetic was coined about forty years ago. Since then, enormous effort and interest have been devoted to mimic the properties of peptides with small molecules or pseudopeptides. The present report aims to review different approaches described in the past to succeed in this goal. Basically, there are two different approaches to design peptidomimetics: a medicinal chemistry approach, where parts of the peptide are successively replaced by non-peptide moieties until getting a non-peptide molecule and a biophysical approach, where a hypothesis of the bioactive form of the peptide is sketched and peptidomimetics are designed based on hanging the appropriate chemical moieties on diverse scaffolds. Although both approaches have been used in the past, the former has been more widely used to design peptidomimetics of secretory peptides, whereas the latter is nowadays getting momentum with the recent interest in designing protein-protein interaction inhibitors. The present report summarizes the relevance of the information gathered from structure-activity studies, together with a short review of the strategies used to design new peptide analogs and surrogates. In the following section, there is a short discussion on the characterization of the bioactive conformation of a peptide, to continue describing the process of designing conformationally constrained analogs producing first and second generation peptidomimetics. Finally, there is a section devoted to reviewing the use of organic scaffolds to design peptidomimetics based on the information available on the bioactive conformation of the peptide.

New Insights into the Stereochemical Requirements of the Bombesin BB1 Receptor Antagonists Binding

“…The presence of a ligand provides a more efficient refinement of the constructed model [ 28 ]. Accordingly, the antagonist PD176252 ( Figure 1 ) [ 17 ] was docked in different conformations into the orthosteric site of the crude model using the GLIDE software (version 6.7) [ 29 ]. Multiple orientations were obtained that were rank ordered using the XP scoring function.…”

“…On the other hand, a few peptide antagonists with a diverse degree of selectivity have also been disclosed for the three receptors [ 2 , 14 , 15 ]. However, the poor oral bioavailability, low absorption, rapid degradation by proteolytic enzymes and immunogenic profile of peptides make nonpeptide molecules more desirable [ 16 , 17 ]. Efforts in this direction resulted in the discovery of second generation peptoids PD168368 and PD176252 ( Figure 1 ) [ 18 ], along with a set of analogs with diverse substitutions [ 19 ] that exhibit an antagonist profile for the BB1R and BB2R, with diverse degrees of selectivity.…”

A Comprehensive Review on Current Advances in Peptide Drug Development and Design

“…Such side-chain functionality-modifying strategies have evolved peptide secondary structures and yielded new peptidic molecules that are referred to as peptidomimetics. Further information on the chemistry and applications of β-/D-amino acids, α-/N-methylations, or backbone-modified semicarbazide-peptides, peptoids and peptidomimetics can be found in these reviews [29,30,31,32,33].…”

Routes to N-glycinamide oxazolidinone derivatives: The reaction of 4-trityloxymethyl-3-oxa-1-azabicyclo[3.1.0]hexan-2-one with active halides

“…Modification of the peptide backbone to generate peptidomimetics provides a route to use both the sequence information of peptides as well as stability and structural constraints imposed by the synthetic components. [1][2][3] Oxazolidinones and related linkers have been used previously to prepare a variety of peptidomimetics. The use of both the oxazolidin-4-one type rings (1) 4 as well as oxazolidine-2-one rings (2) [5][6][7][8][9] (Figure 1) have been reported.…”