12/27/2022 0 Comments Stapled helix![]() ![]() For example, improved binding affinity is observed by overcoming the entropic penalty associated with peptide folding. Proteomimetic compounds of this type demonstrate a number of attractive physicochemical properties in comparison with small molecules, peptides, and biologics. 31, 32įigure 2 Strategies to constrain α-helical peptides. In addition, short α-helical peptides have been nucleated with the help of capping groups 28– 30 and using designed molecules to template the helix. Examples of α-helix constraints include salt bridges between charged amino acid side chain residues, 13, 14 lactam bridges, 15, 16 disulfide bridges, 17 hydrogen bond surrogates, 18, 19 hydrophobic interactions, 20 metal ligation, 21, 22 triazole staples synthesized from alkenyl and azido side chain residues, 23 photocontrollable macrocycles, 24 introduction of α,α-disubstituted amino acids, 25, 26 and hydrocarbon staples 27 ( Figure 2). 12 Particular emphasis has therefore been placed on the design of conformational constraints that induce α-helix structure. 11įigure 1 Structures of small molecule peptidomimetic inhibitors ( A) ABT-737, ( B) ABT-263 that target the Bcl-x L/Bak PPII, ( C) Nutlin-2, and ( D) benzodiazepinedione-1 that target the p53/mDM2 PPI.Ī large proportion of the PPIs that have been reported are mediated by α-helices. 10 Hara et al have developed polyproline-type helix peptoids that target the p53/mDM2 PPI. As well as small molecules, nonpeptidic scaffolds can be used to target PPIs such as the terphenyl scaffolds first developed by the Hamilton group. Additionally, the Nutlin 8 and benzodiazepinedione 9 families of compounds, developed by Hoffman-La Roche and Johnson & Johnson pharmaceuticals, respectively, were found to be inhibitors of the p53/mDM2 PPI. Many different strategies for targeting PPIs have been studied, including the use of small molecule peptidomimetic inhibitors, which include ABT-737 6 and ABT-263 7 from Abbott Laboratories, that were found to be inhibitors of the Bcl-x L/Bak PPI ( Figure 1). 4, 5 The main focus of this review is the design, synthesis, and application of stapled peptides as molecular probes to disrupt PPIs. 2, 3 Proteomimetics, and stapled peptides in particular, are proving useful for targeting PPIs. Many different strategies have been used to interrogate PPIs and these have previously been reviewed. Recent research efforts have focused on the design and synthesis of proteomimetics, molecules that mimic both the structure and/or function of proteins. Peptides also have a number of other therapeutically undesirable properties including poor bioavailability, limited stability toward peptidase proteolysis, and lack of membrane permeability that can potentially limit their use as drugs.Ī challenge therefore exists to design molecules that occupy the chemical space large enough to modulate PPIs and yet small enough to have suitable drug-like physicochemical properties. Although these motifs are usually thermodynamically favored in folded proteins, isolated peptides typically lack the ability to spontaneously adopt these bioactive conformations. 1 At a molecular level, these constellations of residues are frequently found to be specific protein secondary structures such as the α-helix or -strand. While these molecular recognition events involve interactions over large surface areas, the majority of the binding affinity and specificity has been found to originate from constellations of a few amino acid residues that are described as interaction “hotspots”. However, the development of novel, cell-permeable molecules that regulate PPIs remains one of the major challenges in chemical biology due to the relatively large (typically ~1600 Å 2) and dynamic nature of the PPI interface. ![]() Protein–protein interactions (PPIs) are becoming increasingly popular drug targets because the chemical space required for inhibition is underexplored and so the intellectual property landscape is relatively barren. ![]()
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |