Hydrogen Bond and Geometry Effects of Thioamide Backbone Modifications

Abstract

Thioamide substitution of backbone peptide bonds can probe interactions along the main chain of proteins. Despite theoretical predictions of the enhanced hydrogen bonding propensities of thioamides, previous studies often do not consider the geometric constraints imposed by folded peptide secondary structure. This work addresses drawbacks in previous studies that ignored the geometry dependence and local dielectric properties of thioamide hydrogen bonding and identifies cases where thioamides may be either stronger or weaker hydrogen-bonding partners than amides.

Structural impact of thioamide incorporation into a β-hairpin

“…5 Δ δ Hα is dramatically affected for the residue following the thioamide, consistent with previous studies of the steric and electronic impact of thioamide incorporation on neighboring residues. 51,52 The Δ δ Hα value is increased relative to the HPT value for more stable peptides with externally facing thioamides and decreased for less stable peptides with internally facing thioamides.…”

“…Even in the macrocyclic folded peptides, the overall stability derives from an interplay of interactions that vary by position, making it difficult to define a single causative feature for thioamide stability effects. However, the NMR-derived models of these macrocyclic systems enable one to apply more sophisticated electronic structure calculations 51 to help to explain stability effects as well as observations such as the effect on the Δ δ Hα value for the n + 1 residue. We will pursue such computational analysis in conjunction with additional structure determination efforts for constrained systems.…”

“…Observations such as these highlight the importance of structural data attained using the macrocyclized Previous experimental work has suggested that introduction of a thioamide reduces conformational flexibility, 72,73 and theoretical studies demonstrate increased steric constraints for the n + 1 residue. 51,52,74,75 Thioamide incorporation at a residue closer to the b-turn (Glu S 4 ) in the YKL scaffold, has b-sheet character based on Dd Ha analysis, but it is less prevalent than the other positions tested. The decreased stability of YKL-Glu S 4 could be due to an inability of Val 5 to accommodate the additional conformational restraint since it is already constrained by pro 6 and the b-turn.…”

Discovery of small molecule ligands for the von Hippel-Lindau (VHL) E3 ligase and their use as inhibitors and PROTAC degraders

“…An alternative approach to structurally modify VHL inhibitors in their core region is the replacement of one or both Hypadjacent amide bonds by their thioamide isosteres, thereby modulating the strength of the n-p* interaction between the LHS and RHS carbonyl groups. 84,85,90,91 As the cocrystal structure of both the native HIF-1a peptide and VH032 bound to VCB suggested a bound trans amide conformation allowing for n-p* interaction of the adjacent amides of Hyp, thioamidecontaining analogues of VH032 were designed and analysed with regard to their conformational preference and inhibition ability. 92 Synthesis of VHL inhibitors derived from VH032 containing a LHS, RHS or duplex thioamide incorporation was envisioned following the established synthetic route to VH032 with addition of carbonyl to thioamide conversion steps for the LHS and RHS fragments before assembling the whole inhibitor.…”

A General Strategy to Install Amidine Functional Groups Along the Peptide Backbone

“…Recent syntheses of amidines in peptidic molecules have exploited thioamides as a site that can be activated with Ag­(I) salts for conversion into amidines. , Hutton and co-workers similarly demonstrated how other nucleophiles can be reacted with thioamides through activation with Ag­(I). − The installation of thioamides into peptides using standard SPPS procedures can be achieved with activated thioacyl amino acid precursors derived from commercially available Fmoc-amino acids. , Thus, in principle, a thioamide-containing peptide should provide an avenue for the site-selective insertion of amidines into peptides. Unfortunately, examples of such chemistry within the context of polypeptides are noticeably scarce.…”