RESUMO
The development of constrained peptides for inhibition of protein-protein interactions is an emerging strategy in chemical biology and drug discovery. This manuscript introduces a versatile, rapid and reversible approach to constrain peptides in a bioactive helical conformation using BID and RNase S peptides as models. Dibromomaleimide is used to constrain BID and RNase S peptide sequence variants bearing cysteine (Cys) or homocysteine (hCys) amino acids spaced at i and i + 4 positions by double substitution. The constraint can be readily removed by displacement of the maleimide using excess thiol. This new constraining methodology results in enhanced α-helical conformation (BID and RNase S peptide) as demonstrated by circular dichroism and molecular dynamics simulations, resistance to proteolysis (BID) as demonstrated by trypsin proteolysis experiments and retained or enhanced potency of inhibition for Bcl-2 family protein-protein interactions (BID), or greater capability to restore the hydrolytic activity of the RNAse S protein (RNase S peptide). Finally, use of a dibromomaleimide functionalized with an alkyne permits further divergent functionalization through alkyne-azide cycloaddition chemistry on the constrained peptide with fluorescein, oligoethylene glycol or biotin groups to facilitate biophysical and cellular analyses. Hence this methodology may extend the scope and accessibility of peptide stapling.
RESUMO
An enantioselective three-step synthesis of the GABA uptake inhibitor (S)-(+)-homo-ß-proline was developed. The basis for the synthesis was the enantioselective CuI-catalyzed cyclopropanation of N-Boc-pyrrole, a substrate that persistently has proved to be challenging in such transformations. The cyclopropanation can be performed on a 150 mmol scale, and the two subsequent steps (i.e., hydrogenation and in situ cyclopropane-opening/double-deprotection) toward the target molecule proceed smoothly in quantitative yield without loss of enantiopurity.
RESUMO
Interplay between proteins, nucleic acids, carbohydrates and/or lipids is involved in almost every process in life on earth. As a consequence, a wide range of diseases results from abnormal interactions of such biomolecules. The main motivation of foldamer science is the development of scaffolds that are capable of adopting defined structures, mimicking parts of biological protagonists in their function. Among the most fundamental interactions in living beings are those between proteins, the so called protein--protein interactions (PPIs). Therefore, peptidic foldamers bear the promise to be an important tool for the inhibition of PPIs, as they are structurally most similar to the original proteins. The great number of possible permutations given by the combination of proteinogenic α-amino acid residues along with ß-amino acids opens the door for a larger pool of accessible structures with potential applications. Despite the increasing amount of new secondary structure motifs, only few examples for tertiary and quaternary structure design, as well as inhibition of PPIs, have been realized so far. In this review, we summarize the current knowledge and recent progress made in the field of α/ß-peptide foldamers beginning from secondary structure design up to highly sophisticated biological applications, such as protein surface recognition and inhibition of HIV cell entry.