Multicomponent Peptide Stapling as a Diversity‐Driven Tool for the Development of Inhibitors of Protein–Protein Interactions

Abstract

Stapled peptides are chemical entities in‐between biologics and small molecules, which have proven to be the solution to high affinity protein–protein interaction antagonism, while keeping control over pharmacological performance such as stability and membrane penetration. We demonstrate that the multicomponent reaction‐based stapling is an effective strategy for the development of α‐helical peptides with highly potent dual antagonistic action of MDM2 and MDMX binding p53. Such a potent inhibitory activity of p53‐MDM2/X interactions was assessed by fluorescence polarization, microscale thermophoresis, and 2D NMR, while several cocrystal structures with MDM2 were obtained. This MCR stapling protocol proved efficient and versatile in terms of diversity generation at the staple, as evidenced by the incorporation of both exo‐ and endo‐cyclic hydrophobic moieties at the side chain cross‐linkers. The interaction of the Ugi‐staple fragments with the target protein was demonstrated by crystallography.

Macrocyclization strategies for cyclic peptides and peptidomimetics

“…However, this is slow, with reaction times of 96 h. 334 A recent report highlighted the diversity achieved by distinct combinations of amino and isocyanide components, identifying stapled peptides that inhibited p53/MDM2/X. 335 Macrocyclization via Ugi MCR can be combined with subsequent disulfide formation to generate bicyclic peptides. 336 A similar approach called the sulfur-switch Ugi reaction was proposed to synthesize disulfide-linked cyclic peptides de novo from four components, followed by oxidative cyclization of the two cysteines with I 2 to form disulfides (Scheme 40, a).…”

“…However, this is slow, with reaction times of 96 h. 334 A recent report highlighted the diversity achieved by distinct combinations of amino and isocyanide components, identifying stapled peptides that inhibited p53/MDM2/X. 335 …”

Suprastapled Peptides: Hybridization-Enhanced Peptide Ligation and Enforced α-Helical Conformation for Affinity Selection of Combinatorial Libraries

“…Accordingly, stapled peptides are increasingly used in chemical biology and drug discovery. Following the pioneering work establishing the utility of stapled peptides, [9][10][11][12] there has been continued interest to advance the stapling chemistry with a particular emphasis on methodologies (for recent examples, see refs [13][14][15][16][17][18][19][20][21] ) that can be applied to unprotected peptides that can be embraced in genetically encoded libraries. [22][23][24][25] Herein, we report a supramolecular approach to stapling the α-helical conformation leveraged on the hybridization of short peptide nucleic acid [26][27] (PNA) sequences.…”

Solid‐Phase Peptide Macrocyclization and Multifunctionalization via Dipyrrin Construction

“…[6] To this end, a repertoire of peptide macrocyclization and stapling approaches has been developed and diversified over the past decade. [7] Cross-couplings, [8] click reactions, [9] C À H activations/functionalizations, [10] ring-closing olefin metathesis reactions, [11] Diels-Alder cycloaddi-tions, [12] multicomponent Ugi/Petasis-type reactions, [13] and ligation-mediated cyclizations, [14] among others, [15] have been established in site-specific fashions employing a variety of anchoring residues/terminal groups. [16] New structural-functional moieties can be introduced into the backbones of peptide macrocycles via certain above-mentioned approaches as the staple linkers, which can be manipulated to optimize the cyclopeptide ring size/rigidity, and furnish new handling sites for small-molecule drug and fluorescent dye conjugations to access unprecedented chemotypes and become powerful tools to probe PPIs and orchestrate therapeutic applications.…”