Study summary · research use only
5-Hydroxypyrroloindoline Affords Tryptathionine and 2,2'-bis-Indole Peptide Staples: Application to Melanotan-II
Plain-language summary
Paraphrased from the published abstract below — not a verdict on whether anything works.
This chemistry study (species not specified; synthetic/in vitro peptide chemistry, no living subjects) describes a method using 5-hydroxypyrroloindoline condensation with cysteine-thiol or tryptophan-indole to form tryptathionine or 2,2'-bis-indole peptide staples, applied to stapling α-MSH (melanotan-II-related) peptides. The authors report that both classes of stapled peptides showed nanomolar Ki binding values, with one showing a sub-nanomolar Ki value, and describe the approach as providing a basis for investigating chemoselectivity and binding affinity of these novel peptide macrocycle staples.
Abstract
With peptides increasingly favored as drugs, natural product motifs, namely the tryptathionine staple, found in amatoxins and phallotoxins, and the 2,2'-bis-indole found in staurosporine represent unexplored staples for unnatural peptide macrocycles. We disclose the efficient condensation of a 5-hydroxypyrroloindoline with either a cysteine-thiol or a tryptophan-indole to form a tryptathionine or 2-2'-bis-indole staple. Judicious use of protecting groups provides for chemoselective stapling using α-MSH, which provides a basis for investigating both chemoselectivity and affinity. Both classes of stapled peptides show nanomolar Ki's, with one showing a sub-nanomolar Ki value.
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