Stapled and stitched polypeptides and uses thereof
The present invention provides stapled polypeptides of the Formulae (I) and (VI): and salts thereof; wherein the groups ; R 1a , R 1b , R 1c , R 2a , R 3a , R 2b , R 3b , R 4a , R 4b , R A , R Z , L 1a , L 1b , L 2 , L 3 , X AA , v, w, p, m, s, n, t, and q are as defined herein. The present invention further provides methods of preparing the inventive stapled polypeptides from unstapled polypeptide precursors. The present invention further provides pharmaceutical compositions comprising a stapled polypeptide of Formula (I) or (VI), and methods of using the stapled peptides. The present invention also provides modifications of the staples post ring closing metathesis.
1. A stapled peptide comprising a staple, wherein the staple comprises a carbamate moiety or a tertiary amine moiety.
2. The stapled peptide of claim 1 , wherein the staple comprises a carbamate moiety.
3. The stapled peptide of claim 2 , wherein the staple comprises two carbamate moieties.
4. The stapled peptide of claim 2 , wherein the staple is prepared using an amino acid selected from
and an amino acid without a carbamate moiety.
5. The stapled peptide of claim 2 , wherein the staple is prepared using two amino acids selected from
and analogs thereof containing additional methylene units.
6. The stapled peptide of claim 2 , wherein the cross-linking amino acids of the staple are located at positions i and i+4.
7. The stapled peptide of claim 2 , wherein the cross-linking amino acids of the staple are located at positions i and i+7.