Ribosomal Synthesis of Macrocyclic Peptides with ß2- and ß2,3-Homo-Amino Acids for the Development of Natural Product-Like Combinatorial Libraries.
ACS Chem Biol
; 16(6): 1011-1018, 2021 06 18.
Article
em En
| MEDLINE
| ID: mdl-34008946
ABSTRACT
The development of large, natural-product-like, combinatorial macrocyclic peptide libraries is essential in the quest to develop therapeutics for "undruggable" cellular targets. Herein we report the ribosomal synthesis of macrocyclic peptides containing one or more ß2-homo-amino acids (ß2haa) to enable their incorporation into mRNA display-based selection libraries. We confirmed the compatibility of 14 ß2-homo-amino acids, (S)- and (R)-stereochemistry, for single incorporation into a macrocyclic peptide with low to high translation efficiency. Interestingly, N-methylation of the backbone amide of ß2haa prevented the incorporation of this amino acid subclass by the ribosome. Additionally, we designed and incorporated several α,ß-disubstituted ß2,3-homo-amino acids (ß2,3haa) with different R-groups on the α- and ß-carbons of the same amino acid. Incorporation of these ß2,3haa enables increased diversity in a single position of a macrocyclic peptide without significantly increasing the overall molecular weight, which is an important consideration for passive cell permeability. We also successfully incorporated multiple (S)-ß2hAla into a single macrocycle with other non-proteinogenic amino acids, confirming that this class of ß-amino acid is suitable for development of large scale macrocyclic peptide libraries.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Peptídeos
/
Ribossomos
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Biblioteca de Peptídeos
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Compostos Macrocíclicos
Idioma:
En
Revista:
ACS Chem Biol
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
Estados Unidos