Exploring stereochemical constraints and chemical reactivity of vinylogous amino acids in the design of foldamers

Abstract

The relationship between a well defined structure and function of proteins inspire the creation of foldamers from non natural building blocks Among them the most widely studied foldamers are constructed from 946 and 947 amino acid subunits The remarkable protein secondary structure mimetics displayed by these 946 and 947 peptide oligomers have been exploited in designing inhibitors for various protein protein interactions antimicrobials and biomaterials Previously we have showed the utilization of naturally occurring E vinylogous amino acids in the design of 946 hairpins and 946 sheet mimetics In the present study we investigated the utility of these conformationally constrained yet highly reactive 945 946 unsaturated 947 amino acids to engineer the folding in polypeptides and as Michael acceptors to derive a variety of 3 4 disubstituted 947 amino acids We showed that by selective insertion of E vinylogous amino acids in the 945 peptide sequence it is possible to design novel miniature 946 meander as well as helix turn helix type of motifs even in small peptide sequences Further utilizing E vinylogous residues as Michael acceptors we derived highly functionalizable 946 nitromethyl 947 amino acids as well as thiostatines 946 sulfhydryl 947 amino acids Besides their utility as templates in the design of 14 and 12 helical foldamers we showed the multifaceted nature of alkyl nitro group on peptides by transforming it into various functional groups including amines carboxylic acids oximes and 1 3 dipolar addition products Further as E vinylogous amino acids preferred to adopt extended 946 sheets type structures we investigated whether Z vinylogous amino acids can be used to design helical peptide foldamers with conjugated double bond in the helix backbone Finally in the course of our investigation on structural and chemical characterization of unsaturated 947 amino acids and peptides we encountered a base mediated novel rearrangement transforming the vinylogous amides into 947 lactams through double bond m