Aza-Amino Acids Disrupt β-Sheet Secondary Structures

Abstract

Cα to N substitution in aza-amino acids imposes local conformational constraints, changes in hydrogen bonding properties, and leads to adaptive chirality at the nitrogen atom. These properties can be exploited in mimicry and stabilization of peptide secondary structures and self-assembly. Here, the effect of a single aza-amino acid incorporation located in the upper β-strand at a hydrogen-bonded (HB) site of a β-hairpin model peptide (H-Arg-Tyr-Val-Glu-Val-d-Pro-Gly-Orn-Lys-Ile-Leu-Gln-NH2) is reported. Specifically, analogs in which valine3 was substituted for aza-valine3 or aza-glycine3 were synthesized, and their β-hairpin stabilities were examined using Nuclear Magnetic Resonance (NMR) spectroscopy. The azapeptide analogs were found to destabilize β-hairpin formation compared to the parent peptide. The aza-valine3 residue was more disruptive of β-hairpin geometry than its aza-glycine3 counterpart.

Rationally Designed Amanitins Achieve Enhanced Cytotoxicity

“…Noting the sensitivity of the toxin to modification at Ile 6 , we altered its polarity with oxy- and thioethers. In addition, to probe the β-turn, we introduced aza-glycines at positions 5 and 7 . To constrain the staple pitch angle and restrict conformational freedom within “chi-space”, , we introduced β-methyl groups (Scheme ) on the cysteine.…”

Structural impact of thioamide incorporation into a β-hairpin

“…40 For backbone derivatives, Aza-Val 3 incorporation was disruptive to foldedness (1.26 kcal mol −1 ), whereas aza-Gly 3 was better accepted (0.75 kcal mol −1 ), but still less stable than YKL. 42 β-Amino acid or linear ( E )-vinylogous γ 4 -residues substitution was moderately destabilizing (0.5–0.6 kcal mol −1 ). 66,67 Whereas a cyclically constrained γ-residue was stabilizing (−0.3 to −0.6 kcal mol −1 ).…”

“…38,39 This scaffold has been utilized to study the b-hairpin stabilization of cross-strand interactions 38 and strand length, 40 as well as the b-sheet propensity of charged derivatives of b-branched-amino acids 41 and aza-amino acids. 42 This extensively studied scaffold is also a good starting point for structural characterization as several previous studies have reported structural models based on NMR data. [38][39][40]43 This b-hairpin is enforced with a stabilized two-residue b-turn, proGly (where pro is D-proline).…”

Aza-peptides: expectations and reality

“…Aza-peptide synthesis starts from acylation of precursor compound (III) (hydrazine derivative) (Scheme 3), as appropriate acylated hydrazines are very unstable. Powerful acylating agents, such as phosgene or its derivatives [10,20,[67][68][69][70][71], are generally used for this purpose. Thereafter, the chloro-anhydride of the aza-amino acid (V) reacts quickly in situ with the parent peptide (VI), adding the aza-amino acid moiety to the peptide to be synthesized (VII).…”

“…Although aza-peptides are topological analogs of common peptides, they exhibit no chirality [2,9] and have different hydrogen bonding properties and reduced backbone flexibility [9][10][11][12][13][14][15][16][17][18][19][20]. Although these structural changes may disrupt the β-sheet secondary structure of the parent sequence [20], several aza-peptides have shown biological effects on a number of therapeutic targets, including the inhibition of various proteases in the treatment of viral infections [21][22][23][24][25][26]. For example, atazanavir (Reyataz®) is an antiretroviral drug used to treat HIV [27].…”