Peptaibol antibiotics: a study on the helical structure of the 2-9 sequence of emerimicins III and IV.

Abstract

AESThACT ISolution conformations of the protected 2-9 segment of the peptaibol antibiotics emerimicins m and IV [a-aminoisobutyric acid (Aib)]3r-Val-Gly-L.Lkeu(b)2 and the related short _se s b oxy(Ab)Val-OMe and benzwoxy4Ab)jAal.GlyOMe have been investigated bycirculardichroism studies. For.the latter two cpounds the-structural preferences in the solid state have been assayed byx-ray diffraction analyses. The exerimental data described here, along with these previously reported, support the view that the shortest Aib-containing segments (from -tri-through pentapeptides) adopt the 31r-helical structure both in solution and In the solid state. In contrast, the octapeptide appears to adopt the a-helical-structure in solution. The role ofpeptide chain length and specific amino acid-sequences in stabilizing either of the two helicalstrucres and hence their possible implications on the nature of the channel.formed by peptibol antibiotics in the membrane are-also briefly-outline!4 -Peptaibol antibiotics alter the ionic permeability ofmembranes by forming channels (1, 2). They have in common:. (i) a high content (as much as 50%) of the unusual, achiral a-amino acid a-aminoisobutyric acid (Aib) dimethylated at the a carbon, and (ii) an-amino alcohol at the COOH-terminus. Our interest in the stereochemistry of peptides containing a-amino acid residues dialkylated at the a carbon was stimulated by the fiaet that they possess significant constraints on their conformational freedom (3-5). In particular, the 4, ipangles ofan Aib residue in apeptide ain are restricted th values near those associated with rightor left-handed 31 or a (3.6l3) helices.In this paper we present the results of a confdrmational CD investigation,. in solution, of the protected 2-9 segment of emerimicins III and IV (6)two components of the ffamily of peptaibol antibiotics produced by-Emericelop&i microspora (7)-and the related short sequences Z-(Aib)r-xVal-OMe (Z, benzyloxycarbonyl; OMe, methoxy) and Z-(Aib)3-L-Val-GlyOMe. For the latter two compounds, the solid state conformations, as determined by x-ray diffraction analyses, will be discussed. The results of this crystallographic study are complementaryto results on the other shorter sequences t-Boc-Aib-OH (t-Boc, tert-butyloxycarbonyl), Z-(Aib)rOH, and Z-(Aib)3-OtBu (OtBu, tert-butoxy) previously reported (8,9).Selection ofthe emerimicin family for this investigation was based on the fact that, among all the known peptaibol antibiotics, emerimicins IIH and IV each incorporate an octapeptide segment (residues 2-9) which contains the longest sequence (a triplet) of-a-amino acid residues monoalkylated at the a carbon. It was expected that this would provide some information relating the effect ofmain-chain length.-and specific amino acid sequences on the type of-helical structure that is assumed by natural antibiotics ning a high proportion of residues dialkylated at the a carbon. Abbreviations: Aib; a-ahinnoisobutyric aid (ammethyalaine);Iva, isovaline (a-ethylalailne); PheoL-, -plienylal ninol (ph...

Stapled α−helical peptide drug development: A potent dual inhibitor of MDM2 and MDMX for p53-dependent cancer therapy

“…Specifically, His 21 substitution by Ala and Glu provided a significant effect on solubility (i.e., approximately fourfold decreased and fourfold increased, respectively). Incorporation of Glu 21 and modification of Leu 26 by Cba and C-terminal extension with Ala-Ala yielded AcLeu 17 -Thr-Phe-cyclo(R8-Glu-Tyr-Trp-Ala-Gln-Cba-S5)-Ser-AlaAla 30 -NH 2 (ATSP-7041), which exhibited high affinity binding to both MDM2 (K i = 0.9 nM) and MDMX (K i = 7 nM) (Fig. 1A).…”

“…Stapled peptides were first described as a novel approach to creating macrocyclic α-helical peptides through the addition of an all-hydrocarbon cross-link between two α−methyl-substituted amino acids having terminal olefin side-chains to enable ringclosing metathesis using Grubbs ruthenium catalyst (17,18). Historically, it is important to recognize the precedence macrocyclization of the O-allyl-modified peptides by the Grubbs research group (19,20) as well as intrinsic helical-inducing properties of linear peptides incorporating α−methyl-substituted amino acids by the Toniolo research group (21,22). Relative to a previously published stapled peptide, SAH-p53-8 (3,15), the limited biological potency determined in our cellular assays using more stringent physiologic conditions (i.e., in the presence of 10% serum) inspired us to tackle this highly important cancer target and advance a more rigorously tested preclinical lead compound relative to both in vitro and in vivo efficacy.…”

Long polypeptide 3 10 -helices at atomic resolution

“…More recently, by theoretical (7)(8)(9)(10)(11) as well as experimental (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27) investigations, it has been shown that the 4,q, angles ofthe achiral a-aminoisobutyric acid residue (Aib), the prototype of Caa-dialkylated a-amino acids, are restricted to values near those associated either with right-or left-handed a-or 310-helices, unless it is part of a strained cyclic compound (28). The x-ray diffraction structures of aaminoisobutyric acid homopeptides to the pentamer have provided examples of short (less than two complete turns) 310-helical conformations in the solid state (14,15,22,23).…”

The peptideZ-Aib-Aib-Aib-L-Ala-OtBu

“…The sequence Aib-Aib-Aib-Ala represents a segment of the naturally occurring peptaibol antibiotic peptides containing -aminoisobutyric acid (Aib) and a C-terminal -amino alcohol (Brü ckner & Graf, 1983;Benedetti et al, 1982) such as trichotoxin (Brü ckner et al, 1985). We present here the crystal structure of Z-Aib 3 -l-Ala-OtBu containing this tetrapeptide.…”