Helix Nucleation by the Smallest Known α‐Helix in Water

Abstract

Cyclic pentapeptides (e.g. Ac-(cyclo-1,5)-[KAXAD]-NH2 ; X=Ala, 1; Arg, 2) in water adopt one α-helical turn defined by three hydrogen bonds. NMR structure analysis reveals a slight distortion from α-helicity at the C-terminal aspartate caused by torsional restraints imposed by the K(i)-D(i+4) lactam bridge. To investigate this effect on helix nucleation, the more water-soluble 2 was appended to N-, C-, or both termini of a palindromic peptide ARAARAARA (≤5 % helicity), resulting in 67, 92, or 100 % relative α-helicity, as calculated from CD spectra. From the C-terminus of peptides, 2 can nucleate at least six α-helical turns. From the N-terminus, imperfect alignment of the Asp5 backbone amide in 2 reduces helix nucleation, but is corrected by a second unit of 2 separated by 0-9 residues from the first. These cyclic peptides are extremely versatile helix nucleators that can be placed anywhere in 5-25 residue peptides, which correspond to most helix lengths in protein-protein interactions.

Peptide‐Directed Binding for the Discovery of Modulators of α‐Helix‐Mediated Protein–Protein Interactions: Proof‐of‐Concept Studies with the Apoptosis Regulator Mcl‐1

“…Compounds 18,20,21,and 23 induced an increase in caspase-3 activation in BxPC-3 cells 4h after treatment, as indicated by the cleavage of DEVD-pNa and asubsequent increase in optical density at 405 nm. [26] Compounds 18 (Figure 2A).…”

“…Additionally,t he Fmoc-propargylglycine moiety proved effective in several of the identified binders (18,20,21,23,and 25), but again was not afeature that was sufficient for binding on its own (Table S2). Concerns over the Fmoc protecting group were considered, but as these compounds are primarily meant as chemical probes or potential leads, further development may discover more effective alternatives.I ndeed, the Fmoc group is somewhat reminiscent of structural features present in Souers A-1210477…”

“…Ap ossible explanation for this phenomenon is that some small-molecule fragments,w hen bound to the peptide fragment, alter the helicity of the peptide,perhaps increasing the binding affinity of the peptide segment or altering the binding site. [21] Further studies on the power of small-molecule/peptide hybrids as PPI modulators are underway.…”

Mechanische Verstärkung von Coiled Coils mit Lactam und Histidin‐Metall‐Klammern

“…B. His‐[Metall] 2+[17] ) oder auch kovalente Bindungen [14, 15, 18] . Um eine Helixwindung effektiv zu stabilisieren, werden die beteiligten Aminosäuren häufig in einem i → i+4 Abstand eingefügt [14c, 15a,e, 16, 17, 18b,d,f,g] . Ursprünglich wurden geklammerte Peptide zur Erforschung der Nukleation, Faltung und Stabilität von α‐Helices entwickelt [16–18] .…”

Stapled Peptides as HIF‐1α/p300 Inhibitors: Helicity Enhancement in the Bound State Increases Inhibitory Potency

“…Peptide "stapling" has been developed as av ersatile method for targeting a-helix mediated PPIs as well as those mediated by irregular binding interfaces. [12][13][14][15] Constraining ap eptide in an a-helical conformation has been shown to increasep eptide proteolytic stability, [24,25] improvec ellular uptake, [26][27][28] and enhance target binding affinity through pre-organization of the bioactive conformation, [29,30] The toolbox for constraining peptides into ab ioactive (helical) conformation includes:h ydrocarbon "staples", [31,32] lactamb ridges, [33][34][35] Cu I -catalysed azidealkynec ycloaddition, [36][37][38][39][40] hydrogen-bond surrogates, [41,42] and other chemistries. [43,44] Addingt ot his toolbox, the use of, simple disulfideb ridges, crosslinking of (homo)cysteine residues and other modifications of thiols have been described.…”