RESUMO
Inhibiting the histone H3-ASF1 (anti-silencing functionâ 1) protein-protein interaction (PPI) represents a potential approach for treating numerous cancers. As an α-helix-mediated PPI, constraining the key histone H3 helix (residues 118-135) is a strategy through which chemical probes might be elaborated to test this hypothesis. In this work, variant H3118-135 peptides bearing pentenylglycine residues at the i and i+4 positions were constrained by olefin metathesis. Biophysical analyses revealed that promotion of a bioactive helical conformation depends on the position at which the constraint is introduced, but that the potency of binding towards ASF1 is unaffected by the constraint and instead that enthalpy-entropy compensation occurs.
Assuntos
Alcenos/química , Proteínas de Ciclo Celular/metabolismo , Histonas/metabolismo , Chaperonas Moleculares/metabolismo , Fragmentos de Peptídeos/metabolismo , Sequência de Aminoácidos , Histonas/química , Humanos , Fragmentos de Peptídeos/química , Ligação Proteica , Conformação Proteica , TermodinâmicaRESUMO
In the search for foldamer inhibitors of the histone chaperone ASF1, we explored the possibility of substituting four α-residues (≈one helix turn) by 3-urea segments and scanned the sequence of a short α-helical peptide known to bind ASF1. By analysing the impact of the different foldamer replacements within the peptide chain, we uncovered new binding modes of the peptide-urea chimeras to ASF1.
Assuntos
Chaperonas de Histonas , Histonas , Chaperonas de Histonas/metabolismo , Histonas/química , Chaperonas Moleculares/química , Proteínas de Ciclo Celular/metabolismo , Peptídeos/farmacologia , Peptídeos/metabolismoRESUMO
Sequence-specific oligomers with predictable folding patterns, i.e., foldamers, provide new opportunities to mimic α-helical peptides and design inhibitors of protein-protein interactions. One major hurdle of this strategy is to retain the correct orientation of key side chains involved in protein surface recognition. Here, we show that the structural plasticity of a foldamer backbone may notably contribute to the required spatial adjustment for optimal interaction with the protein surface. By using oligoureas as α helix mimics, we designed a foldamer/peptide hybrid inhibitor of histone chaperone ASF1, a key regulator of chromatin dynamics. The crystal structure of its complex with ASF1 reveals a notable plasticity of the urea backbone, which adapts to the ASF1 surface to maintain the same binding interface. One additional benefit of generating ASF1 ligands with nonpeptide oligourea segments is the resistance to proteolysis in human plasma, which was highly improved compared to the cognate α-helical peptide.