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Major Factors for the Persistent Folding of Hybrid ?, ?, ?-Hybrid Peptides Into Hairpins.

ABSTRACT: Factors responsible for the persistent adoption of hairpin conformations by hybrid oligopeptides, each having a central ?/? dipeptide segment flanked by aromatic ?-amino acid (?Ar) residues, are probed. Our recent studies revealed that tetrapeptide 1 and 2, having central dipeptide segments consisting of ?-alanine (?-Ala) and glycine (Gly), and L-?-homophenylalanine (L-?-homoPhe) and Gly residues, respectively, that are flanked by ?Ar residues, fold into well-defined, expanded ?-turns with doubly H-bonded ?Ar residues. Replacing the ?Ar residues of 1 and 2 with L-Val and L-Leu residues results in tetrapetides 1 ' and 2 ' that fail to fold into defined conformations, which confirms the decisive role played by the H-bonded ?Ar residues in the promoting folding of 1 and 2. Attaching L-Val and L-Leu residues to the termini of 1 affords hexapeptide 1a. With an additional H-bond between its L-Val and L-Leu residues, peptide 1a folds into a hairpin with higher stability than that of 1, indicating that the expanded ?-turn can nucleate and stabilize ?-hairpin with longer ?-strands. Attaching L-Val and L-Leu residues to the termini of 2 affords hexapeptide 2a. Substituting the L-?-homoPhe residue of 2a with a D-?-homoPhe residue gives hexapeptide 2b. Surprisingly, hexapeptide 2a fold into a hairpin showing the similar stability as those of tetrapeptides 1 and 2. Hexapeptide 2b, with its combination of a D-?-homoPhe residue and the L-Val/L-Leu pair, fold into a hairpin that is significantly more stable than the other hybrid peptides, demonstrating that a combination of hetero-chirality between the ?-amino acid residue of the dipeptide loop and the ?-amino acid residues of the ?-strands enhances the stability of the resultant ?-hairpin.

SUBMITTER: Zhong Y

PROVIDER: S-EPMC7550740 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Major Factors for the Persistent Folding of Hybrid α, β, γ-Hybrid Peptides Into Hairpins.

Zhong Yulong Y Tang Quan Q Miller Daniel P DP Zurek Eva E Liu Rui R Lu Zhong-Lin ZL Gong Bing B

Frontiers in chemistry 20200929

Factors responsible for the persistent adoption of hairpin conformations by hybrid oligopeptides, each having a central β/α dipeptide segment flanked by aromatic γ-amino acid (γAr) residues, are probed. Our recent studies revealed that tetrapeptide <b>1</b> and <b>2</b>, having central dipeptide segments consisting of β-alanine (β-Ala) and glycine (Gly), and L-β-homophenylalanine (L-β-homoPhe) and Gly residues, respectively, that are flanked by γAr residues, fold into well-defined, expanded β-tu ...[more]

PMID: 33134269

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Project description:As a key cytokine mediator of inflammation, interleukin-1β (IL-1β) binds to the IL-1 receptor (IL-1R) and activates various downstream signaling mediators, including NF-κB, which is required for immune vigilance and cellular protection. Toward the development of IL-1-targeting therapeutics which exhibit functional selectivity, the all-D-amino acid peptide 1 (101.10, H-D-Arg-D-Tyr-D-Thr-D-Val-D-Glu-D-Leu-D-Ala-NH2) was conceived as an allosteric IL-1R modulator that conserves NF-κB signaling while inhibiting other IL-1-activated pathways. Employing β-hydroxy-α-amino-γ-lactam (Hgl) stereoisomers to study the conformation about the Thr3 residue in 1, [(3R,4S)-Hgl3]-1 (2b), among all possible diastereomers, was found to exhibit identical in vitro and in vivo activity as the parent peptide and superior activity to the α-amino-γ-lactam (Agl) counterpart. Noting the relevance of the β-hydroxyl substituent and configuration for the activity of (3R,4S)-2b, fifteen different β-substituted-Agl3 analogs of 1 (e.g., 2c-q) have now been synthesized by a combination of solution- and solid-phase methods employing N-Fmoc-β-substituted-Agl3-Val-OH dipeptide building blocks. Introduction of a β-azido-Agl3 residue into the resin bound peptide and subsequent reduction and CuAAC chemistry gave access to a series of amine and triazole derivatives (e.g., 2h-q). β-Substituted-[Agl3]-1 analogs 2c-q exhibited generally similar circular dichroism (CD) spectra as that of Hgl analog 2b in water, presenting curve shapes indicative of β-turn structures. The relevance of the β-substituent was indicated in rodent models of preterm labor and retinopathy of prematurity (ROP), in which certain analogs inhibited preterm birth and vaso-obliteration, respectively, with activity similar to 1 and 2b. The β-substituted-[Agl3]-1 analogs exhibited functional selectivity on IL-1-induced signaling pathways. The described solid-phase method has provided discerning probes for exploring peptide structure-activity relationships and valuable leads for developing prototypes to treat inflammatory events leading to prematurity and retinopathy of prematurity, which are leading causes of infant morbidity and blindness respectively.

Dataset Information

Major Factors for the Persistent Folding of Hybrid ?, ?, ?-Hybrid Peptides Into Hairpins.

Publications

Major Factors for the Persistent Folding of Hybrid α, β, γ-Hybrid Peptides Into Hairpins.

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