Trung Tran

Discovery and Characterization of a Potent Interleukin-6 Binding Peptide with Neutralizing Activity In Vivo

Interleukin-6 (IL-6) is an important member of the cytokine superfamily, exerting pleiotropic actions on many physiological processes. Over-production of IL-6 is a hallmark of immune-mediated inflammatory diseases such as Castleman’s Disease (CD) and rheumatoid arthritis (RA). Antagonism of the interleukin IL-6/IL-6 receptor (IL-6R)/gp130 signaling complex continues to show promise as a therapeutic target. Monoclonal antibodies (mAbs) directed against components of this complex have been approved as therapeutics for both CD and RA. To potentially provide an additional modality to antagonize IL-6 induced pathophysiology, a peptide-based antagonist approach was undertaken. Using a combination of molecular design, phage-display, and medicinal chemistry, disulfide-rich peptides (DRPs) directed against IL-6 were developed with low nanomolar potency in inhibiting IL-6-induced pSTAT3 in U937 monocytic cells. Targeted PEGylation of IL-6 binding peptides resulted in molecules that retained their potency against IL-6 and had a prolongation of their pharmacokinetic (PK) profiles in rodents and monkeys. One such peptide, PN-2921, contained a 40 kDa polyethylene glycol (PEG) moiety and inhibited IL-6-induced pSTAT3 in U937 cells with sub-nM potency and possessed 23, 36, and 59 h PK half-life values in mice, rats, and cynomolgus monkeys, respectively. Parenteral administration of PN-2921 to mice and cynomolgus monkeys potently inhibited IL-6-induced biomarker responses, with significant reductions in the acute inflammatory phase proteins, serum amyloid A (SAA) and C-reactive protein (CRP). This potent, PEGylated IL-6 binding peptide offers a new approach to antagonize IL-6-induced signaling and associated pathophysiology.

Conformational analysis of thiopeptides: (?,?) maps of thio-substituted dipeptides

Noncoded amino acids such as isobutyric acid have been used extensively in the process of drug design and protein engineering. This article focuses on a noncoded amino acid where the oxygen in the peptide unit is replaced with a sp2 sulfur. It was hypothesized that the conformational space as well as the conformational preferences of thiopeptides will be more restricted and altered by the bulkier atom with different electrostatic properties. In vacuo conformational minima as well as associated energies for the thio‐substituted alanine dipeptides were calculated at the ab initio HF/6‐31G* level. When the bulkier sulfur atom acts as a hydrogen bond acceptor in the C5 conformation or in the C\documentclass{article}\pagestyle{empty}\begin{document}

Topological side-chain classification of β-turns: Ideal motifs for peptidomimetic development

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Intramolecular disulphide bond arrangements in nonhomologous proteins

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Conformational analysis of thiopeptides: derivation of sp2 sulfur parameters for the CFF91 force field

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Conformational searching using a population‐based incremental learning algorithm

\end{document} conformations, the hydrogen bond lengths are much longer than that of normal peptides. Consequently, the ϕ, ψ dihedral angles of the C5, C\documentclass{article}\pagestyle{empty}\begin{document}

Defining scaffold geometries for interacting with proteins: geometrical classification of secondary structure linking regions

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Library of Biphenyl Privileged Substructures using a Safety-Catch Linker Approach

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Conformational analysis of thiopeptides: free energy calculations on the effects of thio-substitutions on the conformational distributions of alanine dipeptides.

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A convenient method for synthesis of cyclic peptide libraries.

\end{document} conformations change to accommodate the longer hydrogen bonds. The thiopeptide group is a poorer hydrogen bond acceptor and a better hydrogen bond donor than the normal peptide group. Therefore, thio‐substitution at the amino terminal leads to disfavoring of the C7 conformations relative to the C5 conformations and thio‐substitution at the carboxyl terminal leads to favoring of the C7 conformations relative to the C5 conformation. To simulate the conformations in solution, (ϕ,ψ) conformational energy maps were calculated for the glycine and alanine dipeptides at various dielectric constants using the CFF91 force field with our previously derived parameters for the thioamide group. The results show that thio‐substitution does restrict the conformations available to amino acids residues in peptides. Thio substitution at the amino terminal introduces unfavorable interactions near ϕ=−120 and 120, where there are increased overlaps between Sn−1Hβ, and Sn−1Cβ atoms, respectively. Thio substitution at the carboxyl terminal restricts the conformations near ψ=60, −60, and 180, which correspond with increase overlaps between SnCβ, SnHβ′ and SnNn atoms, respectively. The effects of dithio substitutions of either the alanine or the glycine dipeptides are similar to the combined effects of the two single thio substitutions.