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Reid P.C.,PeptiDream Inc. | Goto Y.,Tokyo University of Science | Katoh T.,Tokyo University of Science | Suga H.,Tokyo University of Science | Suga H.,University of Tokyo
Methods in Molecular Biology | Year: 2012

In vitro selection methods represent a powerful approach toward identifying high-affinity peptide ligands from highly diverse peptide libraries against a desired target. We herein describe a method for the display and selection of cyclic thioether peptide libraries. Reprogramming the initiation event from fMet to an N-chloroacetyl-amino acid by utilizing flexizyme to rapidly and efficiently prepare the aa-tRNA can be effectively used to initiate translation, upon which the thiol group of an inserted cysteine at the C terminus of the designed library spontaneously reacts to yield a nonreducible cyclic thioether peptide readily compatible with any in vitro display methods. Thus, cyclic peptides already in a nonreducible stable form can be selected directly against the target of interest. © 2012 Springer Science+Business Media, LLC. Source

University of Tokyo and Peptidream Inc. | Date: 2013-09-02

An object of the present invention is to provide a VEGFR2 inhibitor peptide having high specificity and available at a low cost. The present invention provides a peptide having the following amino acid sequence:

Kawakami T.,University of Tokyo | Ishizawa T.,University of Tokyo | Fujino T.,University of Tokyo | Reid P.C.,PeptiDream Inc. | And 2 more authors.
ACS Chemical Biology | Year: 2013

We report the in vitro selection of thioether-macrocyclized peptides against vascular endothelial growth factor receptor 2 (VEGFR2) from multiple, highly diverse peptide libraries constructed utilizing genetic code reprogramming. The macrocyclic peptide libraries consisted of combinations of four types of amino acid linkers for cyclization and two types of elongator amino acid compositions, including four backbone-modified non-proteinogenic amino acids. Affinity selection from these libraries, using our recently developed TRAP (Transcription-translation coupled with Association of Puromycin-linker) display, yielded multiple anti-VEGFR2 macrocyclic peptide leads. Further antagonizing activity-based screening of the chemically synthesized lead peptides identified a potent macrocyclic peptide that inhibited VEGF-induced VEGFR2 autophosphorylation, proliferation, and angiogenesis of living vascular endothelial cells. The TRAP display-based selection from multiple, highly diverse peptide libraries followed by activity-based screening of selected peptides is a powerful strategy for discovering biologically active peptides targeted to various biomolecules. © 2013 American Chemical Society. Source

Holzer P.,Novartis | Masuya K.,Novartis | Masuya K.,PeptiDream Inc. | Furet P.,Novartis | And 13 more authors.
Journal of Medicinal Chemistry | Year: 2015

(Figure Presented). As a result of our efforts to discover novel p53:MDM2 protein-protein interaction inhibitors useful for treating cancer, the potent and selective MDM2 inhibitor NVP-CGM097 (1) with an excellent in vivo profile was selected as a clinical candidate and is currently in phase 1 clinical development. This article provides an overview of the discovery of this new clinical p53:MDM2 inhibitor. The following aspects are addressed: mechanism of action, scientific rationale, binding mode, medicinal chemistry, pharmacokinetic and pharmacodynamic properties, and in vivo pharmacology/toxicology in preclinical species. © 2015 American Chemical Society. Source

Ishizawa T.,University of Tokyo | Kawakami T.,University of Tokyo | Reid P.C.,PeptiDream Inc. | Murakami H.,University of Tokyo
Journal of the American Chemical Society | Year: 2013

Here, we describe a novel method that enables high-speed in vitro selection of functional peptides, peptidomimetics, and proteins via a simple procedure. We first developed a new cell-free translation system, the TRAP system (transcription-translation coupled with association of puromycin linker), which automatically produces a polypeptide library through a series of sequential reactions: transcription, association of puromycin-DNA linker, translation, and conjugation between the nascent polypeptide and puromycin-DNA linker. We then applied the TRAP system for the selection of macrocyclic peptides against human serum albumin. Six rounds of selection using TRAP display were performed in approximately 14 h, yielding macrocyclic peptides with nanomolar affinity to their target protein. Because TRAP display enables high-speed selection of functional polypeptides, it will facilitate the generation of various polypeptides that are useful for biological and therapeutic applications. © 2013 American Chemical Society. Source

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