Artificial human Met agonists based on macrocycle scaffolds

Ito, Kenichiro; Sakai, Katsuya; Suzuki, Yoshinori; Ozawa, Naoya; Hatta, Tomohisa; Natsume, Tohru; Matsumoto, Kunio; Suga, Hiroaki

doi:10.1038/ncomms7373

Cited by 102 publications

(140 citation statements)

References 39 publications

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“…RaPID selection of macrocyclic peptide binders against TET1CD or TET1CCD : The RaPID selection was carried out as described previously . In brief, an initial mRNA library was prepared by in vitro transcription of DNA library.…”

Section: Methodsmentioning

confidence: 99%

Thioether Macrocyclic Peptides Selected against TET1 Compact Catalytic Domain Inhibit TET1 Catalytic Activity

et al. 2018

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The ten-eleven translocation (TET) protein family, consisting of three isoforms (TET1/2/3), have been found in mammalian cells and have a crucial role in 5-methylcytosine demethylation in genomic DNA through the catalysis of oxidation reactions assisted by 2-oxoglutarate (2OG). DNA methylation/demethylation contributes to the regulation of gene expression at the transcriptional level, and recent studies have revealed that TET1 is highly elevated in malignant cells of various diseases and related to malignant alteration. TET1 inhibitors based on a scaffold of thioether macrocyclic peptides, which have been discovered by the random nonstandard peptide integrated discovery (RaPID) system, are reported. The affinity-based selection was performed against the TET1 compact catalytic domain (TET1CCD) to yield thioether macrocyclic peptides. These peptides exhibited inhibitory activity of the TET1 catalytic domain (TET1CD), with an IC value as low as 1.1 μm. One of the peptides, TiP1, was also able to inhibit TET1CD over TET2CD with tenfold selectivity, although it was likely to target the 2OG binding site; this provides a good starting point to develop more selective inhibitors.

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Section: Methodsmentioning

confidence: 99%

Thioether Macrocyclic Peptides Selected against TET1 Compact Catalytic Domain Inhibit TET1 Catalytic Activity

et al. 2018

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“…Monoclonal antibodies, for instance, are able to fully trigger MET phosphorylation and cellular responses (42). Even small artificial MET binding macrocycles and DNA aptamers, which are unlikely to bind further co-receptors, are able to elicit full MET activation when dimerized (43,44).…”

Section: Discussionmentioning

confidence: 99%

MET-activating Residues in the B-repeat of the Listeria monocytogenes Invasion Protein InlB

Bleymüller

Lämmermann

Ebbes

et al. 2016

Journal of Biological Chemistry

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Edited by Norma AllewellThe facultative intracellular pathogen Listeria monocytogenes causes listeriosis, a rare but life-threatening disease. Host cell entry begins with activation of the human receptor tyrosine kinase MET through the bacterial invasion protein InlB, which contains an internalin domain, a B-repeat, and three GW domains. The internalin domain is known to bind MET, but no interaction partner is known for the B-repeat. Adding the B-repeat to the internalin domain potentiates MET activation and is required to stimulate Madin-Darby canine kidney (MDCK) cell scatter. Therefore, it has been hypothesized that the B-repeat may bind a co-receptor on host cells. To test this hypothesis, we mutated residues that might be important for binding an interaction partner. We identified two adjacent residues in strand ␤2 of the ␤-grasp fold whose mutation abrogated induction of MDCK cell scatter. Biophysical analysis indicated that these mutations do not alter protein structure. We then tested these mutants in human HT-29 cells that, in contrast to the MDCK cells, were responsive to the internalin domain alone. These assays revealed a dominant negative effect, reducing the activity of a construct of the internalin domain and mutated B-repeat below that of the individual internalin domain. Phosphorylation assays of MET and its downstream targets AKT and ERK confirmed the dominant negative effect. Attempts to identify a host cell receptor for the B-repeat were not successful. We conclude that there is limited support for a co-receptor hypothesis and instead suggest that the B-repeat contributes to MET activation through low affinity homodimerization.

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“…[226] Nach der Identifizierung der makrocyclischen peptidischen Met-Bindungspartner durch RNA-Display wurde der Ligand dahingehend modifiziert, dass er [227] Dendrimere,d ie mit niedermolekularen Verbindungen konjugiert sind, wurden ebenfalls im Bereich der Antigenwirkstoffe eingesetzt, um antivirale Agentien zu erhalten, [228] beispielsweise SPL7013, einen HIV-Inhibitor,d er derzeit klinisch getestet wird. So wurde ein dimeres cyclisches Peptid entwickelt, um effektiv die Dimerisierung des Hepatozytenwachstumsfaktor(HGF)-Rezeptors (auch Met genannt) auszulçsen.…”

Section: Multimere Liganden Als Proteinkomplexmimetika Oder Zur Proteunclassified

Neue Modalitäten für schwierige Zielstrukturen in der Wirkstoffentwicklung

et al. 2017

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Unsere sich stetig erweiternden Kenntnisse über biologische Systeme haben eine Vielzahl an hoch interessanten neuen biologischen Zielstrukturen aufgedeckt, deren Modulation möglicherweise neuartige Therapiemöglichkeiten für viele Krankheiten erschließt. Diese Angriffspunkte umfassen insbesondere Protein‐Protein‐ und Protein‐Nukleinsäure‐Wechselwirkungen, die jedoch durch klassische niedermolekulare Substanzen oftmals nicht adressierbar sind. Andere Substanzklassen oder Modalitäten werden daher benötigt, um diese Ziele anzuvisieren. Einige akademische Forschungsgruppen und pharmazeutische Unternehmen greifen daher zunehmend das Konzept der so genannten “neuen Modalitäten” auf. Dieser Aufsatz definiert erstmals diesen Begriff, der neuartige Peptidgerüststrukturen, Oligonukleotide, Hybride, molekulare Konjugate sowie auf neuartige Weise eingesetzte, klassische niedermolekulare Verbindungen berücksichtigt. Wir stellen die repräsentativsten Beispiele dieser Modalitäten vor, die auf große Bindungsoberflächen, wie sie in Protein‐Protein‐Wechselwirkungen vorkommen, sowie auf zentrale biologische Zellregulationsvorgänge abzielen.

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Artificial human Met agonists based on macrocycle scaffolds

Cited by 102 publications

References 39 publications

Thioether Macrocyclic Peptides Selected against TET1 Compact Catalytic Domain Inhibit TET1 Catalytic Activity

Thioether Macrocyclic Peptides Selected against TET1 Compact Catalytic Domain Inhibit TET1 Catalytic Activity

MET-activating Residues in the B-repeat of the Listeria monocytogenes Invasion Protein InlB

Neue Modalitäten für schwierige Zielstrukturen in der Wirkstoffentwicklung

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