Aromatic Oligoamide Foldamers with a “Wet Edge” as Inhibitors of the α‐Helix‐Mediated p53–<i>h</i>DM2 Protein–Protein Interaction

Prabhakaran, Panchami; Barnard, Anna; Murphy, Natasha S.; Kilner, Colin A.; Edwards, Thomas A.; Wilson, Andrew J.

doi:10.1002/ejoc.201300069

Cited by 28 publications

(34 citation statements)

References 61 publications

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“…The structure-based design of small molecules that can stabilize or disrupt helix-protein interactions with high specificity and efficacy is a central challenge in medicinal chemistry. Small molecules which can present functional groups on a pre-organized framework have been identified that disrupt the helix-protein recognition surfaces in interactions such as p53/hDM2 (Prabhakaran, Barnard, et al, 2013; Yin, Lee, et al, 2005), Bak/Bcl-x L (Ernst, Becerril, et al, 2003), and the six helix-bundle assembly of GP41 (Ernst, Kutzki, et al, 2002). Plainly, helix-protein interactions are an important and addressable category of biological target.…”

Section: Introductionmentioning

confidence: 99%

Islet Amyloid-Induced Cell Death and Bilayer Integrity Loss Share a Molecular Origin Targetable with Oligopyridylamide-Based α-Helical Mimetics

Kumar

Schlamadinger

Brown

et al. 2015

Chemistry & Biology

100

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SUMMARY Islet amyloid polypeptide (IAPP) is a hormone cosecreted with insulin. IAPP proceeds through a series of conformational changes from random coil to β-sheet via transient α-helical intermediates. An unknown subset of these events are associated with seemingly disparate gains-of-function including catalysis of self-assembly, membrane penetration, loss of membrane integrity, mitochondrial localization and finally cytotoxicity, a central component of diabetic pathology. A series of small molecule, α-helical mimetics, oligopyridylamides, was previously shown to target the membrane bound α-helical oligomeric intermediates of IAPP. In this study, we develop an improved, microwave assisted synthesis of oligopyridylamides. A series of designed tripyridylamides demonstrate that lipid-catalyzed self-assembly of IAPP can be deliberately targeted. These molecules additionally affect IAPP induced leakage of synthetic liposomes and cellular toxicity in insulin secreting cells. The tripyridylamides inhibit these processes with identical rank orders of effectiveness. This indicates a common molecular basis for the disparate set of observed effects of IAPP.

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Section: Introductionmentioning

confidence: 99%

Islet Amyloid-Induced Cell Death and Bilayer Integrity Loss Share a Molecular Origin Targetable with Oligopyridylamide-Based α-Helical Mimetics

Kumar

Schlamadinger

Brown

et al. 2015

Chemistry & Biology

100

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“…Attempts to functionalize the non-recognition face of these scaffolds have been described by Wilson and co-workers. [297, 298] However, the improvement in solubility is associated with a concomitant decrease in the inhibitory activity. A dimeric mimetic of N-alkylated oligoamides lacking positive cooperativity has also been synthesized by means of click chemistry.…”

Section: Methodsmentioning

confidence: 99%

Structure‐Based Design of Inhibitors of Protein–Protein Interactions: Mimicking Peptide Binding Epitopes

et al. 2015

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Protein–protein interactions (PPIs) are involved at all levels of cellular organization, thus making the development of PPI inhibitors extremely valuable. The identification of selective inhibitors is challenging because of the shallow and extended nature of PPI interfaces. Inhibitors can be obtained by mimicking peptide binding epitopes in their bioactive conformation. For this purpose, several strategies have been evolved to enable a projection of side chain functionalities in analogy to peptide secondary structures, thereby yielding molecules that are generally referred to as peptidomimetics. Herein, we introduce a new classification of peptidomimetics (classes A–D) that enables a clear assignment of available approaches. Based on this classification, the Review summarizes strategies that have been applied for the structure-based design of PPI inhibitors through stabilizing or mimicking turns, β-sheets, and helices.

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“…N‐Alkylierte Oligoamide ( 34 ) sind bisher die strukturell einfachsten Oligoamide. Versuche, die Seite des Strukturgerüsts zu funktionalisieren, die nicht für die Erkennung benötigt wird, wurden von Wilson und Mitarbeitern unternommen 297. 298 Allerdings bewirkte eine Verbesserung der Löslichkeit gleichzeitig eine Absenkung der Inhibitoraktivität.…”

Section: Methodikunclassified

Strukturbasierte Entwicklung von Protein‐Protein‐Interaktionsinhibitoren: Stabilisierung und Nachahmung von Peptidliganden

et al. 2015

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Protein‐Protein‐Interaktionen (PPIs) spielen auf allen Ebenen der Zellorganisation eine wichtige Rolle, was die Entwicklung von PPI‐Inhibitoren äußerst interessant macht. Die Herstellung von selektiven Inhibitoren ist wegen der relativ flachen und ausgedehnten Protein‐Protein‐Interaktionsflächen oftmals sehr aufwendig. Derartige Inhibitoren können beispielsweise durch das Nachahmen von Peptidliganden in deren bioaktiver Konformation generiert werden. Für die Entwicklung so genannter Peptidmimetika steht eine Reihe von Ansätzen zur Verfügung, die eine Ausrichtung der Seitenkettenfunktionalitäten in Analogie zu einer bestimmten Peptidsekundärstruktur ermöglichen. In diesem Aufsatz führen wir eine neue Klassifizierung von Peptidmimetika (Klasse A–D) ein, die eine klare Zuordnung der bestehenden Strategien erlaubt. Basierend auf dieser Klassifizierung werden Strategien erörtert, die bereits für ein strukturbasiertes Design von PPI‐Inhibitoren durch Stabilisierung oder Nachahmung von Kehren, β‐Faltblattstrukturen und Helices angewendet wurden.

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Aromatic Oligoamide Foldamers with a “Wet Edge” as Inhibitors of the α‐Helix‐Mediated p53–hDM2 Protein–Protein Interaction

Cited by 28 publications

References 61 publications

Islet Amyloid-Induced Cell Death and Bilayer Integrity Loss Share a Molecular Origin Targetable with Oligopyridylamide-Based α-Helical Mimetics

Islet Amyloid-Induced Cell Death and Bilayer Integrity Loss Share a Molecular Origin Targetable with Oligopyridylamide-Based α-Helical Mimetics

Structure‐Based Design of Inhibitors of Protein–Protein Interactions: Mimicking Peptide Binding Epitopes

Strukturbasierte Entwicklung von Protein‐Protein‐Interaktionsinhibitoren: Stabilisierung und Nachahmung von Peptidliganden

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