Identification of Potent and Selective Non-covalent Inhibitors of the <i>Plasmodium falciparum</i> Proteasome

Li, Hao; Tsu, Christopher; Blackburn, Christopher; Li, Gang; Hales, Paul; Dick, Lawrence R.; Bogyo, Matthew

doi:10.1021/ja507692y

Cited by 48 publications

(77 citation statements)

References 18 publications

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“…Toxicity and regulatory issue may make it difficult to reposition a clinically used proteasome inhibitor. Earlier efforts to develop Plasmodium -specific proteasome inhibitors [114–116] now benefit from a recent tour de force , in which a collaboration led by Dr. Matt Bogyo (Stanford University) applied cryo-electron microscopy and single particle analysis to solve the structure of the P. falciparum 20S proteasome to a resolution of 3.6 Å. Combined with substrate profiling, this provides valuable information regarding active site architecture that can be used to drive optimal inhibitor design [92].…”

Section: Can Resistance To Arts Be Overcome?mentioning

confidence: 99%

Artemisinin Action and Resistance in Plasmodium falciparum

Tilley

Straimer

Gnädig

et al. 2016

Trends in Parasitology

292

278

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The worldwide use of artemisinin-based combination therapies (ACTs) has contributed in recent years to a substantial reduction in deaths resulting from Plasmodium falciparum malaria. Resistance to artemisinins, however, has emerged in Southeast Asia. Clinically, resistance is defined as a slower rate of parasite clearance in patients treated with an artemisinin derivative or an ACT. These slow clearance rates associate with enhanced survival rates of ring-stage parasites briefly exposed in vitro to dihydroartemisinin. We describe recent progress made in defining the molecular basis of artemisinin resistance, which has identified a primary role for the P. falciparum K13 protein. Using K13 mutations as molecular markers, epidemiological studies are now tracking the emergence and spread of artemisinin resistance. Mechanistic studies suggest potential ways to overcome resistance.

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Section: Can Resistance To Arts Be Overcome?mentioning

confidence: 99%

Artemisinin Action and Resistance in Plasmodium falciparum

Tilley

Straimer

Gnädig

et al. 2016

Trends in Parasitology

292

278

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“…[326] Die Verwendung einer aktivitätsbasierten Sonde in P. -falciparum-Kulturen, die mit selektiven, bekannten Inhibitoren der humanen b1-, b2und b5-Untereinheiten vorbehandelt waren, lieferte wichtige Einblicke in das 20S-Proteasom. [328] Dockingexperimente mit der Verbindung 73 an die b5-Untereinheit des Hefeproteasoms,d eren Cokristallstruktur mit einem nichtkovalenten, potenten, b5-selektiven Dipeptid verfügbar ist (PDB ID:3MG4), [329] führten zu der Hypothese, dass die Konformation der S3-Tasche fürd ie selektive Proteasominhibition entscheidend ist, da die Homophenyl-Seitenkette von 73 in die S3-Bindungstasche von Plasmodium passt, aber nicht in das Hefeproteasom. Die vollständige Elimination der Parasitämie in mit P. chabaudi infizierten Mäusen wurde in allen asexuellen Stadien durch Coinhibition der b2-und b5-Untereinheiten mit nur geringer Toxizitäte rreicht.…”

Section: Angewandte Chemieunclassified

Eine strukturelle Evaluierung medizinalchemischer Strategien gegen Wirkstoffresistenzen

Agnello¹,

Brand²,

Chellat³

et al. 2019

Angewandte Chemie

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Das natürliche Phänomen der Wirkstoffresistenz stellt eine universelle Beeinträchtigung des Nutzens von pharmazeutischen Wirkstoffen in vielen klinischen Indikationen dar. Antibakterielle und antifungale Wirkstoffe sind dabei ebenso betroffen wie Wirkstoffe zur Behandlung von Krebs, Virusinfektionen oder durch Parasiten hervorgerufene Erkrankungen. Trotz der unterschiedlichen biologischen Zielstrukturen und Organismen, die bei der Entwicklung von Wirkstoffresistenzen involviert sind, konnten grundlegende molekulare Prozesse identifiziert werden, die zum Verständnis des Auftretens von Resistenzen beitragen und die Bekämpfung dieser nachteiligen Mechanismen erlauben. Strukturelle Informationen über die Prinzipien von Wirkstoffresistenzen sind heute vielfältig vorhanden, sodass neue Wirkstoffe entwickelt werden können, die weniger anfällig gegenüber einer Resistenzbildung sein werden. Dieser wissensbasierte Ansatz ist eine Grundlage für den Kampf gegen das unvermeidbare Auftreten von Wirkstoffresistenzen.

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“…17 Li et al have demonstrated successful inhibition of the Plasmodium falciparum proteasome using macrocyclic biaryl ethers. 18 A SAR by Abell et al on macrocyclic peptide aldehyde inhibitors of ovine calpain found that the addition of an aldehyde to a peptide macrocycle can increase potency as much as ∼1000-fold. 19 The results of Abell et al combined with the proteasome's flexible S 2 and S 4 pockets suggest that a macrocyclic peptide aldehyde with a suitable peptide sequence will yield a potent and selective inhibitor of the 20S proteasome.…”

mentioning

confidence: 99%

Synthesis and Evaluation of Macrocyclic Peptide Aldehydes as Potent and Selective Inhibitors of the 20S Proteasome

Wilson

Meininger

Strater

et al. 2016

ACS Med. Chem. Lett.

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This research explores the first design and synthesis of macrocyclic peptide aldehydes as potent inhibitors of the 20S proteasome. Two novel macrocyclic peptide aldehydes based on the ring-size of the macrocyclic natural product TMC-95 were prepared and evaluated as inhibitors of the 20S proteasome. Both compounds inhibited in the low nanomolar range and proved to be selective for the proteasome over other serine and cysteine proteases, particularly when compared to linear analogues with similar amino acid sequences. In HeLa cells, both macrocycles efficiently inhibited activation of nuclear factor-κB (NF-κB) transcription factor by blocking proteasomal degradation of the inhibitor protein IκBα after cytokine stimulation. Due to their covalent mechanism of binding these compounds represent a 1000-fold increase in inhibitory potency over previously reported noncovalently binding TMC-95 analogues. Molecular modeling of the macrocyclic peptides confirms the preference of the large S 3 pocket for large, hydrophobic residues and the ability to exploit this to improve selectivity of proteasome inhibitors.

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Identification of Potent and Selective Non-covalent Inhibitors of the Plasmodium falciparum Proteasome

Cited by 48 publications

References 18 publications

Artemisinin Action and Resistance in Plasmodium falciparum

Artemisinin Action and Resistance in Plasmodium falciparum

Eine strukturelle Evaluierung medizinalchemischer Strategien gegen Wirkstoffresistenzen

Synthesis and Evaluation of Macrocyclic Peptide Aldehydes as Potent and Selective Inhibitors of the 20S Proteasome

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