- Defining the Determinants of Specificity of Plasmodium Proteasome Inhibitors
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The Plasmodium proteasome is an emerging antimalarial target due to its essential role in all the major life cycle stages of the parasite and its contribution to the establishment of resistance to artemisinin (ART)-based therapies. However, because of a similarly essential role for the host proteasome, the key property of any antiproteasome therapeutic is selectivity. Several parasite-specific proteasome inhibitors have recently been reported, however, their selectivity must be improved to enable clinical development. Here we describe screening of diverse libraries of non-natural synthetic fluorogenic substrates to identify determinants at multiple positions on the substrate that produce enhanced selectivity. We find that selection of an optimal electrophilic "warhead" is essential to enable high selectivity that is driven by the peptide binding elements on the inhibitor. We also find that host cell toxicity is dictated by the extent of coinhibition of the human β2 and β5 subunits. Using this information, we identify compounds with over 3 orders of magnitude selectivity for the parasite enzyme. Optimization of the pharmacological properties resulted in molecules that retained high potency and selectivity, were soluble, sufficiently metabolically stable and orally bioavailable. These molecules are highly synergistic with ART and can clear parasites in a mouse model of infection, making them promising leads as antimalarial drugs.
- Yoo, Euna,Stokes, Barbara H.,De Jong, Hanna,Vanaerschot, Manu,Kumar,Lawrence, Nina,Njoroge, Mathew,Garcia, Arnold,Van Der Westhuyzen, Renier,Momper, Jeremiah D.,Ng, Caroline L.,Fidock, David A.,Bogyo, Matthew
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supporting information
p. 11424 - 11437
(2018/09/06)
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- Novel cell-penetrating α-keto-amide calpain inhibitors as potential treatment for muscular dystrophy
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Dipeptide-derived α-keto-amide compounds with potent calpain inhibitory activity have been identified. These reversible covalent inhibitors have IC50 values down to 25 nM and exhibit greatly improved activity in muscle cells compared to the reference compound MDL28170. Several novel calpain inhibitors have shown positive effects on histological parameters in an animal model of Duchenne muscular dystrophy demonstrating their potential as a treatment option for this fatal disease.
- Lescop, Cyrille,Herzner, Holger,Siendt, Herve,Bolliger, Reto,Henneboehle, Marco,Weyermann, Philipp,Briguet, Alexandre,Courdier-Fruh, Isabelle,Erb, Michael,Foster, Mark,Meier, Thomas,Magyar, Josef P.,Von Sprecher, Andreas
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p. 5176 - 5181
(2007/10/03)
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- Further studies on nociceptin-related peptides: Discovery of a new chemical template with antagonist activity on the nociceptin receptor
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Three series of nociceptin (NC)-related peptides were synthesized and their abilities (i) to bind to the NC sites expressed in mouse forebrain membranes, (ii) to inhibit the electrically evoked contraction of the mouse vas deferens, and (iii) to inhibit f
- Guerrini, Remo,Calo', Girolamo,Bigoni, Raffaella,Rizzi, Anna,Varani, Katia,Toth, Geza,Gessi, Stefania,Hashiba, Eiji,Hashimoto, Yoshio,Lambert, David G.,Borea, Pier Andrea,Tomatis, Roberto,Salvadori, Severo,Regoli, Domenico
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p. 2805 - 2813
(2007/10/03)
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