Inhibitors and chemical probes for molecular chaperone networks

Gestwicki, Jason E.; Shao, Hao

doi:10.1074/jbc.tm118.002813

Cited by 68 publications

(49 citation statements)

References 127 publications

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“…In addition, binding immunoglobulin protein (BiP), the Hsp70 homologue within the ER (PF3D7_0917900), requires ATPase activity to perform the final step of protein translocation from the SEC61 translocon into the ER 71 and could also be a plausible target. Chemical targeting of BiP is feasible 72 . The hypothesis that KAF156/GNF179 targets protein folding in the ER is supported by the role of EMP65 as a guardian factor that protects newly synthesized, unfolded polypeptides from degradation (See Supplementary Fig.…”

Section: Discussionmentioning

confidence: 99%

Pan-active imidazolopiperazine antimalarials target the Plasmodium falciparum intracellular secretory pathway

et al. 2020

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A promising new compound class for treating human malaria is the imidazolopiperazines (IZP) class. IZP compounds KAF156 (Ganaplacide) and GNF179 are effective against Plasmodium symptomatic asexual blood-stage infections, and are able to prevent transmission and block infection in animal models. But despite the identification of resistance mechanisms in P. falciparum, the mode of action of IZPs remains unknown. To investigate, we here combine in vitro evolution and genome analysis in Saccharomyces cerevisiae with molecular, metabolomic, and chemogenomic methods in P. falciparum. Our findings reveal that IZPresistant S. cerevisiae clones carry mutations in genes involved in Endoplasmic Reticulum (ER)-based lipid homeostasis and autophagy. In Plasmodium, IZPs inhibit protein trafficking, block the establishment of new permeation pathways, and cause ER expansion. Our data highlight a mechanism for blocking parasite development that is distinct from those of standard compounds used to treat malaria, and demonstrate the potential of IZPs for studying ER-dependent protein processing.

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Section: Discussionmentioning

confidence: 99%

Pan-active imidazolopiperazine antimalarials target the Plasmodium falciparum intracellular secretory pathway

et al. 2020

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“…Specifically, we wondered whether inhibiting the association of HSP70 with DNAJB6b with small molecules might partially protect against LGMD1D phenotypes in mammalian disease models. As a proof-of-concept, we tested four different compounds known to modulate HSP70 interactions with co-chaperones [20]. YM-01, JG98 and JG231 inhibit HSP70 activity by interfering with its interactions with co-chaperones, including DNAJ proteins [21].…”

Section: Resultsmentioning

confidence: 99%

Inhibition of DNAJ-HSP70 interaction improves strength in muscular dystrophy

Bengoechea¹,

Findlay²,

Bhadra³

et al. 2020

Preprint

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Introduction: 41Limb-girdle muscular dystrophies (LGMD) are a family of hereditary muscle diseases 42 that are inherited in an autosomal recessive or dominant manner [1]. Most recessively 43 inherited LGMDs are postulated to be caused by a loss-of-function mechanism, 44 because the protein is absent in patient muscle tissue and many mutations lead to 45 premature stops or frameshifts. However, the mechanisms of dominantly inherited 46LGMDs are less clear: they may be due to haploinsufficiency, a gain of new toxic 47 function or a dominant interaction leading to protein dysfunction. 48 49One common pathologic feature seen in some dominantly inherited myopathies, 50including LGMD1D, myofibrillar myopathy and inclusion body myopathy, are protein 51 aggregates and myofiber vacuolation [2]. The inclusions in LGMD1D muscle are 52 heterogeneous and contain myofibrillar proteins, such as desmin and myotilin [3, 4]. 53Additionally, they contain proteins that aggregate in neurodegenerative disorders, such 54 as TDP-43 and SQSTM1 [3, 4]. Together, these features suggest that a subset of 55 inherited myopathies might involve an impairment in protein quality control. Indeed, one 56 family of muscle diseases with myofibrillar disorganization (e.g. myofibrillar myopathies) 57 are caused by missense mutations in Z-disc associated structural proteins, such as 58 desmin, myotilin or filamin-C that lead to their aggregation [2]. Likewise, myofibrillar 59 myopathies are also associated with mutations in molecular chaperones, such as 60 BAG3, HSPB5 and DNAJB6 [2, 5, 6]. These "chaperonopathies" are autosomal 61 dominantly inherited and lead to the accumulation and aggregation of Z-disc proteins, 62 such as desmin and filamin-C. Moreover, several chaperones are known to be 63 4 necessary for sarcomere development and maintenance [7]. Our aim was to better 64 understand the mechanisms associated with dominantly inherited LGMD1D caused by 65 mutations in DNAJB6 in order to gain insight into the relationship between protein 66 quality control and myopathy. 67 68 DNAJB6 is a ubiquitously expressed HSP40 co-chaperone that facilitates HSP70 69 functionality via its J domain [8]. DNAJB6, like other DNAJB family members, has a 70 canonical J domain, a C-terminal dimerization motif and a glycine-and phenylalanine-71 rich region (termed a G/F domain) [8]. Interestingly, all reported LGMD1D mutations 72 reside within the G/F domain [3, 4,[9][10][11]. DNAJB6 has two isoforms, DNAJB6a and 73DNAJB6b, which differ in the length of their C-terminal region and in their cellular 74 localization. DNAJB6a is longer and localizes to the nucleus; whereas DNAJB6b is 75 shorter and cytoplasmic [12]. Although both isoforms share the G/F domain containing 76LGMD1D disease mutations, it is thought that DNAJB6b is the pathogenic isoform [3, 77 12]. Patients with LGMD1D have insidious onset of weakness in the second to sixth 78 decade of life that affects their ability to ambulate [3, 4, 9, 10, 13]. The muscle tissue of 79LGMD1D patients is characteristically...

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“…Chemical targeting of BiP is feasible. 61 The hypothesis that KAF156/GNF179 targets protein folding in the ER is supported by the role of EMP65 as a guardian factor that protects newly synthesized, unfolded polypeptides from degradation (See Figure S5 for model). If pfcarl-emp65 is mutated, more premature degradation may occur in the presence of GNF179/KAF156, which may allow the cells to tolerate 10X more GNF179.…”

Section: Discussionmentioning

confidence: 99%

Pan-active imidazolopiperazine antimalarials target thePlasmodium falciparumintracellular secretory pathway

LaMonte

Marapana

Gnädig

et al. 2019

Preprint

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AbstractOne of the most promising new compound classes in clinical development for the treatment of malaria is the imidazolopiperazines (IZPs) class. Human trials have demonstrated that members of the IZP series, which includes KAF156 (Ganaplacide) and GNF179, are potent and effective against Plasmodium symptomatic asexual blood-stage infections. Unlike other commonly used antimalarials, they also prevent transmission and block future infection in animal models. Despite the identification of several Plasmodium falciparum resistance mechanisms including mutations in ER-localized PfCARL (PfEMP65), Acetyl-coA transporter, and PfUGT transporter, IZP’s mechanism of action remains unknown.To investigate, we combined in vitro evolution and whole-genome analysis in the model organism Saccharomyces cerevisiae with molecular, metabolomic, and chemogenomic methods, in P. falciparum. S. cerevisiae clones that resist IZP activity carry multiple mutations in genes that encode endoplasmic reticulum(ER)-based lipid homeostasis and autophagy including elo2, elo3, sur2, atg15 and lcb4, as well as ER-based sec66. In Plasmodium, IZPs cause inhibition of protein trafficking, block the establishment of new permeation pathways and result in ER expansion. We also observe sensitization with other secretion inhibitors such as brefeldin A and golgicidin as well as synthetic lethality with PfSEC62. Our data show that IZPs target the secretory pathway and highlight a novel mechanism for blocking parasite growth and development that is distinct from those of standard compounds used to treat malaria. In addition, we provide physiological signatures and hallmarks for inhibitors that work through this mechanism of action and show that IZPs are tool compounds for studying ER-dependent protein processing in different species.

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Inhibitors and chemical probes for molecular chaperone networks

Cited by 68 publications

References 127 publications

Pan-active imidazolopiperazine antimalarials target the Plasmodium falciparum intracellular secretory pathway

Pan-active imidazolopiperazine antimalarials target the Plasmodium falciparum intracellular secretory pathway

Inhibition of DNAJ-HSP70 interaction improves strength in muscular dystrophy

Pan-active imidazolopiperazine antimalarials target thePlasmodium falciparumintracellular secretory pathway

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