A potent and selective reaction hijacking inhibitor of Plasmodium falciparum tyrosine tRNA synthetase exhibits single dose oral efficacy in vivo

PLoS Pathogens, Год журнала: 2024, Номер 20(12), С. e1012429 - e1012429

Опубликована: Дек. 9, 2024

The Plasmodium falciparum cytoplasmic tyrosine tRNA synthetase ( Pf TyrRS) is an attractive drug target that susceptible to reaction-hijacking by AMP-mimicking nucleoside sulfamates. We previously identified exemplar pyrazolopyrimidine ribose sulfamate, ML901, as a potent reaction hijacking inhibitor of TyrRS. Here we examined the stage specificity action showing very good activity against schizont stage, but lower trophozoite activity. explored series ML901 analogues and ML471, which exhibits improved potency trophozoites enhanced selectivity human cell line. Additionally, it has no inhibitory ubiquitin-activating enzyme (UAE) in vitro . ML471 low nanomolar asexual blood P liver parasites, gametocytes transmissible gametes. It fast-acting long vivo half-life. well-tolerated shows single dose oral efficacy SCID mouse model malaria. confirm converted into tight binding Tyr-ML471 conjugate TyrRS enzyme. A crystal structure TyrRS/ complex offers insights potency, while molecular docking UAE provides rationale for selectivity.

Язык: Английский

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Scfβ-Trcp Targets Ajuba for Degradation in a Gsk3β-Dependent Manner in Colorectal Cancer

Опубликована: Янв. 1, 2024

Язык: Английский

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Transcriptome-based screening in TARDBP/TDP-43 knock-in motor neurons identifies the NEDD8-activating enzyme inhibitor MLN4924

Research Square (Research Square), Год журнала: 2024, Номер unknown

Опубликована: Дек. 16, 2024

A growing body of knowledge implicates perturbed RNA homeostasis in amyotrophic lateral sclerosis (ALS), a neurodegenerative disease that currently has no cure and few available treatments. Dysregulation the multifunctional RNA-binding protein TDP-43 is increasingly regarded as convergent feature this disease, evidenced at neuropathological level by detection pathology most patient tissues, genetic identification disease-associated mutations its coding gene TARDBP. To characterize transcriptional landscape induced TARDBP mutations, we performed whole-transcriptome profiling motor neurons differentiated from two knock-in iPSC lines expressing ALS-linked variants p.A382T or p.G348C. Our results show significantly altered expression profiles mRNAs microRNAs 14q32 cluster MNs. Using mutation-induced signatures Connectivity Map database, identified compounds predicted to restore toward wild-type levels. Among top-scoring selected for further investigation, NEDD8-activating enzyme inhibitor MLN4924 effectively improved cell viability neuronal activity, highlighting possible role post-translational modification via NEDDylation pathobiology ALS.

Язык: Английский

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Effects of neddylation on viral infection: an overview

Archives of Virology, Год журнала: 2023, Номер 169(1)

Опубликована: Дек. 11, 2023

Язык: Английский

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