Neuronal loss characterizes many of the most intractable nervous system diseases that deprive our ageing population of their quality of life. Neuroprotective pharmacological modalities are urgently needed to address this burgeoning population. Small ubiquitin-like modifier (SUMO) conjugation has been established as an endogenous neuroprotective response, and we have discovered several classes of small molecules that enhance SUMO conjugation. Herein we describe the hit to lead campaign that enabled the discovery of 3 diverse classes of drug-like SUMOylation activators. Optimized compounds were ultimately validated in cell-based models of neuronal loss and provide a foundation for establishing systemically active SUMO activators to treat degenerative diseases such as Parkinson's disease, Alzheimer's disease, and stroke.

01 Aug 2015·Journal of Antimicrobial ChemotherapyQ2 · MEDICINE

Identification of an anti-TB compound targeting the tyrosyl-tRNA synthetase

Q2 · MEDICINE

Article

Author: Li, Dongsheng ; Gao, Nana ; Zhu, Ningyu ; Jiang, Wei ; Liu, Chang ; Jiang, Jiandong ; Lin, Yuan ; You, Xuefu ; Si, Shuyi

AbstractObjectivesDrug-resistant Mycobacterium tuberculosis poses a great threat to human health. Tyrosyl-tRNA synthetase (TyrRS) is one of the aminoacyl tRNA synthetases that catalyse the attachment of amino acids to their cognate tRNAs and are essential for protein synthesis. There are several distinctive differences between bacterial and human TyrRS and therefore it could be a potential target for developing antimicrobial agents. This study aimed to identify a new anti-TB agent targeting M. tuberculosis TyrRS (MtTyrRS).MethodsWe first used Mycobacterium smegmatis for a phenotypic screening of 20 000 compounds. The hit compounds were then screened with MtTyrRS. The interaction between hit compound IMB-T130 and the target protein was analysed by surface plasmon resonance (SPR) assay and molecular docking experiments. The target of IMB-T130 was further confirmed by the overexpression of the target protein. The antibacterial activity of IMB-T130 against various standard and clinical drug-resistant M. tuberculosis strains was evaluated using the microplate Alamar blue assay.ResultsCompound IMB-T130 was identified as a hit compound that inhibits the growth of M. smegmatis and the in vitro activity of MtTyrRS. The interaction between IMB-T130 and MtTyrRS was confirmed by SPR assay and molecular docking analysis. The higher MIC for a strain overexpressing the target protein also suggests that MtTyrRS is likely to be the target of IMB-T130. IMB-T130 shows excellent anti-TB activity and low cytotoxicity.ConclusionsIMB-T130 inhibits the growth of MDR-TB and XDR-TB by targeting MtTyrRS. Because of its low cytotoxicity against mammalian cells, IMB-T130 is a promising new agent against drug-resistant M. tuberculosis.

Scientific ReportsQ3 · CROSS-FIELD

IMB-T130 targets 3-dehydroquinate synthase and inhibits Mycobacterium tuberculosis

Q3 · CROSS-FIELD

ArticleOA

Author: Li, Dongsheng ; Zhu, Ningyu ; Jiang, Wei ; You, Xuefu ; Si, Shuyi ; Xu, Yanni ; Jiang, Jiandong ; Lin, Yuan ; Wang, Xia

AbstractThe anti-tuberculosis (TB) agent IMB-T130 was speculated to be a multi-target compound. In this research, we found that IMB-T130 inhibits the catalytic activity of Mycobacterium tuberculosis 3-dehydroquinate synthase (MtDHQS), the enzyme in the second step of the shikimate pathway. IMB-T130 was identified as a selective inhibitor of MtDHQS with an IC50 value of 0.87 μg/mL. The interaction between the compound and protein was analysed by surface plasmon resonance and circular dichroism. Based on the in silico molecular docking results, the essential amino acids in the binding pocket were then confirmed by site-directed mutagenesis. Overexpression of DHQS reduced the antibacterial activity of IMB-T130 in cells, verifying that DHQS is the target of IMB-T130. IMB-T130 inhibited standard and drug-resistant M. tuberculosis strains by targeting DHQS. Our findings improve our understanding of MtDHQS and make it to be a potential target for new anti-TB drug discovery.

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Indication	Highest Phase	Country/Location	Organization	Date
Tuberculosis	Discovery	China	Biotechnology Research Institute of Chinese Academy of Agricultural Sciences	09 May 2015

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