the-mub40-peptide-for-use-detecting-neutrophil-mediated-inflammation

The MUB<sub>40</sub> Peptide for Use in Detecting Neutrophil-Mediated Inflammation Events

Here, we provide a protocol involving the use of MUB40, a synthesized peptide with the ability to bind glycosylated lactoferrin stored at high ...

Institut Pasteur

Somatic gain-of-function mutations in isocitrate dehydrogenases () 1 and 2 are found in multiple hematologic and solid tumors, leading to accumulation of the oncometabolite ()-2-hydroxyglutarate (2HG). 2HG competitively inhibits α-ketoglutarate-dependent dioxygenases, including histone demethylases and methylcytosine dioxygenases of the TET family, causing epigenetic dysregulation and a block in cellular differentiation.  studies have provided proof of concept for mutant IDH inhibition as a therapeutic approach. We report the discovery and characterization of AG-221, an orally available, selective, potent inhibitor of the mutant IDH2 enzyme. AG-221 suppressed 2HG production and induced cellular differentiation in primary human  mutation-positive acute myeloid leukemia (AML) cells  and in xenograft mouse models. AG-221 also provided a statistically significant survival benefit in an aggressive IDH2-mutant AML xenograft mouse model. These findings supported initiation of the ongoing clinical trials of AG-221 in patients with  mutation-positive advanced hematologic malignancies. Mutations in  are identified in approximately 20% of patients with AML and contribute to leukemia via a block in hematopoietic cell differentiation. We have shown that the targeted inhibitor AG-221 suppresses the mutant IDH2 enzyme in multiple preclinical models and induces differentiation of malignant blasts, supporting its clinical development. .

AG-221, a First-in-Class Therapy Targeting Acute Myeloid Leukemia Harboring Oncogenic  Mutations.

Shigella is a leading cause of dysentery worldwide, with the majority of infections caused by two subgroups, S. flexneri and S. sonnei. Although S. flexneri has been highly prevalent in low-income countries, global development has brought an increase in S. sonnei at the expense of S. flexneri. However, the mechanisms behind this shift are not understood. Here we report that S. sonnei, but not S. flexneri, encodes a type VI secretion system (T6SS) that provides a competitive advantage in the gut. S. sonnei competes against E. coli and S. flexneri in mixed cultures, but this advantage is reduced in T6SS mutant strains. In addition, S. sonnei can persist as well as outcompete E. coli and S. flexneri in mice in a T6SS-dependent manner. These findings suggest that S. sonnei has a competitive advantage over S. flexneri and potentially explain the increasing global prevalence of S. sonnei.

Shigella sonnei Encodes a Functional T6SS Used for Interbacterial Competition and Niche Occupancy.

Neutrophils represent the most abundant immune cells recruited to inflamed tissues. A lack of dedicated tools has hampered their detection and study. We show that a synthesized peptide, MUB, binds to lactoferrin, the most abundant protein stored in neutrophil-specific and tertiary granules. Lactoferrin is specifically produced by neutrophils among other leukocytes, making MUB a specific neutrophil marker. Naive mammalian neutrophils (human, guinea pig, mouse, rabbit) were labeled by fluorescent MUB conjugates (-Cy5, Dylight405). A peptidase-resistant retro-inverso MUB (RI-MUB) was synthesized and its lactoferrin-binding property validated. Neutrophil lactoferrin secretion during in vitro Shigella infection was assessed with RI-MUB-Cy5 using live cell microscopy. Systemically administered RI-MUB-Cy5 accumulated at sites of inflammation in a mouse arthritis inflammation model in vivo and showed usefulness as a potential tool for inflammation detection using non-invasive imaging. Improving neutrophil detection with the universal and specific MUB marker will aid the study of broad ranges of inflammatory diseases.

Article	Year
AG-221, a First-in-Class Therapy Targeting Acute Myeloid Leukemia Harboring Oncogenic Mutations. Cancer discovery\| PubMed ID: 28193778	2017
Shigella sonnei Encodes a Functional T6SS Used for Interbacterial Competition and Niche Occupancy. Cell host & microbe\| PubMed ID: 28618272	2017
MUB Binds to Lactoferrin and Stands as a Specific Neutrophil Marker. Cell chemical biology\| PubMed ID: 29478905	2018

Benoit S. Marteyn

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