Dual protein kinase and nucleoside kinase modulators for rationally designed polypharmacology

Hammam, Kahina; Saez-Ayala, Magali; Rebuffet, E.; Gros, Laurent; Lopez, Sophie; Hajem, Bérengère; Humbert, M.; Baudelet, Emilie; Audebert, Stéphane; Betzi, S.; Lugari, Adrien; Combes, Sébastien; Letard, Sébastien; Castéran, Nathalie; Mansfield, Colin D.; Moussy, Alain; Sepulveda, Paulo De; Morelli, Xavier; Dubreuil, Patrice

doi:10.1038/s41467-017-01582-5

Cited by 21 publications

(16 citation statements)

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“…Our approach conceptualizes how the rate‐limiting transition state of a transporter can be characterized structurally, informing on potential druggable sites to develop allosteric modulators, and provides a method to investigate the kinetic effects of post‐translational modifications (Czuba et al , 2018). We anticipate that our methodology can be adapted to accelerate the expansion of therapeutic allosteric modulators in other protein systems with conformationally selective pockets, such as kinases (Hammam, Saez‐Ayala et al , 2017; Zorba, Nguyen et al , 2019).…”

Section: Discussionmentioning

confidence: 99%

The high‐energy transition state of the glutamate transporter homologue GltPh

et al. 2020

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Membrane transporters mediate cellular uptake of nutrients, signaling molecules, and drugs. Their overall mechanisms are often well understood, but the structural features setting their rates are mostly unknown. Earlier single-molecule fluorescence imaging of the archaeal model glutamate transporter homologue Glt Ph from Pyrococcus horikoshii suggested that the slow conformational transition from the outward-to the inward-facing state, when the bound substrate is translocated from the extracellular to the cytoplasmic side of the membrane, is rate limiting to transport. Here, we provide insight into the structure of the high-energy transition state of Glt Ph that limits the rate of the substrate translocation process. Using bioinformatics, we identified Glt Ph gain-of-function mutations in the flexible helical hairpin domain HP2 and applied linear free energy relationship analysis to infer that the transition state structurally resembles the inward-facing conformation. Based on these analyses, we propose an approach to search for allosteric modulators for transporters.

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Section: Discussionmentioning

confidence: 99%

The high‐energy transition state of the glutamate transporter homologue GltPh

et al. 2020

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“…Masitinib is a selective tyrosine kinase inhibitor that mainly targets type III growth factor receptors like c-Kit, Lyn, and Fyn kinases, and is particularly effective in controlling the survival, differentiation, and degranulation of mast cells. Masitinib has been found to prevent the CNS neuro-inflammation by targeting the degranulation of the mast cells accumulating around the degenerating neuronal axons and by decreasing the release of inflammatory cytokines (Trias et al, 2016; Hammam et al, 2017). It can even target the microglia cells which are the resident macrophages of the brain.…”

Section: Therapeutic Strategies For Alsmentioning

confidence: 99%

Molecular Mechanisms of TDP-43 Misfolding and Pathology in Amyotrophic Lateral Sclerosis

Prasad

Bharathi

Sivalingam

et al. 2019

Front. Mol. Neurosci.

537

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TAR DNA binding protein 43 (TDP-43) is a versatile RNA/DNA binding protein involved in RNA-related metabolism. Hyper-phosphorylated and ubiquitinated TDP-43 deposits act as inclusion bodies in the brain and spinal cord of patients with the motor neuron diseases: amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). While the majority of ALS cases (90–95%) are sporadic (sALS), among familial ALS cases 5–10% involve the inheritance of mutations in the TARDBP gene and the remaining (90–95%) are due to mutations in other genes such as: C9ORF72, SOD1, FUS , and NEK1 etc. Strikingly however, the majority of sporadic ALS patients (up to 97%) also contain the TDP-43 protein deposited in the neuronal inclusions, which suggests of its pivotal role in the ALS pathology. Thus, unraveling the molecular mechanisms of the TDP-43 pathology seems central to the ALS therapeutics, hence, we comprehensively review the current understanding of the TDP-43's pathology in ALS. We discuss the roles of TDP-43's mutations, its cytoplasmic mis-localization and aberrant post-translational modifications in ALS. Also, we evaluate TDP-43's amyloid-like in vitro aggregation, its physiological vs. pathological oligomerization in vivo , liquid-liquid phase separation (LLPS), and potential prion-like propagation propensity of the TDP-43 inclusions. Finally, we describe the various evolving TDP-43-induced toxicity mechanisms, such as the impairment of endocytosis and mitotoxicity etc. and also discuss the emerging strategies toward TDP-43 disaggregation and ALS therapeutics.

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“…Today, there is a growing interest in the rational design of multi-target drugs (Bolognesi, 2019;Hammam et al, 2017;Proschak et al, 2019). However, it is still very challenging to identify targets that can be simultaneously inhibited with a single compound and that are both therapeutically relevant for a specific disease (Proschak et al, 2019).…”

Section: Articlementioning

confidence: 99%