Discovery of a novel family of FKBP12 'reshapers' and their use as calcium modulators in skeletal muscle under nitro-oxidative stress
| Autor: | Garazi Aldanondo, Maite Eceiza, José I. Miranda, Ainara Vallejo-Illarramendi, Maialen Sagartzazu-Aizpurua, Pablo Marco-Moreno, Aitziber Irastorza, Pablo Ferrón, Jesus M. Aizpurua, Adolfo López de Munain, Haizpea Lasa-Fernández, Endika Torres, Naroa Dadie |
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| Rok vydání: | 2021 |
| Předmět: |
chemistry.chemical_element
Tacrolimus Binding Protein 1A Calcium Muscle disorder 01 natural sciences Structure-Activity Relationship 03 medical and health sciences chemistry.chemical_compound Drug Discovery medicine Humans Muscle Skeletal 030304 developmental biology Pharmacology RYR1 0303 health sciences Dose-Response Relationship Drug Molecular Structure 010405 organic chemistry Ryanodine receptor Myogenesis Calcium channel Organic Chemistry Skeletal muscle Ryanodine Receptor Calcium Release Channel General Medicine Triazoles 0104 chemical sciences Cell biology Oxidative Stress HEK293 Cells medicine.anatomical_structure chemistry Peroxynitrite |
| Zdroj: | European Journal of Medicinal Chemistry. 213:113160 |
| ISSN: | 0223-5234 |
| DOI: | 10.1016/j.ejmech.2021.113160 |
| Popis: | The hypothesis of rescuing FKBP12/RyR1 interaction and intracellular calcium homeostasis through molecular “reshaping” of FKBP12 was investigated. To this end, novel 4-arylthioalkyl-1-carboxyalkyl-1,2,3-triazoles were designed and synthesized, and their efficacy was tested in human myotubes. A library of 17 compounds (10a-n) designed to dock the FKBP12/RyR1 hot-spot interface contact residues, was readily prepared from free α-amino acids and arylthioalkynes using CuAAC “click” protocols amenable to one-pot transformations in high overall yields and total configurational integrity. To model nitro-oxidative stress, human myotubes were treated with the peroxynitrite donor SIN1, and evidence was found that some triazoles 10 were able to normalize calcium levels, as well as FKBP12/RyR1 interaction. For example, compound 10 b at 150 nM rescued 46% of FKBP12/RyR1 interaction and up to 70% of resting cytosolic calcium levels in human myotubes under nitro-oxidative stress. All compounds 10 analyzed showed target engagement to FKBP12 and low levels of cytotoxicity in vitro. Compounds 10b, 10c, 10h, and 10iR were identified as potential therapeutic candidates to protect myotubes in muscle disorders with underlying nitro-oxidative stress, FKBP12/RyR1 dysfunction and calcium dysregulation. |
| Databáze: | OpenAIRE |
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