Discovery of a novel family of FKBP12 "reshapers" and their use as calcium modulators in skeletal muscle under nitro-oxidative stress.

Abstract

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.

• Authors: Jesus M Aizpurua, José I Miranda, Aitziber Irastorza, Endika Torres, Maite Eceiza, Maialen Sagartzazu-Aizpurua, Pablo Ferrón, Garazi Aldanondo, Haizpea Lasa-Fernández, Pablo Marco-Moreno, Naroa Dadie, Adolfo López de Munain, Ainara Vallejo-Illarramendi
• Journal: European journal of medicinal chemistry (Eur J Med Chem) Vol. 213 Pg. 113160 (Mar 05 2021) ISSN: 1768-3254 [Electronic] France
• PMID: 33493827 (Publication Type: Journal Article)
• Copyright: Copyright © 2021 Elsevier Masson SAS. All rights reserved.

Chemical References

• RYR1 protein, human
• Ryanodine Receptor Calcium Release Channel
• Triazoles
• Tacrolimus Binding Protein 1A
• Calcium

Topics

• Calcium (metabolism)
• Dose-Response Relationship, Drug
• Drug Discovery
• HEK293 Cells
• Humans
• Molecular Structure
• Muscle, Skeletal (drug effects, metabolism)
• Oxidative Stress (drug effects)
• Ryanodine Receptor Calcium Release Channel (chemistry, metabolism)
• Structure-Activity Relationship
• Tacrolimus Binding Protein 1A (chemistry, metabolism)
• Triazoles (chemical synthesis, chemistry, pharmacology)