Exploiting Peptidomimetics to Synthesize Compounds That Activate Ryanodine Receptor Calcium Release Channels

Abstract

Ryanodine receptor (RyR) Ca -release channels are essential for contraction in skeletal and cardiac muscle and are prime targets for modification of contraction in disorders that affect either the skeletal or heart musculature. We designed and synthesized a number of compounds with structures based on a naturally occurring peptide (A peptides) that modifies the activity of RyRs. In total, 34 compounds belonging to eight different classes were prepared. The compounds were screened for their ability to enhance Ca release from isolated cardiac sarcoplasmic reticulum (SR) vesicles, with 25 displaying enhanced Ca release. Competition studies with the parent peptides indicated that the synthetic compounds act at a competing site. The activity of the most effective of the compounds, BIT 180, was further explored using Ca release from skeletal SR vesicles and contraction in intact skeletal muscle fibers. The compounds did not alter tension in intact fibers, indicating that (as expected) they are not membrane permeable, but importantly, that they are not toxic to the intact cells. Proof in principal that the compounds would be effective in intact muscle fibers if rendered membrane permeable was obtained with a structurally related membrane-permeable scorpion toxin (imperatoxin A), which was found to enhance contraction.

Therapeutic implications of novel peptides targeting ER–mitochondria Ca2+-flux systems

“…Lipoamino acid conjugation of peptide A increased the cell permeability while maintaining structural and functional properties of the peptide. In addition, recent peptidomimetic approaches have led to the production of several compounds mimicking peptide A activity [61]. As such, these compounds could in the future hold therapeutic value in muscle diseases caused by impaired RyR1 activity.…”

A Synthetic Galectin Mimic

“…As is shown in Scheme 1, the synthesis of 5 was realized by reaction of pentafluorophenyl(PFP)-activatedi sophthalamide derivative 1 with tetra amine salt 2, [15] followed by ad erivatization of the resulting PFP-ester 3 using 3-aminopyridine 4.A fter the reaction forming 3,m ost of the unreacted starting material 1 could be recovered during column chromatographic purification of 3.T etrapyridyl ligand 5 could also be isolated with conventional silica gel column chromatography.…”