Identification of c[D-Trp-Phe-β-Ala-β-Ala], the First κ-Opioid Receptor-Specific Negative Allosteric Modulator.

Recently, the fungus secondary metabolite cyclotetrapetide c[Trp-Phe-D-Pro-Phe] (CJ-15,208) and its derivatives deserved some attention for their unusual structure and distinctive in vitro and in vivo activity. These tryptophan-containing noncationic opioid peptides can be truly regarded as versatile picklocks capable of activating all opioid receptors. Intriguingly, minimal modification of the potent κ-opioid receptor (KOR) agonist c[D-Trp-Phe-Gly-β-Ala] () yielded c[D-Trp-Phe-β-Ala-β-Ala] (), the first KOR-specific negative allosteric modulator (NAM) reported to-date.

Mutant SPART causes defects in mitochondrial protein import and bioenergetics reversed by Coenzyme Q.

Pathogenic variants in cause Troyer syndrome, characterized by lower extremity spasticity and weakness, short stature and cognitive impairment, and a severe mitochondrial impairment. Herein, we report the identification of a role of Spartin in nuclear-encoded mitochondrial proteins. biallelic missense variants were detected in a 5-year-old boy with short stature, developmental delay and muscle weakness with impaired walking distance.

Quantitative Systems Pharmacology and Biased Agonism at Opioid Receptors: A Potential Avenue for Improved Analgesics.

Chronic pain is debilitating and represents a significant burden in terms of personal and socio-economic costs. Although opioid analgesics are widely used in chronic pain treatment, many patients report inadequate pain relief or relevant adverse effects, highlighting the need to develop analgesics with improved efficacy/safety. Multiple evidence suggests that G protein-dependent signaling triggers opioid-induced antinociception, whereas arrestin-mediated pathways are credited with modulating different opioid adverse effects, thus spurring extensive research for G protein-biased opioid agonists as analgesic candidates with improved pharmacology.