Turn-Mimic Hydantoin-Based Loops Constructed by a Sequential Multicomponent Reaction.

A collection of peptidomimetics characterized by having an aspartic acid motif embedded in a rigid hydantoin heterocycle are synthesized through a sequential multicomponent domino process followed by standard regioselective deprotection/coupling reactions based on acid-base liquid/liquid purification protocols. 1H nuclear magnetic resonance experiments, molecular modeling, and X-ray analysis showed that the resulting hydantoin-based loops I (in particular) and II (to a lesser extent) can be considered novel ß-turn inducer motifs being able to project two peptide-like strands in a U-shaped conformation driven by the formation of intermolecular hydrogen bonds.

Novel Therapeutic Horizons: SNCA Targeting in Parkinson's Disease.

Alpha-synuclein (αSyn) aggregates are the primary component of Lewy bodies, which are pathological hallmarks of Parkinson's disease (PD). The toxicity of αSyn seems to increase with its elevated expression during injury, suggesting that therapeutic approaches focused on reducing αSyn burden in neurons could be beneficial. Additionally, studies have shown higher levels of SNCA mRNA in the midbrain tissues and substantia nigra dopaminergic neurons of sporadic PD post-mortem brains compared to controls. Therefore, the regulation of SNCA expression and inhibition of αSyn synthesis could play an important role in the pathogenesis of injury, resulting in an effective treatment approach for PD. In this context, we summarized the most recent and innovative strategies proposed that exploit the targeting of SNCA to regulate translation and efficiently knock down cytoplasmatic levels of αSyn. Significant progress has been made in developing antisense technologies for treating PD in recent years, with a focus on antisense oligonucleotides and short-interfering RNAs, which achieve high specificity towards the desired target. To provide a more exhaustive picture of this research field, we also reported less common but highly innovative strategies, including small molecules, designed to specifically bind 5'-untranslated regions and, targeting secondary nucleic acid structures present in the SNCA gene, whose formation can be modulated, acting as a transcription and translation control. To fully describe the efficiency of the reported strategies, the effect of αSyn reduction on cellular viability and dopamine homeostasis was also considered.