In the last decade, innovative therapeutic strategies against inherited retinal degenerations (IRDs) have emerged. In particular, chemical- and opto-genetics approaches or a combination of them have been identified for modulating neuronal/optical activity in order to restore vision in blinding diseases. The 'chemical-genetics approach' (optopharmacology) uses small molecules (exogenous photoswitches) for restoring light sensitivity by activating ion channels. The 'opto-genetics approach' employs light-activated photosensitive proteins (exogenous opsins), introduced by viral vectors in injured tissues, to restore light response. These approaches offer control of neuronal activities with spatial precision and limited invasiveness, although with some drawbacks. Currently, a combined therapeutic strategy (optogenetic pharmacology) is emerging. This review describes the state of the art and provides an overview of the future perspectives in vision restoration.
Summary Aims We recently described multifunctional tools ( 2a – c ) as potent inhibitors of human Cholinesterases (ChEs) also able to modulate events correlated with A β aggregation. We herein propose a thorough biological and computational analysis aiming at understanding their mechanism of action at the molecular level. Methods We determined the inhibitory potency of 2a–c on A β 1–42 self‐aggregation, the interference of 2a with the toxic A β oligomeric species and with the postaggregation states by capillary electrophoresis analysis and transmission electron microscopy. The modulation of A β toxicity was assessed for 2a and 2b on human neuroblastoma cells. The key interactions of 2a with A β and with the A β ‐preformed fibrils were computationally analyzed. 2a – c toxicity profile was also assessed (human hepatocytes and mouse fibroblasts). Results Our prototypical pluripotent analogue 2a interferes with A β oligomerization process thus reducing A β oligomers‐mediated toxicity in human neuroblastoma cells. 2a also disrupts preformed fibrils. Computational studies highlighted the bases governing the diversified activities of 2a . Conclusion Converging analytical, biological, and in silico data explained the mechanism of action of 2a on A β 1–42 oligomers formation and against A β ‐preformed fibrils. This evidence, combined with toxicity data, will orient the future design of safer analogues.
Compelling new support has been provided for histone deacetylase isoform 6 (HDAC6) as a common thread in the generation of the dysregulated proinflammatory and fibrotic phenotype in cystic fibrosis (CF). HDAC6 also plays a crucial role in bacterial clearance or killing as a direct consequence of its effects on CF immune responses. Inhibiting HDAC6 functions thus eventually represents an innovative and effective strategy to tackle multiple aspects of CF-associated lung disease. In this Perspective, we not only showcase the latest evidence linking HDAC(6) activity and expression with CF phenotype but also track the new dawn of HDAC(6) modulators in CF and explore potentialities and future perspectives in the field.
Breakthroughs in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes is a series of editorials which is published on a biannual basis by the Editorial Board of the Medicinal Chemistry section of the journal Molecules [...]
Here we describe the identification and preliminary characterization of a new class of pyrrolo(imidazo)quinoxaline hydrazones as flurescent probes for Aβ1-42 fibrils. All the newly developed compounds were able to bind amyloid fibrils formed in vitro and some of them displayed an increase of their fluorescence upon binding. When tested on brain tissue preparations presenting Aβ deposits, the described hydrazones selectively stained amyloid structures and did not display aspecific binding. The hydrazones did not show antifibrillogenic activity and electron microscopy analysis revealed that they do not interfere with fibrils structure. The described pyrrolo(imidazo)quinoxalines could be useful for studying amyloid structures in vitro. Moreover, their experimentally proven ability to cross the blood–brain barrier in mouse opens the possibility of developing these compounds as potential amyloid imaging agents for in vivo applications.
