Neurodegenerative diseases represent nowadays one of the major health problems. Despite the efforts made to unveil the mechanism leading to neurodegeneration, it is still not entirely clear what triggers this phenomenon and what allows its progression. Nevertheless, it is accepted that neurodegeneration is a consequence of several detrimental processes, such as protein aggregation, oxidative stress, and neuroinflammation, finally resulting in the loss of neuronal functions. Starting from these evidences, there has been a wide search for novel agents able to address more than a single event at the same time, the so-called multitarget-directed ligands (MTDLs). These compounds originated from the combination of different pharmacophoric elements which endowed them with the ability to interfere with different enzymatic and/or receptor systems, or to exert neuroprotective effects by modulating proteins and metal homeostasis. MTDLs have been the focus of the latest strategies to discover a new treatment for Alzheimer’s disease (AD), which is considered the most common form of dementia characterized by neurodegeneration and cognitive dysfunctions. This review is aimed at collecting the latest and most interesting target combinations for the treatment of AD, with a detailed discussion on new agents with favorable in vitro properties and on optimized structures that have already been assessed in vivo in animal models of dementia.
Neurodegenerative diseases such as Alzheimer’s, Huntington’s and Parkinson’s diseases have multifaceted nature because of the different factors contributing to their progression. The complex nature of neurodegenerative diseases has developed a pressing need to design multitarget-directed ligands to address the complementary pathways involved in these diseases. The major enzyme targets for development of therapeutics for Alzheimer’s disease are cholinesterase and β-secretase enzymes. In this review, we discuss recent advances in profiling single target inhibitors based on these enzymes to multitarget-directed ligands as potential therapeutics for this devastating disease. In addition, therapeutics based on iron chelation strategy are discussed as well.
Tetraphenylethylenes in which one or two of the core phenyl rings have been replaced with pyridine or pyridinium groups have been prepared and evaluated as aggregation-induced emission fluorophores.
The synthesis and photophysical properties of luminescent Re(i) tricarbonyl complexes prepared from bis(pyridyl)- and bis(quinolyl) tetraarylethylene (TAE) ligands are reported. Emission wavelengths of the complexes are influenced by structural variation in the tetraarylethylene ligands, and several complexes display aggregation-induced enhanced emission in aqueous solution. A Re(i) complex prepared from an indole-functionalized TAE ligand shows significant enhancement in its luminescence intensity accompanied by a remarkable blue shift (∼95 nm) upon specific binding to site II of human serum albumin.
V-domain
Ig suppressor of T-cell activation (VISTA) is an immune
checkpoint that affects the ability of T-cells to attack tumors. A
FRET-based high throughput screening identified NSC622608 as the first
small-molecule ligand for VISTA. Investigation of the interaction
of NSC622608 with VISTA using STD NMR and molecular modeling enabled
the identification of a potential binding site in VISTA for NSC622608.
Screening NSC622608 against a library of single-point VISTA mutants
revealed the key residues in VISTA interacting with NSC622608. Further
structural optimization resulted in a lead with submicromolar VISTA
binding affinity. The lead compound blocked VISTA signaling in vitro,
enhanced T-cell proliferation, and restored T-cell activation in the
presence of VISTA-expressing cancer cell lines. This work would enable
future development of small molecules targeting VISTA as immunomodulators
and imaging probes.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.