The absence of effective therapeutics against Alzheimer's disease (AD) is a result of the limited understanding of its multifaceted aetiology. Because of the lack of chemical tools to identify pathological factors, investigations into AD pathogenesis have also been insubstantial. Here we report chemical regulators that demonstrate distinct specificity towards targets linked to AD pathology, including metals, amyloid-β (Aβ), metal–Aβ, reactive oxygen species, and free organic radicals. We obtained these chemical regulators through a rational structure-mechanism-based design strategy. We performed structural variations of small molecules for fine-tuning their electronic properties, such as ionization potentials and mechanistic pathways for reactivity towards different targets. We established in vitro and/or in vivo efficacies of the regulators for modulating their targets' reactivities, ameliorating toxicity, reducing amyloid pathology, and improving cognitive deficits. Our chemical tools show promise for deciphering AD pathogenesis and discovering effective drugs.
Cyclic dinucleotides are second messengers in the cyclic
GMP–AMP
synthase (cGAS)–stimulator of interferon genes (STING) pathway,
which plays an important role in recognizing tumor cells and viral
or bacterial infections. They bind to the STING adaptor protein and
trigger expression of cytokines via TANK binding kinase 1 (TBK1)/interferon
regulatory factor 3 (IRF3) and inhibitor of nuclear factor-κB
(IκB) kinase (IKK)/nuclear factor-κB (NFκB) signaling
cascades. In this work, we describe an enzymatic preparation of 2′–5′,3′–5′-cyclic
dinucleotides (2′3′CDNs) with use of cyclic GMP–AMP
synthases (cGAS) from human, mouse, and chicken. We profile substrate
specificity of these enzymes by employing a small library of nucleotide-5′-triphosphate
(NTP) analogues and use them to prepare 33 2′3′CDNs.
We also determine affinity of these CDNs to five different STING haplotypes
in cell-based and biochemical assays and describe properties needed
for their optimal activity toward all STING haplotypes. Next, we study
their effect on cytokine and chemokine induction by human peripheral
blood mononuclear cells (PBMCs) and evaluate their cytotoxic effect
on monocytes. Additionally, we report X-ray crystal structures of
two new CDNs bound to STING protein and discuss structure–activity
relationship by using quantum and molecular mechanical (QM/MM) computational
modeling.
STING protein (stimulator of interferon genes) plays an important role in the innate immune system. A number of potent compounds regulating its activity have been reported, mostly derivatives of cyclic dinucleotides (CDNs), natural STING agonists. Here, we aim to provide complementary information to large-scale "ligand-profiling" studies by probing the importance of STING− CDN protein−ligand interactions on the protein side. We examined in detail six typical CDNs each in complex with 13 rationally devised mutations in STING: S162A,
The strong electronegativity of O dictates that the ground state of singlet CO has positively charged C and negatively charged O, in agreement with ab initio charge analysis, but in disagreement with the dipole direction. Though this unusual phenomenon has been fairly studied, the study of electrostatic potential (EP) for noncovalent interactions of CO is essential for better understanding. Here we illustrate that both C and O atom-ends show negative EP (where the C end gives more negative EP), favoring positively charged species, whereas the cylindrical surface of the CO bond shows positive EP, favoring negatively charged ones. This is demonstrated from the interactions of CO with Na+, Cl–, H2O, CO and benzene. It can be explained by the quadrupole driven electrostatic nature of CO (like N2) with very weak dipole moment. The EP is properly described by the tripole model taking into account the electrostatic multipole moments, which has a large negative charge at a certain distance protruded from C, a large positive charge on C, and a small negative charge on O. We also discuss the EP of the first excited triplet CO.
STING (stimulator of interferon genes) is ak ey regulator of innate immunity that has recently been recognized as ap romising drug target. STING is activated by cyclic dinucleotides (CDNs) whiche ventually leads to expression of type Ii nterferons and other cytokines.F actors underlying the affinity of various CDN analogues are poorly understood. Herein, we correlate structural biology,isothermal calorimetry (ITC) and computational modeling to elucidate factors contributing to binding of six CDNs-three pairs of natural (ribo) and fluorinated (2'-fluororibo) 3',3'-CDNs.X -ray structural analyses of six {STING:CDN} complexes did not offer any explanation for the different affinities of the studied ligands. ITC showed entropy/enthalpyc ompensation up to 25 kcal mol À1 for this set of similar ligands.T he higher affinities of fluorinated analogues are explained with help of computational methods by smaller loss of entropyupon binding and by smaller strain (free) energy.
Bromophenols are known as antioxidant radical scavengers for some biomolecules such as those in marine red alga. Full understanding of the role played by bromophenols requires detailed knowledge of the radical scavenging activities in probable pathways, a focus of ongoing research. To gain detailed insight into two suggested pathways, H-atom transfer and electron transfer, theoretical studies employing first principle quantum mechanical calculations have been carried out on selected bromophenols. Detailed investigation of the aforementioned routes revealed that upon H-atom abstraction or the electron transfer process, bromophenols cause an increase in radical species in which the unpaired electron appears to be delocalized as much as possible over the whole aromatic ring, especially in the bromine substituent. The O-H bond dissociation energies (BDEs) and ionization potential energies (IPs) are reported at the B3LYP level of theory, providing the first complete series of BDEs and IPs for bromophenols. The observations are compared to those of other antioxidants for which BDEs and IPs have been previously obtained.
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