Accumulation
of cytotoxic lipofuscin bisretinoids may contribute to atrophic age-related macular
degeneration (AMD) pathogenesis. Retinal bisretinoid synthesis depends
on the influx of serum all-trans-retinol (1) delivered via a tertiary retinol binding protein 4 (RBP4)–transthyretin
(TTR)–retinol complex. We previously identified selective RBP4
antagonists that dissociate circulating RBP4–TTR–retinol
complexes, reduce serum RBP4 levels, and inhibit bisretinoid synthesis
in models of enhanced retinal lipofuscinogenesis. However, the release
of TTR by selective RBP4 antagonists may be associated with TTR tetramer
destabilization and, potentially, TTR amyloid formation. We describe
herein the identification of bispecific RBP4 antagonist–TTR
tetramer kinetic stabilizers. Standout analogue (±)-44 possesses suitable potency for both targets, significantly lowers
mouse plasma RBP4 levels, and prevents TTR aggregation in a gel-based
assay. This new class of bispecific compounds may be especially important
as a therapy for dry AMD patients who have another common age-related
comorbidity, senile systemic amyloidosis, a nongenetic disease associated
with wild-type TTR misfolding.
Francisella tularensis is a Gram-negative bacterium responsible for causing tularemia in the northern hemisphere. F. tularensis has long been developed as a biological weapon due to its ability to cause severe illness upon inhalation of as few as ten organisms and, based on its potential to be used as a bioterror agent is now classified as a Tier 1 Category A select agent by the CDC. The stringent response facilitates bacterial survival under nutritionally challenging starvation conditions. The hallmark of stringent response is the accumulation of the effector molecules ppGpp and (p)ppGpp known as stress alarmones. The relA and spoT gene products generate alarmones in several Gram-negative bacterial pathogens. RelA is a ribosome-associated ppGpp synthetase that gets activated under amino acid starvation conditions whereas, SpoT is a bifunctional enzyme with both ppGpp synthetase and ppGpp hydrolase activities. Francisella encodes a monofunctional RelA and a bifunctional SpoT enzyme. Previous studies have demonstrated that stringent response under nutritional stresses increases expression of virulence-associated genes encoded on Francisella Pathogenicity Island. This study investigated how stringent response governs the oxidative stress response of F. tularensis. We demonstrate that RelA/SpoT-mediated ppGpp production alters global gene transcriptional profile of F. tularensis in the presence of oxidative stress. The lack of stringent response in relA/spoT gene deletion mutants of F. tularensis makes bacteria more susceptible to oxidants, attenuates survival in macrophages, and virulence in mice. This work is an important step forward towards understanding the complex regulatory network underlying the oxidative stress response of F. tularensis.
The retinoid visual cycle is an ocular retinoid metabolism specifically dedicated to support vertebrate vision. The visual cycle serves not only to generate light-sensitive visual chromophore 11-cis-retinal, but also to clear toxic byproducts of normal visual cycle (i.e. all-trans-retinal and its condensation products) from the retina, ensuring both the visual function and the retinal health. Unfortunately, various conditions including genetic predisposition, environment and aging may attribute to a functional decline of the all-trans-retinal clearance. To combat all-trans-retinal mediated retinal degeneration, we sought to slow down the retinoid influx from the RPE by inhibiting the visual cycle with a small molecule. The present study describes identification of CU239, a novel non-retinoid inhibitor of RPE65, a key enzyme in the visual cycle. Our data demonstrated that CU239 selectively inhibited isomerase activity of RPE65, with IC of 6 μM. Further, our results indicated that CU239 inhibited RPE65 via competition with its substrate all-trans-retinyl ester. Mice with systemic injection of CU239 exhibited delayed chromophore regeneration after light bleach, and conferred a partial protection of the retina against injury from high intensity light. Taken together, CU239 is a potent visual cycle modulator and may have a therapeutic potential for retinal degeneration.
Glycine
neurotransmission in the dorsal horn of the spinal cord
plays a key role in regulating nociceptive signaling, but in chronic
pain states reduced glycine neurotransmission is associated with the
development of allodynia and hypersensitivity to painful stimuli.
This suggests that restoration of glycine neurotransmission may be
therapeutic for the treatment of chronic pain. Glycine transporter
2 inhibitors have been demonstrated to enhance glycine neurotransmission
and provide relief from allodynia in rodent models of chronic pain.
In recent years, photoswitchable compounds have been developed to
provide the possibility of controlling the activity of target proteins
using light. In this study we have developed a photoswitchable noncompetitive
inhibitor of glycine transporter 2 that has different affinities for
the transporter at 365 nm compared to 470 nm light.
Dissociation of transthyretin (TTR) tetramers may lead to misfolding and aggregation of pro-amyloidogenic monomers, which underlies TTR amyloidosis (ATTR) pathophysiology. ATTR is a progressive disease resulting from the deposition of toxic fibrils in tissues that predominantly presents clinically as amyloid cardiomyopathy and peripheral polyneuropathy. Ligands that bind to and kinetically stabilize TTR tetramers prohibit their dissociation and may prevent ATTR onset. Drawing from clinically investigated AG10, we designed a constrained congener (18a) that exhibits excellent TTR tetramer binding potency, prevents TTR aggregation in a gel-based assay, and possesses desirable pharmacokinetics in mice. Additionally, 18a significantly lowers murine serum retinol-binding protein 4 (RBP4) levels despite a lack of binding at that protein's all-trans-retinol site. We hypothesize that kinetic stabilization of TTR tetramers via 18a is allosterically hindering all-trans-retinol-dependent RBP4-TTR tertiary complex formation and that the compound could present ancillary therapeutic utility for indications treated with RBP4 antagonists, such as macular degeneration.
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.