Journals
2025 EN
Louka Anastasia · Spacho Ntaniela · Korovesis Dimitris
+6 more
Abstract Small molecule modulators are powerful tools for selectively probing and manipulating proteins in native biological systems. However, the development of versatile modulators that exhibit desired properties is hindered by the lack of a rapid and robust synthetic strategy. Here, we develop a facile and reliable one‐step methodology for the generation of multifunctional toolboxes encompassing a wide variety of chemical modulators with different desired features. These modulators bind irreversibly to the protein target via a selective warhead. Key elements are introduced onto the warhead in a single step using multi‐component reactions. To illustrate the power of this new technology, we synthesized a library of diverse modulators designed to explore a highly challenging and poorly understood protein, human 15‐lipoxygenase‐1. Modulators made include; activity‐based/photoaffinity probes, chemosensors, photocrosslinkers, as well as light‐controlled and high‐affinity inhibitors. The efficacy of our compounds was successfully established through the provision of on demand inhibition and labeling of our target protein in vitro , in cellulo and in vivo ; thus, proving that this technology has promising potential for applications in many complex biological systems.
Journals
2025 EN
Regnier Morgan · Vega Clara · Ioannou Dimitris I.
+2 more
Abstract Cyclopropanes are valuable motifs in organic synthesis, widely featured in pharmaceuticals and functional materials. Herein, we report an efficient electrochemical methodology for the cyclopropanation of alkenes, leveraging a nickel‐catalyzed process in continuous‐flow. The developed protocol demonstrates broad substrate scope, accommodating both electron‐rich and electron‐poor alkenes with high functional group tolerance. Beyond dichloromethane as a feedstock methylene source, the methodology enables the synthesis of methylated, deuterated, and chloro‐substituted cyclopropanes. Mechanistic investigations suggest the electro‐generation of a nickel carbene as key intermediate. Notably, the reaction operates under ambient conditions, tolerates air and moisture, and achieves scalability through continuous‐flow technology, offering a straightforward route to multi‐gram quantities with enhanced throughput.
Journals
2025 EN
Wang Andrew L. · Bhattacharya Aparajita · Lee Frances
+11 more
Abstract Protein‐based nanocarriers bear highly desirable properties such as biodegradability and the ability to facilitate passage through biological barriers such as the blood–brain‐barrier. Using modular protein engineering, we develop a strategy for iteratively improving the delivery efficacy of hydrophobic small molecules for the treatment of glioblastoma multiforme (GBM). By increasing the multiplicity m of the coiled‐coil and RGD peptide targeting regions from 1 to 2, we can increase both the hydrodynamic micellar size and drug loading capacity of the targeted multidomain protein assembly (TMPA) relative to its predecessor thermoresponsive assembled protein (TRAP). An upper limit of m is likely determined by steric interactions. TMPA shows a 1.7‐fold increase in doxorubicin (Dox) encapsulation compared to TRAP and demonstrates a 1.3‐fold improvement in uptake by U87 human GBM cells. Near‐infrared (NIR) dye‐labelled TMPA (NIR‐TMPA) is intravenously administered to mice orthotopically implanted with GBM cells and to control mice. Pharmacokinetic analysis using a 2‐compartment pharmacokinetic model reveals a significantly prolonged distribution‐phase (short‐phase) half‐life in tumor‐bearing mice compared to control, while the elimination‐phase (slow‐phase) half‐life remains comparable between groups. This suggests altered early‐phase kinetics likely due to tumor‐associated sequestration or retention. The resulting increased area under the concentration‐time curve (AUC) in tumor‐bearing mice supports enhanced accumulation or slower clearance. Ex vivo fluorescence imaging of organs and 3D reconstructions of whole mouse heads further corroboratesa preferential localization of NIR‐TMPA in tumor regions. These findings highlight the potential of TMPA and its future derivatives for targeted GBM therapy.
Journals
2025 EN
Psarrou Maria · Chatzaki Ioanna · Mavromanolakis Antonis
+3 more
Abstract Stimuli–reversible, chemically cross‐linked polymers capable of altering their physicochemical and mechanical properties on demand, upon application of external stimuli (e.g., light, temperature), are highly desirable for the development of multifunctional materials. Herein, we report a facile chemical platform for the synthesis of photodegradable and thermo‐reversible, model hydrogels consisting of poly(ethylene glycol) (PEG) as the elastic strands and dithioacetal moieties at the cross‐link points. The gels were synthesized via an acid‐catalyzed step‐growth reaction of a difunctional PEG‐thiol macromer with a wisely selected aromatic dialdehyde cross‐linker. The formation of the photosensitive dithioacetal bonds at the cross−links rendered the hydrogels photodegradable, whereas the production of the initial comonomers as the main photoproducts after irradiation endowed the material with thermoreversible properties. The linear viscoelastic behavior of water‐swollen gels, their photodegradation under UV ( λ = 254 nm) irradiation at very low intensity (0.063 mW cm −1 ), and the reversible reformation of the hydrogel upon heating were investigated by dynamic shear rheology. Mechanistic insights for the photodegradation mechanism of the system were gained by 1 H NMR spectroscopy and kinetic studies on a model dithioacetal compound.
Journals
2025 EN
Louka Anastasia · Spacho Ntaniela · Korovesis Dimitris
+6 more
Abstract Small molecule modulators are powerful tools for selectively probing and manipulating proteins in native biological systems. However, the development of versatile modulators that exhibit desired properties is hindered by the lack of a rapid and robust synthetic strategy. Here, we develop a facile and reliable one‐step methodology for the generation of multifunctional toolboxes encompassing a wide variety of chemical modulators with different desired features. These modulators bind irreversibly to the protein target via a selective warhead. Key elements are introduced onto the warhead in a single step using multi‐component reactions. To illustrate the power of this new technology, we synthesized a library of diverse modulators designed to explore a highly challenging and poorly understood protein, human 15‐lipoxygenase‐1. Modulators made include; activity‐based/photoaffinity probes, chemosensors, photocrosslinkers, as well as light‐controlled and high‐affinity inhibitors. The efficacy of our compounds was successfully established through the provision of on demand inhibition and labeling of our target protein in vitro , in cellulo and in vivo ; thus, proving that this technology has promising potential for applications in many complex biological systems.
Journals
2025 EN
Regnier Morgan · Vega Clara · Ioannou Dimitris I.
+2 more
Abstract Cyclopropanes are valuable motifs in organic synthesis, widely featured in pharmaceuticals and functional materials. Herein, we report an efficient electrochemical methodology for the cyclopropanation of alkenes, leveraging a nickel‐catalyzed process in continuous‐flow. The developed protocol demonstrates broad substrate scope, accommodating both electron‐rich and electron‐poor alkenes with high functional group tolerance. Beyond dichloromethane as a feedstock methylene source, the methodology enables the synthesis of methylated, deuterated, and chloro‐substituted cyclopropanes. Mechanistic investigations suggest the electro‐generation of a nickel carbene as key intermediate. Notably, the reaction operates under ambient conditions, tolerates air and moisture, and achieves scalability through continuous‐flow technology, offering a straightforward route to multi‐gram quantities with enhanced throughput.
Journals
2025 EN
Wang Andrew L. · Bhattacharya Aparajita · Lee Frances
+11 more
Abstract Protein‐based nanocarriers bear highly desirable properties such as biodegradability and the ability to facilitate passage through biological barriers such as the blood–brain‐barrier. Using modular protein engineering, we develop a strategy for iteratively improving the delivery efficacy of hydrophobic small molecules for the treatment of glioblastoma multiforme (GBM). By increasing the multiplicity m of the coiled‐coil and RGD peptide targeting regions from 1 to 2, we can increase both the hydrodynamic micellar size and drug loading capacity of the targeted multidomain protein assembly (TMPA) relative to its predecessor thermoresponsive assembled protein (TRAP). An upper limit of m is likely determined by steric interactions. TMPA shows a 1.7‐fold increase in doxorubicin (Dox) encapsulation compared to TRAP and demonstrates a 1.3‐fold improvement in uptake by U87 human GBM cells. Near‐infrared (NIR) dye‐labelled TMPA (NIR‐TMPA) is intravenously administered to mice orthotopically implanted with GBM cells and to control mice. Pharmacokinetic analysis using a 2‐compartment pharmacokinetic model reveals a significantly prolonged distribution‐phase (short‐phase) half‐life in tumor‐bearing mice compared to control, while the elimination‐phase (slow‐phase) half‐life remains comparable between groups. This suggests altered early‐phase kinetics likely due to tumor‐associated sequestration or retention. The resulting increased area under the concentration‐time curve (AUC) in tumor‐bearing mice supports enhanced accumulation or slower clearance. Ex vivo fluorescence imaging of organs and 3D reconstructions of whole mouse heads further corroboratesa preferential localization of NIR‐TMPA in tumor regions. These findings highlight the potential of TMPA and its future derivatives for targeted GBM therapy.
Journals
2025 EN
Psarrou Maria · Chatzaki Ioanna · Mavromanolakis Antonis
+3 more
Abstract Stimuli–reversible, chemically cross‐linked polymers capable of altering their physicochemical and mechanical properties on demand, upon application of external stimuli (e.g., light, temperature), are highly desirable for the development of multifunctional materials. Herein, we report a facile chemical platform for the synthesis of photodegradable and thermo‐reversible, model hydrogels consisting of poly(ethylene glycol) (PEG) as the elastic strands and dithioacetal moieties at the cross‐link points. The gels were synthesized via an acid‐catalyzed step‐growth reaction of a difunctional PEG‐thiol macromer with a wisely selected aromatic dialdehyde cross‐linker. The formation of the photosensitive dithioacetal bonds at the cross−links rendered the hydrogels photodegradable, whereas the production of the initial comonomers as the main photoproducts after irradiation endowed the material with thermoreversible properties. The linear viscoelastic behavior of water‐swollen gels, their photodegradation under UV ( λ = 254 nm) irradiation at very low intensity (0.063 mW cm −1 ), and the reversible reformation of the hydrogel upon heating were investigated by dynamic shear rheology. Mechanistic insights for the photodegradation mechanism of the system were gained by 1 H NMR spectroscopy and kinetic studies on a model dithioacetal compound.
Journals
2025 EN
Santos Dulce · Christopoulou VasilikiMaria · Taning Clauvis Nji Tizi
+6 more
ABSTRACT The discovery that infections of viruses are pervasive among insects has considerable potential for future applications, such as new strategies for pest control through the manipulation of virus‐host interactions. However, few studies can be found that aim to minimize (for beneficial insects) or maximize (for pests) virus impact or virulence. Viruses generally employ molecular mechanisms that deviate from the cells’ to increase their replication efficiency and to avoid the immune response. In this research, a screening system is presented for the detection of molecules that interfere with the internal ribosomal entry site (IRES) of Cricket paralysis virus ( Dicistroviridae ) which has been well characterized in previous research. Over‐expression and RNAi experiments identified the importance of eIF4A, a component of the cap‐dependent translation initiation complex, to modify the activity of IRES‐mediated translation. Application of Rocaglamide A (RocA), a natural product from Aglaia plants and inhibitor of eIF4A, resulted in strong stimulation of IRES‐mediated translation in reporter assays as well as increased CrPV genome replication and virion production in lepidopteran Hi5 cells. At 100 nM of RocA, dsRNA molecules accumulated in infected cells, corresponding to full‐length genome (9.5 kb) and a smaller fragment (0.8 kb) with unknown function. Treatment of silkworm larvae with RocA by injection or topically was highly toxic while no strong stimulation of CrPV infection could be observed. The prospect of the use of rocaglamates as insecticides and enhancers of CrPV infection is discussed together with its potential impact on mammalian cells.
Journals
2025 EN
Park Jungweon V. · Pitchumani Priyanka K. · Tatakis Dimitris N.
Abstract Background Betel leaf chewing habit has been studied extensively, as it has been an ancient practice in many Asian countries. Although betel leaf has been reported to have potential beneficial properties, it has also been shown to have a strong association with oral diseases, including periodontitis. This case series addresses the presentation of periodontitis among betel quid users, to help clinicians identify and manage such patients when they are encountered in settings outside the countries and territories where betel quid use is common. Methods Four patients of Asian ethnicity were referred to The Ohio State University College of Dentistry Graduate Periodontology clinic for periodontal treatment. Targeted questioning resulted in all four patients reporting a past and current betel leaf chewing habit, established at a young age, typically in a family setting, and long before their immigration from their native country. Results All four patients exhibited similar reddish‐brown staining on the teeth and generalized radiographic bone loss. Notably, the patients disclosed the betel chewing habit only after different vernacular names for betel quid were used during questioning, which complicated history taking. Severe periodontitis (stage III/IV, grade C) was diagnosed in all four patients, who were given appropriate periodontal treatment plans. Conclusion Betel leaf chewing, prevalent in many Asian countries, is associated with periodontitis and may present with extensive tooth staining. Oral healthcare providers should consider this cultural habit and pursue thorough assessment and history taking for their patients originating from countries where the habit is common practice. Key pointsClinicians should be aware of the clinical presentation and oral findings in betel quid users. Given the increasing diversity of the patient pool that clinicians are encountering, knowledge of vernacular names for betel quid usage can prove valuable in history taking. A protocol for betel quid cessation should be incorporated into the management strategy for these patients in clinical practice.Plain Language Summary Betel quid (paan) chewing is a widespread cultural habit, especially in Asia. The chewing of betel quid, whether alone or with tobacco, has been strongly associated with periodontitis and other oral conditions, such as leukoplakia, oral cancer, and oral submucous fibrosis. This report illustrates the typical presentation of periodontitis patients who habitually chew betel quid, highlights the associated clinical features, such as reddish‐brown tooth staining and severe bone loss, and underlines the challenge of obtaining a complete history because of the very many vernacular names used for betel quid in different countries and the fact that for many of the patients, this is considered a routine cultural tradition. It is unusual to encounter patients chewing betel quid in this country because the practice is not common. However, immigrants from countries where betel quid chewing is commonplace may continue the habit after they move to the United States. Oral healthcare providers should be aware of this possibility and elicit the relevant information from the patients. This will help practitioners to properly address this underlying factor and to provide appropriate care to these patients, including cessation advice and support, and establishment of routine oral screenings and regular periodontal maintenance.