Biology subjects

Rajewski, B. H.

Publications and source records attributed to Rajewski, B. H..

3 recordsLinked to original sources

bioRxiv2025

Dual Activation of MC3R and MC4R Drives Weight Loss and Reduces Food Intake in Obese Primates

Introductory ParagraphThe melanocortin system plays a central role in regulating hunger and satiety, making it an attractive target for treating metabolic disease. However, the limited clinical success of selective melanocortin-4 receptor (MC4R) agonists prompted the investigation of whether concurrent melanocortin-3 receptor (MC3R) and MC4R activation is key to unlocking the melanocortin system for the treatment of general obesity. To test this hypothesis, we designed and synthesized novel peptides to probe the distinct and combined roles of MC3R and MC4R in nonhuman primates (NHPs). We show that selectively agonizing MC3R modulates food intake in a state-dependent manner. Moreover, co-agonism of MC3R and MC4R results in more substantial metabolic effects than selective MC4R agonism, highlighting both a non-redundant and a cooperative role of MC3R. To leverage these discoveries, we developed 710GO, an orally-available MC3R/MC4R dual agonist peptide that induces significant weight loss in diet-induced obese (DIO) NHPs. Oral 710GO treatment demonstrates limited weight rebound, has additive effects in combination with GLP-1s, and exhibits a clean safety profile. These results reestablish the melanocortin system, specifically concerted MC3R/MC4R agonism, as a viable mechanism for next-generation obesity therapeutics.

neuroscience↗

bioRxiv2024

N-Amino Peptide-Graphene Quantum Dot Loaded Small Extracellular Vesicles for Targeted Therapy of Tauopathies

Tauopathies, a group of neurodegenerative disorders, are characterized by the abnormal aggregation of tau proteins into neurofibrillary tangles (NFTs), driving synaptic dysfunction, neuronal loss, and disease progression through tau aggregate propagation. Graphene quantum dots (GQDs) functionalized with D- cysteine (D-GQDs) have shown promise in inhibiting tau aggregation and transmission via {pi}-{pi} stacking and electrostatic interactions with tau proteins. However, the non-specific binding of GQDs to various proteins in the physiological environment, such as serum albumin, limits their clinical translation. In this study, we aim to enhance the specificity of D-GQDs toward tau protein by incorporating a tau-targeting N- amino peptide, mxyl-NAP2. The mxyl-NAP2/D-GQD complex demonstrated improved selectivity for tau protein over serum albumin, effectively enhancing the inhibition of tau aggregation. To further minimize off-target effects and optimize therapeutic delivery, we loaded the mxyl-NAP2/D-GQD complex into small extracellular vesicles (sEVs), followed by functionalization of sEVs with neuron targeting ligand, rabies viral glycoprotein peptides. This strategy not only reduced off-target effects, but also enhanced uptake by neuron cells, which further improved inhibition of tau transmission between neurons. Our results indicated that mxyl-NAP2/D-GQD-loaded sEVs hold great promise for overcoming the off-target limitations of D- GQDs and advancing the development of precision therapeutics for neurodegenerative diseases.

bioengineering↗

bioRxiv2022

Inhibition and Disassembly of Tau Aggregates by Engineered Graphene Quantum Dots

Tauopathies are a class of neurodegenerative diseases resulting in cognitive dysfunction, executive dysfunction, and motor disturbance. The primary pathological feature of tauopathies is the presence of neurofibrillary tangles in the brain composed of tau protein aggregates. Although numerous small molecules are known to inhibit tau aggregation, it is still challenging to use them for therapeutic applications due to their limitations in specific targeting and the blood-brain barrier (BBB) penetration. Graphene quantum dots (GQDs), one of graphene nanoparticles, can penetrate the BBB and are amenable to functionalization for targeted delivery. Moreover, these nanoscale biomimetic particles can self-assemble or assemble with various biomolecules including proteins. In this paper, for the first time, we showed that GQDs interacted with tau proteins via electrostatic and {pi}-{pi} stacking interactions to inhibit the fibrillization of monomeric tau and to trigger the disaggregation of tau filaments. In vitro thioflavin T assays demonstrated that negatively charged GQDs with larger sizes inhibited tau aggregation more efficiently, while positively charged ones were more effective in the disassembly of tau fibrils. Moreover, GQDs blocked the seeding activity of tau fibrils in a cellular propagation assay. Overall, our studies indicate GQDs with engineered properties can efficiently inhibit and disassemble pathological aggregation of tau proteins, which supports their future developments as a potential treatment for tauopathies.

bioengineering↗