Badeau, B. A. | bioRxiv Science

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↗

bioRxiv2023

Versatile Tissue-Injectable Hydrogels with Extended Hydrolytic Release of Bioactive Protein Therapeutics

Hydrogels generally have broad utilization in healthcare due to their tunable structures, high water content, and inherent biocompatibility. FDA-approved applications of hydrogels include spinal cord regeneration, skin fillers, and local therapeutic delivery. Drawbacks exist in the clinical hydrogel space, largely pertaining to inconsistent therapeutic exposure, short-lived release windows, and difficulties inserting the polymer into tissue. In this study, we engineered injectable, biocompatible hydrogels that function as a local protein therapeutic depot with a high degree of user-customizability. We showcase a PEG-based hydrogel functionalized with bioorthogonal strain-promoted azide-alkyne cycloaddition (SPAAC) handles for its polymerization and functionalization with a variety of payloads. Small-molecule and protein cargos, including chemokines and antibodies, were site-specifically modified with hydrolysable "azidoesters" of varying hydrophobicity via direct chemical conjugation or sortase-mediated transpeptidation. These hydrolysable esters afforded extended release of payloads linked to our hydrogels beyond diffusion; with timescales spanning days to months dependent on ester hydrophobicity. Injected hydrogels polymerize in situ and remain in tissue over extended periods of time. Hydrogel-delivered protein payloads elicit biological activity after being modified with SPAAC-compatible linkers, as demonstrated by the successful recruitment of murine T-cells to a mouse melanoma model by hydrolytically released murine CXCL10. These results highlight a highly versatile, customizable hydrogel-based delivery system for local delivery of protein therapeutics with payload release profiles appropriate for a variety of clinical needs. Translational ImpactWe developed injectable hydrogels that provide loco-regional, controlled release of protein therapeutics. Local delivery is especially suitable for potent, protein-based drugs like chemokines and monoclonal antibodies whose systemic toxicities can be life threatening. Our hydrogel is equipped with slowly hydrolyzing linkers for transient payload coupling, prolonging its therapeutic window and minimizing the need for repeat surgeries in a clinical setting. A range of release profiles, spanning days to over a month, and a broad compatibility to therapeutically relevant, recombinant proteins provide clinicians with flexible therapeutic options to suit a variety of circumstances.

bioengineering↗