2026-10-13T13:52:23Z https://api.figshare.com/v2/oai

oai:figshare.com:article/33993558 2026-09-25T06:09:32Z category_4 category_8 category_13 category_24 category_931 category_61 category_64 category_132 category_135 portal_63 item_type_3 month_year_09_2026

A Redox-Mediated Negative Feedback Loop Based on Tetrazine-Thiol Exchange Angelina Tyumina (25107969) Ivanna Vasylkiv (25107972) A. Hazal Koyuncu (25107975) Thomas J. Rutjes (25107978) Kevin Neumann (2888342) Albert S. Y. Wong (4105534) Biochemistry Microbiology Genetics Evolutionary Biology Information Systems not elsewhere classified Developmental Biology Cancer Infectious Diseases Computational Biology microfluidic flow setup equilibrium reaction networks equilibrium behavior ubiquitous dynamic covalent reactions negative feedback mechanism negative feedback loop chemical feedback loops redox reactivity within activated upon tetex limited redox activity negative feedback tetex ). redox activity chemical environment activated tetrazines thereby constituting systems chemistry synthetic toolbox significant advances regulatory steps rationally expand output signal molecular level mediated exchange exchange process critical components carboxylic acids Feedback loops are critical components for rationalizing the out-of-equilibrium behavior ubiquitous in life. Despite the significant advances in systems chemistry, strategies to rationally expand the complexity of chemical feedback loops in a defined and modular way remain scarce. Here, we designed a negative feedback loop based on thiol-tetrazine exchange (TeTEx). Negative feedback is broadly defined as a set of regulatory steps that feed the output signal, inverted, back to the input. In our case, the inputs are thiols, which react with tetrazines exhibiting only limited redox activity, and the outputs are redox-activated tetrazines, i.e., TeTEx products. More specifically, we demonstrated that tetrazines could become redox-activated upon TeTEx, after which then become dihydrotetrazines via two distinct reduction pathways. The reduction pathways directly compete with the exchange process, as they deplete the source of thiols, thereby constituting a negative feedback mechanism at the molecular level. A microfluidic flow setup was developed to show that the chemical environment of the thiol-containing substratesparticularly when additional thiols or carboxylic acids are present as neighboring groupscould enhance the redox activity of tetrazines. The method to create a negative feedback loop, integrating thiol-mediated exchange and redox reactivity within the same system, will be applicable to many other dynamic covalent reactions, paving the way to advance our synthetic toolbox for creating out-of-equilibrium reaction networks with ever-increasing complexity. 2026-09-25T00:00:00Z Dataset Dataset 10.1021/jacs.6c12662.s002 https://figshare.com/articles/dataset/A_Redox-Mediated_Negative_Feedback_Loop_Based_on_Tetrazine-Thiol_Exchange/33993558 CC BY-NC 4.0