Mike Pluth

Main Group Chemical Biology & Bioinorganic Chemistry
Our research program operates at the interface of bioinorganic chemistry and chemical biology, with a central goal of understanding how small, reactive molecules regulate biological function. We are particularly interested in gasotransmitters and protic small molecule bioregulators (PSMBs) comprised of main group elements, including sulfur, selenium, carbon, and nitrogen. Our program aims to develop new chemical tools and model systems to investigate how these molecules function in complex biological systems. By integrating synthetic chemistry, mechanistic analysis, spectroscopy, and cellular studies, our goal is to define how fundamental chemical properties such as speciation, reactivity, and specific reaction profiles govern biological signaling and function.

Our work directly addresses the challenge that many small molecules in biology remain poorly understood due to the lack of precise tools for cellular modulation. In general, our fundamental understanding of how these small molecules interact with other biomolecules often remains limited due to the lack of suitable model compounds that allow for fundamental chemical reactivity to be investigated. To address these challenges, our research emphasizes chemically defined, tunable platforms that enable rigorous study of how these species function in biologically relevant contexts. By developing new tools and conceptual frameworks for studying reactive small molecules, our research program addresses both fundamental and applied questions with the goal of advancing knowledge related to how these small and reactive biomolecule function in biology.

Research Areas
H₂S and Reactive Sulfur Species (RSS) Delivery
Hydrogen sulfide (H₂S) and related reactive sulfur species (RSS) are central regulators of cellular signaling, redox biology, and metabolism. Direct delivery of H₂S is impractical, and common RSS like persulfides cannot be delivered directly due to their instability. Our research focuses on developing responsive tools for H₂S and RSS delivery that enable precise and tunable spatiotemporal control. As one example, we have developed fundamentally new approaches for H₂S delivery that respond to specific stimuli to release carbonyl sulfide (COS), which is rapidly converted to H₂S by ubiquitous enzymes like carbonic anhydrase. More broadly, our approaches allow us to systematically investigate how responsive H₂S delivery impacts biological outcomes, to probe mechanisms of downstream signaling, and to explore how subcellular targeting can modulate localized sulfur signaling.

H₂Se and Bioselenium Chemistry
Selenium plays essential roles in antioxidant defense, redox regulation, and enzymatic function, yet the chemistry of biologically relevant selenium species remains far less developed than that of sulfur. In particular, hydrogen selenide (H₂Se) is a key but poorly understood intermediate in selenium metabolism and in the installation of selenium in selenoproteins. Our work develops chemical platforms for controlled H₂Se delivery while simultaneously investigating the fundamental reactivity of selenium-containing species. These studies include the development of direct H₂Se donors with tunable kinetics, as well as approaches to probe selenium incorporation and trafficking in cells. By directly comparing sulfur and selenium analogues, we also seek to define how subtle differences in electronic structure translate into distinct biological behavior. Together, this research establishes a chemical foundation for understanding bioselenium chemistry and its unique contributions to redox biological.

Fundamental Chemistry of Persulfides
Persulfides (RSSH and RSS⁻) are increasingly recognized as key intermediates and structural motifs involved in redox biology yet their chemistry and reactivity often remain poorly defined. To address this knowledge gap, we investigate the intrinsic properties, such as enhanced nucleophilicity, unique redox behavior, and dual reactivity as both nucleophiles and electrophiles, that differentiate persulfides from thiols. This work has included preparing isolable small-molecule persulfides that allows us to directly examine structure-reactivity relationships, delineate mechanisms of persulfide formation and decomposition, and quantify how specific factors influence persulfide persistence. As a whole, our work aims to clearly define the chemical underpinnings that establish the role of persulfides in redox regulation, protein modification, and reactive sulfur signaling.

Bioinorganic Chemistry of Metal Persulfides
Metal-sulfur interactions are central to enzymatic catalysis, redox regulation, and metalloprotein structure, yet synthetic examples of late metal persulfides remain significantly underexplored relative to thiols and sulfides. Addressing this limitation, we have developed and applied new approaches to prepare and isolate well-defined persulfide and related dichalcogenide complexes. These systems allow us to investigate the structure, bonding, and reactivity of metal persulfide complexes and to understand how coordination to metals can be used to modulate persulfide chemistry. By establishing these fundamental principles, we aim to both establish and clarify how metals control reactive sulfur speciation in biological environments.

Crosstalk of Protic Small Molecule Bioregulators
A curious property of many small molecule bioregulators is that in addition to reacting with molecular targets, many of these small molecules also participate in a complex web of ‘crosstalk’ reactions with other regulatory molecules. Building from these observations, we are interested in uncovering new chemical mechanisms that provide missing links between small molecule bioregulator reactivity. Within this context, we have observed that protic small molecule bioregulators (PSMBs) often exhibit unique reactivity in which protonation or interaction with Lewis acids can further modulate reactivity. As one example, we recently demonstrate that oxidation products of NO and H₂S can react through proton-mediated reactivity to provide chemical pathways for generating hybrid ‘crosstalk’ species like SNO- and SSNO-. By establishing new investigative frameworks for investigating these interactions, our work seeks to both uncover and clarify how overlapping chemical networks collectively regulate redox biology, metabolism, and signaling manifolds

Expanding the Chemistry of Emerging Small Molecule Bioregulators
Many small, reactive molecules are emerging targets for exerting biological function. We are particularly interested in the action of small molecules like carbonyl sulfide (COS) and hydrogen cyanide (HCN). Focusing on the latter, HCN is widely recognized as a potent toxin, yet emerging evidence suggests that it may also function as a previously unappreciated PSMB or gasotransmitter. Our research seeks to redefine cyanide chemical biology by developing the first generation of chemically precise tools for its controlled delivery and study. Early work has developed new and innovative approaches for responsive and biocompatible HCN delivery that enable systematic investigation of how concentration, timing, and delivery modality influence biological outcomes. Using these tools, we aim to establish clear boundaries between regulatory and toxic exposure regimes, probe the effects of HCN on cellular processes, and investigate potential crosstalk with other PSMBs. By moving beyond historically crude delivery approaches, our work expands cyanide from a purely toxicological molecule into a chemically tractable and biologically relevant signaling molecule.
 

Students and researchers in the Pluth research group can look forward to working in an interdisciplinary group with research interests at the interfaces between organic/inorganic chemistry and chemical biology. Our research relies on many preparative and analytical techniques ranging from organic and organometallic synthesis to tissue culture preparation and computational chemistry. Spectroscopic methods include UV-vis and fluorescence spectroscopy, fluorescence microscopy, X-ray crystallography, advanced multidimensional NMR techniques, and other forms of spectroscopy.

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