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Abstract Small molecules play important roles in a variety of biological processes such as metabolism, cell signaling and enzyme regulation, and can serve as valuable biomarkers for human diseases. Moreover, they are essential to drug discovery and development, and are important targets for environmental monitoring and food safety. Due to the size incompatibility, small molecule transport is difficult to be monitored with a nanopore. A popular strategy for nanopore detection of small molecules is to introduce a molecular probe as a ligand (or recognition element) and rely on their effect on the ligand transport. One limitation for this sensing strategy is that the probe molecule needs to have a slightly smaller size than the nanopore constriction or can be easily unfolded or unzipped through the pore. Herein, by taking advantage of replacement and complexation chemical interactions, a generic approach is reported for detection of small molecules by using large biomolecules with well‐defined stable 3D structures such as aptamers as recognition elements. Given the versatile use of aptamers as capture agents for a wide variety of species, the developed nanopore sensing strategy should find applications in many fields.
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This content will become publicly available on December 1, 2026
Protic small molecule bioregulators
Small molecule gases such as nitric oxide (NO), carbon monoxide (CO), and hydrogen sulfide (H₂S) have long been recognized as endogenous signaling molecules with diverse physiological roles. Often described as “gasotransmitters”, these molecules complement other small molecule bioregulators (SMBs) that exert biological function across all kingdoms of life. One underappreciated distinction, however, is that many of these molecules – irrespective of whether or not they are gases in their native states outside of biology – exhibit similar molecular signaling potential mediated by protonation-dependent chemical speciation. In this review, we propose the new cross-cutting classification of protic small molecule bioregulators (PSMBs) to describe molecules in which biological function and reactivity are modulated by protonation state. Examples of PSMBs include the canonical gasotransmitter H2S, emerging gasotransmitters (H2Se, HCN), small molecule crosstalk species (e.g., SNO–, SSNO–, SO42–, ONOO–, NO2–, SCN–, OCl–), and other species where protonation state modulation is accessible at physiological pH. Importantly, these species exist in equilibrium between their neutral and anionic forms, with speciation governed by local pH and molecular environment, directly impacting their membrane nucleophilicity, permeability, redox activity, and interaction with metal centers. We describe the evolutionary origins, biosynthesis, and crosstalk of PSMBs, including roles in redox signaling, post-translational modification, and mitochondrial regulation. Reframing these important molecules in a class defined by their protic ability rather than gaseous state does not diminish prior gasotransmitter designations, but rather serves to recognize commonalities in chemical characteristics that drive the unique biological chemistry and regulation.
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- Award ID(s):
- 2004150
- PAR ID:
- 10651386
- Publisher / Repository:
- Redox Biology
- Date Published:
- Journal Name:
- Redox Biology
- Volume:
- 88
- Issue:
- C
- ISSN:
- 2213-2317
- Page Range / eLocation ID:
- 103921
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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