SMALL MOLECULE MODULATORS OF BIOLOGICAL SULFUR AND SELENIUM TRANSFER

Abstract

Chalcogens, sulfur and selenium, play essential biological roles as components of functional groups in biomolecules, and are closely involved in redox reactions. Hydrogen sulfide (H2S) is involved in various mammalian physiological processes such as vasodilation, regulation of inflammation and intracellular redox homeostasis. Similarly, selenium (Se) is an essential trace element for humans and derived from inorganic selenium sources. H2Se is likely produced during synthesis of Se-containing biomolecules. While these chalcogens share many similarities, they also have distinct reactivity patterns. An important problem is to understand how these species are transferred from one biomolecule to another, and if it affects function of these biomolecules. Here, we have developed a set of new tools that can help study and modulate chalcogen transfer. 3-mercaptopyruvate sulfurtransferase (3-MST), one of the major H2S-producing enzymes in bacteria, aids in microbial survival and contributes to antibiotic tolerance in bacteria. In order to prevent efficient sulfur transfer through 3-MST, we designed, synthesized, and evaluated potential inhibitors for this enzyme. We carried out a systematic structure-activity relationship (SAR) study and found that the lead molecule, containing a β-keto thioether scaffold, selectively inhibits bacterial 3-MST over its mammalian analog in a concentration-dependent and reversible manner. The inhibitor also potentiates bactericidal properties of aminoglycosidic antibiotics supporting previous studies that demonstrate that inhibition of H2S can enhance the potency of antibiotics. Next, in order to study selenium transfer, we designed a series of phenacylselenoesters, which are cleaved by esterase. Subsequently, to produce phenacylselenide (PhCOCH2-SeH), it was reacted with a thiol to generate H2Se. Lastly, since detection of selenium-species is challenging, we incorporated a latent fluorophore in the H2Se donor. This tool is designed to report the generation of H2Se and may be useful for imaging-based investigations into selenium biology. We studied the activation and selenium release mechanisms from these compounds. Together, we have developed a series of small molecules that we anticipate will be helpful in expanding the understanding of the biology of chalcogens.