Hydrogen sulfide (H2S) is a highly-toxic chemical hazard in the gas and farming industry. It has also been used as a chemical weapon, terrorists? threat, and a method of suicide. Exposure to high levels of H2S has been reported to cause acute neurotoxic, cardiovascular, and respiratory effects, as well as persistent neurologic deficits and neurodegeneration. Many victims are found in cardiopulmonary arrest at the scene requiring cardiopulmonary resuscitation (CPR) with dismal outcomes. Currently, there is no specific antidote for H2S intoxication. Although nonspecific scavengers such as hydroxocobalamin have been investigated as antidote for H2S intoxication, these compounds scavenge not only H2S, but also cyanide, nitric oxide (NO), and CO. Because NO and CO are important signaling molecules, nonspecific scavenging may have adverse effects. Development of more specific H2S scavengers should enhance our ability to counter H2S intoxication. However, to the best of our knowledge, specific H2S scavengers have not been systematically explored. Here, we propose a data-driven identification of specific H2S scavengers and initial characterization. The criteria of ?ideal? H2S scavengers are: 1) highly reactive to H2S, 2) highly selective to H2S, 3) negligible biological activity, and 4) structural flexibility for modifications. These criteria are very much the same as the criteria for H2S sensors/fluorescent probes. Xian laboratory has recently constructed a comprehensive on-line searchable database on H2S fluorescent sensors (http://sensor.eecs.wsu.edu/index/). It covers all reported sensors with key parameters. Because the most critical parameter of effective scavengers is their reactivity toward H2S, which is determined by the H2S-reaction site, we analyzed the time needed for the sensors to complete the reaction with H2S and group them based on their specific H2S-reactive sites. We identified 9 major types: 1) benzoxadiazole based sensors, 2) aryl nitro based sensors, 3) aryl azide based sensors, 4) 2,4-dinitro benzene based sensors, 5) aldehyde-based sensors, 6) disulfide linkage based sensors, 7) sulfonyl azide based sensors, 8) indolium based sensors, and 9) selenium oxide based compounds. Based on in vitro and cell-based screening assays, we identified sulfonyl azide-based and selenium oxide-based compounds as promising H2S scavengers. To start characterizing in vivo efficacy of candidate compounds, we examined effects of one sulfonyl azide-based compound SS-20 in a mouse model of H2S intoxication. While less than 50% of vehicle-treated mice survive after H2S poisoning, all mice treated with SS-20 survived. These preliminary results suggest that H2S sensors may function as effective antidotes for H2S poisoning. To screen and identify lead compounds for further development, we specifically propose to screen additional candidate compounds and identify lead candidate H2S scavengers for further development (Specific Aim 1), and to examine the antidotal effects of lead candidate H2S scavengers in mice models of H2S intoxication simulating real-life scenarios (Specific Aim 2).

Public Health Relevance

Hydrogen sulfide (H2S) is a highly-toxic chemical hazard in the gas and farming industry, which was also used as a chemical weapon, terrorists' threat, and a method of suicide. However, there is no specific antidotes for H2S intoxication. This study seeks to develop novel and specific antidotes for H2S poisoning by screening and characterizing in vitro and in vivo effects of chemical H2S scavengers.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZRG1)
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Spriggs, Shardell M
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Massachusetts General Hospital
United States
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