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Hydrogen Sulfide and Carbonyl Sulfide Delivery for Biological Applications

项目来源

美国卫生和人类服务部基金(HHS)

项目主持人

ASLAN, KADIR

项目受资助机构

UNIVERSITY OF OREGON

项目编号

2R01GM113030-06

立项年度

2021

立项时间

未公开

项目级别

国家级

研究期限

未知 / 未知

受资助金额

295412.00美元

学科

未公开

学科代码

未公开

基金类别

Non-SBIR/STTR RPGs

关键词

未公开

参与者

PLUTH, MICHAEL

参与机构

NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

项目标书摘要：Project Summary Hydrogen sulfide (H2S) plays important roles in human health ranging from vascular biology to tissue regeneration. To advance investigations into roles, researchers often use H2S donors to directly modulate sulfide levels during experiments. Despite this broad utility, key unmet needs remain that will be addressed in this proposal. The long-term goal of this research is to develop and deploy COS/H2S donors to investigate and advance the multifaceted roles of reactive sulfur species related to human health. The overall objectives of this proposal are to broaden the platform of COS/H2S releasing motifs, to understand how different CA isoforms impact COS to H2S conversion, and to apply COS/H2S donors to in vivo models of bone regeneration. The rationale for these studies is that the functional tools for COS/H2S delivery and a greater understanding of differential CA isoform activity toward COS hydrolysis will enable future applications in which COS/H2S release is targeted to systems where key CA isoforms are present and H2S is known to play a protective effect. The proposed investigations include three specific aims: (1) Expansion, refinement, and application of COS/H2S releasing platforms; (2) Investigation in to the differential CA isoform activity toward COS hydrolysis; and (3) Application of COS/H2S donors to bone regeneration. This proposal builds from prior work establishing that COS releasing molecules can function as H2S donors due to the rapid enzymatic conversion of COS to H2S by carbonic anhydrase (CA). In Aim 1, new chemical approaches are used to enable COS/H2S delivery, expand the dynamic range and palette of traceable COS/H2S donors, and provide amplified release. In Aim 2, the hydrolytic activity of individual CA isoforms toward COS and model thioester/thionoester substrates are investigated to understand isoform differences in CA efficiency toward COS hydrolysis. In Aim 3, the developed COS/H2S donors are used to investigate the role of H2S in cell and animal models of bone regeneration. This approach is innovative because it provides new approaches to COS/H2S delivery that address key unmet needs in the field and provides the first insights into the differential activity of CA isoforms for COS to H2S conversion. Moreover, the proposed applications in bone regeneration are innovative because they not only leverage the protective effects of H2S and high local activity of CA during osteogenesis, but also leverages the underutilized connection of H2S with Ca2+ recruitment in osteoclasts. The proposed research is significant because it provides new approaches that directly address key limitations in the field, including amplified release systems, trackable donors, and analyte replacement methodologies. In addition, the proposed research provides the first insights into CA isoform differences for COS to H2S conversion, which will be leveraged in model systems relevant to human health in which both CA activity and H2S delivery are important. Successful completion of the proposed Aims will provide a positive impact in the field of H2S biology and will result a greater understanding of the roles of COS/H2S in human health.

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  • 1.NBD-based synthetic probes for sensing small molecules and proteins: design, sensing mechanisms and biological applications

    • 关键词：
    • INFRARED FLUORESCENT-PROBE; TURN-ON PROBE; CYSTATHIONINE-BETA-SYNTHASE;PUSH-PULL FLUOROPHORE; SMALL D-PEPTIDES; HYDROGEN-SULFIDE; LIVING CELLS;SELECTIVE DETECTION; CANCER-CELLS; OXIDATIVE STRESS

    Compounds with a nitrobenzoxadiazole (NBD) skeleton exhibit prominent useful properties including environmental sensitivity, high reactivity toward amines and biothiols (including H2S) accompanied by distinct colorimetric and fluorescent changes, fluorescence-quenching ability, and small size, all of which facilitate biomolecular sensing and self-assembly. Amines are important biological nucleophiles, and the unique activity of NBD ethers with amines has allowed for site-specific protein labelling and for the detection of enzyme activities. Both H2S and biothiols are involved in a wide range of physiological processes in mammals, and misregulation of these small molecules is associated with numerous diseases including cancers. In this review, we focus on NBD-based synthetic probes as advanced chemical tools for biomolecular sensing. Specifically, we discuss the sensing mechanisms and selectivity of the probes, the design strategies for multi-reactable multi-quenching probes, and the associated biological applications of these important constructs. We also highlight self-assembled NBD-based probes and outline future directions for NBD-based chemosensors. We hope that this comprehensive review will facilitate the development of future probes for investigating and understanding different biological processes and aid the development of potential theranostic agents.

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  • 2.Moving Past Quinone-Methides: Recent Advances Toward Minimizing Electrophilic Byproducts from COS/H2S Donors

    • 关键词：
    • Hydrogen sulfide; Carbonyl sulfide; Donors; Self-immolation; Engineeredrelease; Reactive sulfur species;HYDROGEN-SULFIDE DELIVERY; H2S DONORS; CARBONYL SULFIDE;FLUORESCENT-PROBES; SMALL-MOLECULE; CHEMISTRY; RELEASE; COS; DONATION;INSIGHTS

    Hydrogen sulfide (H2S) is an important biomolecule that plays key signaling and protective roles in different physiological processes. With goals of advancing both the available research tools and the associated therapeutic potential of H2S, researchers have developed different methods to deliver H2S on demand in different biological contexts. A recent approach to develop such donors has been to design compounds that release carbonyl sulfide (COS), which is quickly converted to H2S in biological systems by the ubiquitous enzyme carbonic anhydrase (CA). Although highly diversifiable, many approaches using this general platform release quinone methides or related electrophiles after donor activation. Many such electrophiles are likely scavenged by water, but recent efforts have also expanded alternative approaches that minimize the formation of electrophilic byproducts generated after COS release. This mini-review focuses specifically on recent examples of COS-based H2S donors that do no generate quinone methide byproducts after donor activation.

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