The Z variant of 1-antitrypsin (AT) polymerizes within the liver and gives rise to liver cirrhosi... more The Z variant of 1-antitrypsin (AT) polymerizes within the liver and gives rise to liver cirrhosis and the associated plasma deficiency leads to emphysema. In this work, a combinatorial approach based on the inhibitory mechanism of 1-AT was developed to arrest its pathogenic polymerization. One peptide, Ac-TTAI-NH2, emerged as the most tight-binding ligand for Z 1-AT. Characterization of this tetrapeptide by gel electrophoresis and biosensor analysis revealed its markedly improved binding specificity and affinity compared with all previously reported peptide inhibitors. In addition, the peptide is not cytotoxic to lung cell lines. A model of the peptide-protein complex suggests that the peptide interacts with nearby residues by hydrogen bonds, hydrophobic interactions, and cavity-filling stabilization. The combinatorially selected peptide not only effectively blocks the polymerization but also promotes dissociation of the oligomerized 1-AT. These results are a significant step towar...
Recent advances in “designer solvents” have facilitated the development of ultrasensi‐ tive gas s... more Recent advances in “designer solvents” have facilitated the development of ultrasensi‐ tive gas sensing ionic liquids (SILs) based on quartz crystal microbalance (QCM) that can real‐time detect and discriminate volatile molecules. The amalgamation of tailored‐made SILs and label‐free QCM resulted in a new class of qualitative and semi‐quantitative gas sensing device, which represents a model system of electronic nose. Because a myriad of human‐made or naturally occurring volatile organic compounds (VOCs) are of great interest in many areas, several functional SILs have been designed to detect gaseous alde‐ hyde, ketone, amine and azide molecules chemoselectively in our laboratory. The versa‐ tility of this platform lies in the selective capture of volatile compounds by thin‐coated reactive SILs on QCM at room temperature. Notably, the detection limit of the proto‐ type system can be as low as single‐digit parts‐per‐billion. This chapter briefly introduces some conventional gas sensi...
Gas sensing technologies are of importance for a variety of industrial, environmental, medical, a... more Gas sensing technologies are of importance for a variety of industrial, environmental, medical, and even military applications. Many gases, such as man-made or naturally occurring volatile organic compounds (VOCs), can adversely affect human health or cause harm to the environment. Recent advances in “designer solvents” and sensor technologies have facilitated the development of ultrasensitive gas sensing ionic liquids (SILs) based on quartz crystal microbalance (QCM) that can real-time detect and discriminate VOCs. Based on specific chemical reactions at room temperature, thin-coated functionalized ionic liquids on quartz chips are able to capture VOCs chemoselectively with a single-digit parts-per-billion detection limit. The amalgamation of tailor-made functional SILs and QCM results in a new class of qualitative and semiquantitative gas sensing device, which represents a prototype of electronic nose. This review vignettes some conventional gas sensing approaches and collates lat...
Methods in molecular biology (Clifton, N.J.), 2013
α-Conotoxins are peptide neurotoxins isolated from the venom ducts of carnivorous marine cone sna... more α-Conotoxins are peptide neurotoxins isolated from the venom ducts of carnivorous marine cone snails that exhibit exquisite pharmacological potency and selectivity for various nicotinic acetylcholine receptor subtypes. As such, they are important research tools and drug leads for treating various diseases of the central nervous system, including pain and tobacco addiction. Despite their therapeutic potential, the chemical synthesis of α-conotoxins for use in structure-activity relationship studies is complicated by the possibility of three disulfide bond isomers, where inefficient folding methods can lead to a poor recovery of the pharmacologically active isomer. In order to achieve higher yields of the native isomer, especially in high-throughput syntheses it is necessary to select appropriate oxidative folding conditions. Moreover, the poor biochemical stability exhibited by α-conotoxins limits their general therapeutic applicability in vivo. Numerous strategies to enhance their s...
1-Antitrypsin (AT) is a major proteinase inhibitor within the lung. The Z variant of AT (E342K) p... more 1-Antitrypsin (AT) is a major proteinase inhibitor within the lung. The Z variant of AT (E342K) polymerizes within the liver and lung, resulting in hepatic aggregation of AT and tissue deficiency, predis- posing to early onset of cirrhosis and emphysema, respectively. Polymerization of the aberrant protein can be prevented in vitro by specific peptides such as FLEAIG. This peptide serves
Native, metastable serpins inherently tend to undergo stabilizing conformational transitions in m... more Native, metastable serpins inherently tend to undergo stabilizing conformational transitions in mechanisms of health (e.g., enzyme inhibition) and disease (serpinopathies). This intrinsic tendency is modifiable by ligand binding, thus structure-based drug design is an attractive strategy in the serpinopathies. This can be viewed as a labor-intensive approach, and historically, its intellectual attractiveness has been tempered by relatively limited success in development of drugs reaching clinical practice. However, the increasing availability of a range of powerful experimental systems and higher-throughput techniques is causing academic and early-stage industrial pharmaceutical approaches to converge. In this review, we outline the different systems and techniques that are bridging the gap between what have traditionally been considered distinct disciplines. The individual methods are not serpin-specific. Indeed, many have only recently been applied to serpins, and thus investigators in other fields may have greater experience of their use to date. However, by presenting examples from our work and that of other investigators in the serpin field, we highlight how techniques with potential for automation and scaling can be combined to address a range of context-specific challenges in targeting the serpinopathies.
The Z variant of 1-antitrypsin (AT) polymerizes within the liver and gives rise to liver cirrhosi... more The Z variant of 1-antitrypsin (AT) polymerizes within the liver and gives rise to liver cirrhosis and the associated plasma deficiency leads to emphysema. In this work, a combinatorial approach based on the inhibitory mechanism of 1-AT was developed to arrest its pathogenic polymerization. One peptide, Ac-TTAI-NH2, emerged as the most tight-binding ligand for Z 1-AT. Characterization of this tetrapeptide by gel electrophoresis and biosensor analysis revealed its markedly improved binding specificity and affinity compared with all previously reported peptide inhibitors. In addition, the peptide is not cytotoxic to lung cell lines. A model of the peptide-protein complex suggests that the peptide interacts with nearby residues by hydrogen bonds, hydrophobic interactions, and cavity-filling stabilization. The combinatorially selected peptide not only effectively blocks the polymerization but also promotes dissociation of the oligomerized 1-AT. These results are a significant step towar...
Recent advances in “designer solvents” have facilitated the development of ultrasensi‐ tive gas s... more Recent advances in “designer solvents” have facilitated the development of ultrasensi‐ tive gas sensing ionic liquids (SILs) based on quartz crystal microbalance (QCM) that can real‐time detect and discriminate volatile molecules. The amalgamation of tailored‐made SILs and label‐free QCM resulted in a new class of qualitative and semi‐quantitative gas sensing device, which represents a model system of electronic nose. Because a myriad of human‐made or naturally occurring volatile organic compounds (VOCs) are of great interest in many areas, several functional SILs have been designed to detect gaseous alde‐ hyde, ketone, amine and azide molecules chemoselectively in our laboratory. The versa‐ tility of this platform lies in the selective capture of volatile compounds by thin‐coated reactive SILs on QCM at room temperature. Notably, the detection limit of the proto‐ type system can be as low as single‐digit parts‐per‐billion. This chapter briefly introduces some conventional gas sensi...
Gas sensing technologies are of importance for a variety of industrial, environmental, medical, a... more Gas sensing technologies are of importance for a variety of industrial, environmental, medical, and even military applications. Many gases, such as man-made or naturally occurring volatile organic compounds (VOCs), can adversely affect human health or cause harm to the environment. Recent advances in “designer solvents” and sensor technologies have facilitated the development of ultrasensitive gas sensing ionic liquids (SILs) based on quartz crystal microbalance (QCM) that can real-time detect and discriminate VOCs. Based on specific chemical reactions at room temperature, thin-coated functionalized ionic liquids on quartz chips are able to capture VOCs chemoselectively with a single-digit parts-per-billion detection limit. The amalgamation of tailor-made functional SILs and QCM results in a new class of qualitative and semiquantitative gas sensing device, which represents a prototype of electronic nose. This review vignettes some conventional gas sensing approaches and collates lat...
Methods in molecular biology (Clifton, N.J.), 2013
α-Conotoxins are peptide neurotoxins isolated from the venom ducts of carnivorous marine cone sna... more α-Conotoxins are peptide neurotoxins isolated from the venom ducts of carnivorous marine cone snails that exhibit exquisite pharmacological potency and selectivity for various nicotinic acetylcholine receptor subtypes. As such, they are important research tools and drug leads for treating various diseases of the central nervous system, including pain and tobacco addiction. Despite their therapeutic potential, the chemical synthesis of α-conotoxins for use in structure-activity relationship studies is complicated by the possibility of three disulfide bond isomers, where inefficient folding methods can lead to a poor recovery of the pharmacologically active isomer. In order to achieve higher yields of the native isomer, especially in high-throughput syntheses it is necessary to select appropriate oxidative folding conditions. Moreover, the poor biochemical stability exhibited by α-conotoxins limits their general therapeutic applicability in vivo. Numerous strategies to enhance their s...
1-Antitrypsin (AT) is a major proteinase inhibitor within the lung. The Z variant of AT (E342K) p... more 1-Antitrypsin (AT) is a major proteinase inhibitor within the lung. The Z variant of AT (E342K) polymerizes within the liver and lung, resulting in hepatic aggregation of AT and tissue deficiency, predis- posing to early onset of cirrhosis and emphysema, respectively. Polymerization of the aberrant protein can be prevented in vitro by specific peptides such as FLEAIG. This peptide serves
Native, metastable serpins inherently tend to undergo stabilizing conformational transitions in m... more Native, metastable serpins inherently tend to undergo stabilizing conformational transitions in mechanisms of health (e.g., enzyme inhibition) and disease (serpinopathies). This intrinsic tendency is modifiable by ligand binding, thus structure-based drug design is an attractive strategy in the serpinopathies. This can be viewed as a labor-intensive approach, and historically, its intellectual attractiveness has been tempered by relatively limited success in development of drugs reaching clinical practice. However, the increasing availability of a range of powerful experimental systems and higher-throughput techniques is causing academic and early-stage industrial pharmaceutical approaches to converge. In this review, we outline the different systems and techniques that are bridging the gap between what have traditionally been considered distinct disciplines. The individual methods are not serpin-specific. Indeed, many have only recently been applied to serpins, and thus investigators in other fields may have greater experience of their use to date. However, by presenting examples from our work and that of other investigators in the serpin field, we highlight how techniques with potential for automation and scaling can be combined to address a range of context-specific challenges in targeting the serpinopathies.
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Papers by Yi-Pin Chang