• Bulletin of the Korean Chemical Society
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• 제22권11호
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• pp.1236-1242
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• 2001

(3S,1'S)-3-(1'-Carboxy-2'-phenyl)ethylamino-2-oxetanone (1a) and (3R,1'S)-3-(1'-carboxy-2'-phenyl)ethylamino-2-oxetanone (1b) were designed, synthesized, and evaluated as inhibitors for carboxypeptidase A, a prototypical zinc protease that removes the C-terminal amino acid having an aromatic side chain from oligopeptide substrate. It was concluded from the analysis of inhibition kinetics that while 1a inactivates CPA irreversibly, its diastereoisomer, 1b is a weak competitive inhibitor for CPA. A possible explanation for the observed difference in inhibition mode that is dependent on the inhibitor stereochemistry is offered.

• Bulletin of the Korean Chemical Society
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• 제23권4호
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• pp.593-597
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• 2002

(R,S)- and (R)-2-Benzylcysteine (1) and (R,S)-2-phenethylcysteine (2) were synthesized and evaluated as inhibitors for carboxypeptidase A (CPA) with the expectation that these compounds exhibit improved inhibitory activities over 2-benzyl-3-mercaptopropanoic acid (BMPA), a potent CPA competitive inhibitor, possibly having additional interactions of their amino group with the carboxylate of Glu-270 of the enzyme upon binding to CPA. Contrary to the expectation, however, the CPA inhibitory potencies of these compounds were found to be much reduced compared with that of BMPA, suggesting that the amino group in the inhibitors rather exerts steric hindrance in binding of these inhibitors to CPA.

• IMMUNE NETWORK
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• 제10권3호
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• pp.99-103
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• 2010

Background: Glycogen synthase kinase $3{\beta}$ ($GSK3{\beta}$) is a ubiquitous serine/threonine kinase that is regulated by serine phosphorylation at 9. Recent studies have reported the beneficial effects of a number of the pharmacological $GSK3{\beta}$ inhibitors in rodent models of septic shock. Since most of the $GSK3{\beta}$ inhibitors are targeted at the ATP-binding site, which is highly conserved among diverse protein kinases, the development of novel non-ATP competitive $GSK3{\beta}$ inhibitors is needed. Methods: Based on the unique phosphorylation motif of $GSK3{\beta}$, we designed and generated a novel class of $GSK3{\beta}$ inhibitor (GSK3i) peptides. In addition, we investigated the effects of a GSK3i peptide on lipopolysaccharide (LPS)-stimulated cytokine production and septic shock. Mice were intraperitoneally injected with GSK3i peptide and monitored over a 7-day period for survival. Results: We first demonstrate its effects on LPS-stimulated pro-inflammatory cytokine production including interleukin (IL)-6 and IL-12p40. LPS-induced IL-6 and IL-12p40 production in macrophages was suppressed when macrophages were treated with the GSKi peptide. Administration of the GSK3i peptide potently suppressed LPS-mediated endotoxin shock. Conclusion: Collectively, we present a rational strategy for the development of a therapeutic GSK3i peptide. This peptide may serve as a novel template for the design of non-ATP competitive GSK3 inhibitors.

• Biomolecules & Therapeutics
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• 제30권2호
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• pp.184-190
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• 2022

Targeting the cystine/glutamate exchange transporter, system x_c^-, is a promising anticancer strategy that induces ferroptosis, which is a distinct form of cell death mediated by iron-dependent lipid peroxidation. The concentration of ⳑ-cystine in culture medium is higher than the physiological level. This study was aimed to evaluate the effects of ⳑ-cystine concentration on the efficacy of ferroptosis inducers in hepatocellular carcinoma cells. This study showed that treatment with sulfasalazine or erastin, a system x_c^- inhibitor, decreased the viability of Huh6 and Huh7 cells in a dose-dependent manner, and the degree of growth inhibition was greater in medium containing a physiological ⳑ-cystine concentration of 83 µM than in commercial medium with a concentration of 200 µM ⳑ-cystine. However, RSL3, a glutathione peroxidase 4 inhibitor, decreased cell viability to a similar extent in media containing both ⳑ-cystine concentrations. Sulfasalazine and erastin significantly increased the percentages of propidium iodide-positive cells in media with 83 µM ⳑ-cystine, but not in media with 200 µM ⳑ-cystine. Sulfasalazine- or erastin-induced accumulation of lipid peroxidation as monitored by C11-BODIPY probe was higher in media with 83 µM ⳑ-cystine than in media with 200 µM ⳑ-cystine. In contrast, the changes in the percentages of propidium iodide-positive cells and lipid peroxidation by RSL3 were similar in both media. These results showed that sulfasalazine and erastin, but not RSL3, were efficacious under conditions of physiological ⳑ-cystine concentration, suggesting that medium conditions would be crucial for the design of a bioassay for system x_c^- inhibitors.

• 농약과학회지
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• 제5권3호
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• pp.1-11
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• 2001

신규 제초제 작용점의 발굴은 유전체학과 조합화학 등 새로운 기술이 등장하여 그 가능성이 높아지고 있다. 대략 $10^{30}$에서 $10^{50}$여 개의 화학물질의 합성이 가능하고 50,000여 개의 식물 유전자 지도가 완성되어 이들의 조합으로 새로운 제초제의 작용점 발굴 가능성이 높아지게 될 것이다. 즉, 고등식물이 가지고 있는 50,000여 개의 유전자 가운데 0.1%, 1.0% 또는 10%가 신규 작용점이 된다면 50, 500, 5000개의 신규 작용점을 발견할 수 있는 것이다. 신규 제초제의 개발을 위해서는 target enzyme의 선택과 결정, 저해제의 설계, 작용점까지 도달하는 과정, 대사적인 운명 등 여러가지 요인들이 검토되어야 한다. 이러한 과정에서 가장 중요한 것은 확실한 작용점의 선택에 있다. 또한 다양한 생화학적 정보를 통하여 작용점/효소의 저해로부터 고사에 이르는 과정을 이해함은 물론 보다 강력한 저해제의 합성과 살초과정을 이해할 수 있어야 할 것이다. 그 동안에는 이미 알려진 작용점을 대상으로 신규 화합물을 합성하거나 유도체를 개발하는 것이 대부분이었지만 최근에는 antisense 기법 등을 활용하여 새로운 치사관련 작용점을 찾아내는데 잠재력과 가능성을 확대시켜주고 있다. 새로운 치사관련 작용점을 발굴한 후에는 대상효소의 화학적, 생화학적 기능과 단백질의 구조를 분석하여 강력한 저해제를 설계하는데 활용하게 될 것이다. 치사관련 돌연변이체와 antisense 기법을 활용하고, 식물 생리학적 반응을 기초로 하여 리드화합물을 탐색하는 것은 새로운 접근방식이며 농약 화학적 특성을 갖는 효소 저해제들의 합성은 크게 6가지로 할 수 있다. 공통특이시얀 기질 유사체 합성, affinity labels, 자살기질체, 반응중간산물, 그리고 extraneous site inhibitors 등을 들 수 있다. 이와 같은 방법으로 후보화합물이 선발된다 하여도 실제식물에 처리하여 흡수, 이행, 대사 등에 관한 시험이 반드시 이루어져야 새로운 제초제를 탄생시킬 수 있다. 또한 약물의 전달과정과 무독화작용을 통하여 pro-herbicide에 대한 연구를 진행하게 될 것이며, 마지막으로 잡초와 작물간의 선택성이 고려되어야 효소 측이적 접근방식에 의한 신규 선택성 제초제의 개발이 성공할 수 있는 것이다.