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제124회 대한화학회 학술발표회, 총회 및 기기전시회 안내 Identification of Target Protein of Novel Antifungal Agents Using an Affinity Bait and Chemical Reporter Strategy

2019년 8월 29일 12시 54분 16초
MEDI.P-278 이곳을 클릭하시면 발표코드에 대한 설명을 보실 수 있습니다.
10월 17일 (목요일) 11:00~12:30
Medicinal Chemistry
저자 및
Ji Won Choi, Bo Ko Jang, Siwon Kim, Hyeon Jeong Kim, Sun Jun Park, Jong Seok Yoo, AReum Song, Byung Eun Kim, Yoowon Kim, Jong-Hyun Park, Ki Duk Park*
Convergence Research Center for Dementia, Korea Institute of Science and Technology, Korea
Cryptococcus neoformans is an opportunistic fungal pathogen that causes pneumonia and meningitis mainly in immunocompromised people. Current antifungal drugs have failed treatment for a variety of reasons, including direct drug resistance to C.neoformans. Therefore, it is necessary to develop new antifungal agents and to identify the target proteins for them to reveal the mechanism. We previously developed a novel series of functionalized amino acid (FAA) library for antifungal compounds and derived KDS1090 as a potent lead compound by antifungal susceptibility (minimal inhibitory concentration (MIC)) test against representative fungal pathogens (KDS1090 MIC: C.neoformans = 4 μg/mL, C.albicans = 16 μg/mL, C.glabrata = 16 μg/mL). Furthermore, we optimized FAA to improve antifungal efficacy and drug-like properties. Among the optimized compounds, KDS5098 was the most promising drug candidate with excellent antifungal efficacies (MIC: C.neoformans = 2 μg/mL, C.albicans = 4 μg/mL) and drug-like properties (microsomal stability (human): 90%, (mouse) 78% remaining after 30 min; CYP inhibition (1A2, 2C9, 2C19, 2D6): IC50 > 10 μM, (3A4; 56% inhibition at 10 μM); single dose toxicity (mice): LD50 > 1,000 mg/kg; PK: F=40%). In this study, we attempt to identify targets and pharmacological pathways of lead compounds through a useful strategy called an affinity bait and a chemical reporter (AB&CR). First, we developed AB&CR agents containing isothiocyanate and alkyne group to identify their targets. We began the identification study by treating the C.neoformans soluble lysate with AB&CR agents and then reacting the treated lysates with chemical probe under cycloaddition condition. Furthermore, we would like to demonstrate drug binding target proteins through the AB&CR strategy for identify drug protein binding partners