인문학
사회과학
자연과학
공학
의약학
농수해양학
예술체육학
복합학
DBpia AI
AI 에이전트
AI 아이디어
AI 리더
AI 뷰어
Citeasy
크롬 서지관리 다운로드
지원사업
학술연구/단체지원/교육 등 연구자 활동을 지속하도록 DBpia가 지원하고 있어요.
커뮤니티
연구자들이 자신의 연구와 전문성을 널리 알리고, 새로운 협력의 기회를 만들 수 있는 네트워킹 공간이에요.
초록·키워드
Due to the rise of antibiotic resistance in bacterial pathogens, there remains a large unmet need for novel therapeutic antibiotics to treat infections.Novel molecules with diverse structures that target different cellular machinery are of high importance as the majority of clinical antibiotics rely on inhibiting the same targets and make use of similar chemical scaffolds, which are susceptible to resistance.Promising research has shown that the bacterial ClpP protease, involved in protein homeostasis, is a viable target for antibiotic drug development.A previous chemical screen from our group has identified novel scaffolds that dysregulate the protease and were termed Activators of Self-Compartmentalized Proteases (ACPs) due to their ability to cause the nonspecific degradation of essential cellular housekeeping proteins, ultimately resulting in cell death.Co-crystal structure data of compound-ClpP complexes suggested that ACPs adopt two configurations in the binding site.A new class of ACP compounds has been developed that leverages a phosphine oxide moiety connecting the two aryl groups to adopt both configurations in the binding pocket.Using this strategy, novel derivatives were synthesized in the initial medicinal chemistry panel, expanding the chemical space of the analogs.The analogs were then screened for activity against ClpP, and hits were prioritized in subsequent biological assays.Lastly, activity results and co-crystal structures validate the structure-based approach to drug discovery as efficacy was improved and the binding conformation
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