2. Academic Validation
  3. Discovery of CYP1A1 Inhibitors for Host-Directed Therapy against Sepsis

Discovery of CYP1A1 Inhibitors for Host-Directed Therapy against Sepsis

  • J Med Chem. 2025 Jun 12;68(11):11606-11627. doi: 10.1021/acs.jmedchem.5c00493.
Fangjie Wang 1,  Sheng-Li Niu 2,  Wei Li 1,  Hong-Yuan Liu 2,  Xue Gong 2,  Xiaoyuan Ma 1,  Bo Zhao 2,  Dongmei He 1,  Jinyu Xia 2,  Liang Gong 2,  Yiqin Cui 1,  Rui Gao 1,  Huaping Liang 1,  Jing Gu 2,  Qin Ouyang 2
Affiliations

Affiliations

  • 1 The First Research Department, State Key Laboratory of Trauma and Chemical Poisoning, Army Medical Center of PLA, Army Medical University, Chongqing 400042, China.
  • 2 Department of Medicinal Chemistry, Army Medical University, Chongqing 400038, China.
PMID: 40442943 DOI: 10.1021/acs.jmedchem.5c00493
Abstract

Bacterial sepsis remains a leading cause of death globally, exacerbated by the rise of multidrug resistance (MDR). Host-directed therapy (HDT) has emerged as a promising nonantibiotic approach to combat infections; thus, multiple HDT targets have been identified. However, the translation of HDT targets into therapeutic drugs, particularly small-molecule drugs, remains rare. Our study focuses on cytochrome P4501A1 (CYP1A1), a negative regulator of host antiinfection capabilities. Using deep learning, virtual screening, and biological evaluation, we identified novel small-molecule inhibitors of CYP1A1. After structural optimization, compounds 38 and 47 demonstrated exceptional activity, reducing Bacterial loads of methicillin-resistant Staphylococcus aureus (MRSA) and Acinetobacter baumannii by over 70% by enhancing macrophage phagocytosis. This work highlights CYP1A1 as a valuable HDT target and shows that inhibiting it with a single small-molecule compound can offer a potential solution to treat MDR bacterial-induced sepsis.

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