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
  • 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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