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  3. Rational design of dual PB2/JAK2 inhibitors achieving balanced antiviral and host-directed immunomodulatory effects

Rational design of dual PB2/JAK2 inhibitors achieving balanced antiviral and host-directed immunomodulatory effects

  • Eur J Med Chem. 2026 Apr 5:307:118642. doi: 10.1016/j.ejmech.2026.118642.
Yujian Yang 1,  Binhao Rong 2,  Huanyu Shi 1,  Kunyu Lu 2,  Xinxin Lin 2,  Yuanmei Wen 1,  Xingyu Zhou 3,  Peisen Zheng 1,  Xinshan Deng 4,  Xumu Zhang 5,  Shuwen Liu 6,  Qifan Zhou 7
Affiliations

Affiliations

  • 1 Shenzhen Key Laboratory of Small Molecule Drug Discovery and Synthesis, Department of Chemistry, Shenzhen Grubbs Institute and Medi-X Pingshan, Southern University of Science and Technology, Shenzhen, 518000, China.
  • 2 Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China.
  • 3 Department of Computer Science and Engineering, Southern University of Science and Technology, Shenzhen, 518000, China.
  • 4 Hunan Provincial Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations, Changsha Medical University, Changsha, 410219, China.
  • 5 Shenzhen Key Laboratory of Small Molecule Drug Discovery and Synthesis, Department of Chemistry, Shenzhen Grubbs Institute and Medi-X Pingshan, Southern University of Science and Technology, Shenzhen, 518000, China. Electronic address: zhangxm@sustech.edu.cn.
  • 6 Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China; NMPA Key Laboratory for Research and Evaluation of Drug Metabolism, Department of Pharmacy, Pingshan Hospital, Southern Medical University, Shenzhen, 518100, China; State Key Laboratory of Multi-organ Injury Prevention and Treatment, MOE Key Laboratory of Infectious Diseases Research in South China, MOE Innovation Center for Medical Basic Research on Inflammation and Immune Related Diseases, Southern Medical University, Guangzhou, 510515, China. Electronic address: liusw@smu.edu.cn.
  • 7 Shenzhen Key Laboratory of Small Molecule Drug Discovery and Synthesis, Department of Chemistry, Shenzhen Grubbs Institute and Medi-X Pingshan, Southern University of Science and Technology, Shenzhen, 518000, China. Electronic address: zhouqf@sustech.edu.cn.
PMID: 41691996 DOI: 10.1016/j.ejmech.2026.118642
Abstract

Infection with the Influenza Virus provokes an excessive immune reaction, triggering a cytokine storm that can cause severe inflammation and lead to conditions such as pneumonia and myocarditis. Herein, we propose a dual-target strategy that simultaneously targets the viral PB2 protein and the host JAK2 kinase, aiming to not only eliminate the virus but also modulate the immune response, facilitating rapid recovery of the body's health. In this article, the design and discovery of novel PB2/JAK2 dual-target inhibitors are reported. Through rational design and structure-guided optimization, we identified compound 4B, which exhibited potent anti-H1N1 activity (MDCK cell EC50 = 15 nM) and JAK2 inhibitory activity (JAK2 IC50 = 49 nM). Notably, 4B demonstrated favorable pharmacokinetic properties in mice, achieving excellent oral bioavailability (F = 99.4%). Furthermore, our findings show that compound 4B significantly downregulates NP and PB2 protein expression. Concurrently, 4B also inhibits the mRNA expression of key pro-inflammatory cytokines (IL-6, TNF-α, IFN-β) in both inflammatory and influenza-infected models. This study demonstrates the promising potential of dual inhibition, targeting both viral replication and the host inflammatory response, for the development of anti-influenza therapeutics.

Keywords

Dual-target inhibitor; Immunomodulation; Influenza A virus; JAK kinase; PB2 cap-binding domain.

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