2. Academic Validation
  3. Design of the Inhibitors for Pseudorabies Virus Replication by Reinforcement Learning from HSV-1 DNA Polymerase Inhibitors

Design of the Inhibitors for Pseudorabies Virus Replication by Reinforcement Learning from HSV-1 DNA Polymerase Inhibitors

  • ACS Omega. 2025 Jan 23;10(4):3389-3397. doi: 10.1021/acsomega.4c06508.
Lin Wei 1,  Yang Hu 1,  Licheng Bai 1,  Chenxu Xiao 1,  Zhang Liu 1,  Yun You 1,  Keke Wang 1,  Yunyuan Huang 2,  Junfei Zhu 1,  Jun Weng 1 3,  Wenling Zhou 1,  Han Li 1,  Honghe Zhao 1,  Zhiyong Wu 1,  Meng Mei 1,  Zigong Wei 1 4 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Biocatalysis and Enzyme Engineering, School of Life Sciences, Hubei University, Wuhan, Hubei 430061, PR China.
  • 2 Hubei Key Laboratory of Genetic Regulation and Integrative Biology, School of Life Sciences, Central China Normal University, Wuhan, Hubei 430079, PR China.
  • 3 Key Laboratory of Molecular Biophysics of Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei 430074, PR China.
  • 4 Hubei Jiangxia Laboratory, Wuhan, Hubei, PR China.
  • 5 Hubei Province Key Laboratory of Biotechnology of Chinese Traditional Medicine, National & Local Joint Engineering Research Center of High-throughput Drug Screening Technology, School of life sciences, Hubei University, Wuhan, Hubei 430061, PR China.
PMID: 39926536 DOI: 10.1021/acsomega.4c06508
Abstract

The reintroduction of the pseudorabies virus (PRV) has led to the emergence of epidemics in some pig farms in China, resulting in significant economic losses. Moreover, the number of human infections with PRV has increased. Therefore, research into the prevention and treatment of PRV strains is imperative. In this work, the PRV DNA Polymerase (DNA pol) was found to exhibit a high degree of sequence and structural similarity to the herpes simplex virus 1 (HSV-1) DNA pol. Consequently, we provided the first experimental evidence that PNU-183792, a non-nucleoside inhibitor of HSV-1, inhibited PRV replication in cell assay, with an EC50 of 100 pM, providing the basis for further studies on PRV inhibitors. Then, with the great help of reinforcement learning, some new potential hits were discovered based on the HSV-1 DNA pol inhibitors. One of the compounds, c14, which showed significant anti-PRV potency and safety, with an EC50 of 14 pM and a CC50 of 343.7 μM, can be considered as a highly promising lead compound to support drug discovery and development for anti-PRV.

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