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

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.