Synthesis and Antiviral Activity of Camphene Derivatives against Different Types of Viruses

Sokolova, Anastasiya S.; Putilova, Valentina P.; Yarovaya, Olga I.; Zybkina, Anastasiya V.; Mordvinova, Ekaterina D.; Zaykovskaya, Anna V.; Shcherbakov, Dmitriy N.; Orshanskaya, Iana R.; Sinegubova, Ekaterina O.; Esaulkova, Iana L.; Borisevich, Sophia S.; Bormotov, Nikolay I.; Shishkina, Larisa N.; Zarubaev, Vladimir V.; Pyankov, Oleg V.; Maksyutov, Rinat A.; Salakhutdinov, Nariman F.

To date, the ‘one bug-one drug’ approach to antiviral drug development cannot effectively respond to the constant threat posed by an increasing diversity of viruses causing outbreaks of viral infections that turn out to be pathogenic for humans. Evidently, there is an urgent need for new strategies to develop efficient antiviral agents with broad-spectrum activities. In this paper, we identified camphene derivatives that showed broad antiviral activities in vitro against a panel of enveloped pathogenic viruses, including influenza virus A/PR/8/34 (H1N1), Ebola virus (EBOV), and the Hantaan virus. The lead-compound 2a, with pyrrolidine cycle in its structure, displayed antiviral activity against influenza virus (IC(50) = 45.3 µM), Ebola pseudotype viruses (IC(50) = 0.12 µM), and authentic EBOV (IC(50) = 18.3 µM), as well as against pseudoviruses with Hantaan virus Gn-Gc glycoprotein (IC(50) = 9.1 µM). The results of antiviral activity studies using pseudotype viruses and molecular modeling suggest that surface proteins of the viruses required for the fusion process between viral and cellular membranes are the likely target of compound 2a. The key structural fragments responsible for efficient binding are the bicyclic natural framework and the nitrogen atom. These data encourage us to conduct further investigations using bicyclic monoterpenoids as a scaffold for the rational design of membrane-fusion targeting inhibitors.