Chemically Modified Plant Metabolites as Potent Antivirals

Background. Viral infections represent serious challenge to human health and even life itself. Virus-caused diseases vary in clinical course from mild and asymptomatic processes to life-threatening diseases with fatal outcome. Due to wide spreading of viral diseases and ability of viruses to develop resistance to antivirals there is an urgent need for search and development of novel low-toxic compounds effective against viruses. Plant secondary metabolites represent extremely rich source of scaffolds prospective as potential pharmacologically active compounds including anti-viral ones. It is, therefore, highly probable to develop new effective compounds by chemical modification of natural plant metabolites. Objective. The objective of our study was to evaluate anti-viral potential of chemical derivatives of plant secondary metabolites. Methods. We have tested several libraries of chemical compounds – derivatives of plant secondary metabolites: cage compounds camphor and ginsenol, alkaloid cytisine and triterpene-based glycirrhetinic acid. All compounds were assessed in vitro for their cytotoxicity, influenza and parainfluenza virus-inhibiting activity and selectivity of their anti-viral effect. Based on the results obtained, values of 50% cytotoxic dose (CC50), 50% virus-inhibiting dose (IC50) and selectivity index (ratio of CC50 to IC50) have been calculated for each compound. Results. As shown in experiments, all initial scaffolds were inactive or of low activity against influenza virus. Their chemical modifications, however, resulted in dramatic increase of their virus-inhibiting activity. In particular, amine and imine derivatives of camphor and ginsenol gave sets of derivatives with low toxicity and IC50’s values of hundreds nanomoles to single-digit micromoles and selectivity indices of several hundreds, up to 1500. These compounds appeared able to inhibit fusion of viral envelope with plasma membrane thus suppressing the penetration of viral genome into cell. While cytisine itself was of low activity against both influenza and parainfluenza viruses, its derivatives obtained by cyclisation with N-acetylmaleinimide allowed to obtain library whose compounds were highly effective against either of these two viruses. Finally, although glycerrhitinic acid was of relatively high toxicity and low anti-viral activity, its combination with amino acids-derived moieties led to highly active compounds with nanomolar values of IC50’s and selectivity of more than 100. Conclusion. Naturally occurred scaffolds of plant secondary metabolites represent rich source of chemical structures whose appropriate chemical modification can result in development of low-toxic and highly effective antivirals with alternative targets and mechanisms of virus-suppressing activity.